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. 2022 Jun 1;12(1):236–255. doi: 10.1002/cam4.4896

Traditional Chinese medicines and capecitabine‐based chemotherapy for colorectal cancer treatment: A meta‐analysis

Hui‐Zhong Jiang 1, Ya‐Li Jiang 1, Bing Yang 1, Feng‐Xi Long 1, Zhu Yang 1,2,✉, Dong‐Xin Tang 1,2,✉
PMCID: PMC9844598  PMID: 35650714

Abstract

This meta‐analysis was conducted to evaluate the efficacy and safety of the addition of Traditional Chinese Medicine (TCMs) to capecitabine‐based regimens for colorectal cancer (CRC) in term of tumor. The eight electronic databases including Cochrane Library, PubMed, Web of Science (WOS), Excerpt Medica Database (Embase), Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), Chinese Science and Technology Journals (CQVIP), and Wanfang Database were systematically searched for eligible studies from their inception to March 2021. Thirty‐nine randomized controlled trials were involved in this study, and all the data were analyzed by Review Manager 5.3 (Nordic Cochran Centre, Copenhagen, Denmark) and R 4.0.5 software. The meta‐analyses suggested that TCMs in combination with capecitabine‐based regimens increased objective response rate (ORR) in the palliative treatment of CRC (risk ratio [RR], 1.35 [1.17, 1.55], I 2 = 0%), disease control rate (DCR) (RR, 1.22 [1.12, 1.32], I 2 = 3%), and quality of life (QOL) (RR, 1.71 [1.44, 2.03], I 2 = 0%), with decreased risks of myelosuppression, anemia, thrombocytopenia, liver/renal dysfunction, neurotoxicity, nausea/vomiting, neutropenia, diarrhea, leukopenia, improved the peripheral lymphocyte, reduced the expression of tumor markers, and related factors. Further sensitivity analysis of specific plant‐based TCMs found that dangshen, fuling, and gancao had significantly higher contributions to the results of the RR. The results show that capecitabine‐based chemotherapy combined with TCM in the treatment of CRC increases the efficiency of ORR and DCR, reduces chemotherapeutic agents‐associated adverse reactions, and improves their life quality as compared with chemotherapy alone, but further randomized and large sample of studies are needed.

Keywords: capecitabine, colorectal cancer, meta‐analysis, traditional Chinese medicine

Our research found that the combination of TCM and capecitabine‐based chemotherapy was more effective than the capecitabine‐only regimen. Additionally, it has the potential to decrease adverse responses in patients, enhance survival rates and the body's capacity to fight off infection, lower tumor marker expression levels, and even slow tumor development. Specific TCMs may have the potential to improve the efficacy of capecitabine‐based chemotherapy for CRC.

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1. INTRODUCTION

Globally, the incidence of colorectal cancer (CRC) ranks third among all cancers, second in mortality, 1 and cancer cases and deaths represent 10% of all cancer cases and deaths. 2 Despite radiotherapy and chemotherapy is the main treatment method nowadays, the outcome of advanced CRC remains poor due to tumor recurrence and metastasis and drug resistance. For patients who cannot tolerate surgery, the goal is to minimize the tumor and control its further spread and growth. 3 , 4

Current first‐line chemotherapy approach to treating CRC is fluoropyrimidine (5‐FU) 5 or multidrug combination regimen including oxaliplant (OX), irinotecan (IRI), and carbapitabine (CAP). However, the adverse drug reactions during chemotherapy have not been effectively solved, and the treatment outcomes are often unsatisfactory. 6 As a predrug of fluorouracine, capecitabine achieves similar efficacy after oral administration. The incidence of adverse reactions with the capecitabine modified XELIRI (CAP+ IRI) protocol was significantly reduced. 7 However, capecitabine still produces adverse reactions such as hand‐foot syndrome, myelosuppression, liver/renal dysfunction, and gastrointestinal reactions during patients. 8

Traditional Chinese Medicines (TCM) has been widely used in China for the supplementary treatment of cancer, including colorectal cancer (CRC). 9 , 10 As an adjuvant therapy, TCM reduces the side effects of cancer reagents and increases the chemotherapeutic efficacy. 11 However, its substantial evidence is inefficient to prove whether the TCM combined capitabine‐based regimen is more effective than capitabine alone.

In this study a systematic review and meta‐analysis is performed to compare the clinical efficacy and safety between the capecitabine‐based chemotherapy combined with TCM and capecitabine alone in the treatment of CRC. At the same time, the frequencies of combined TCMs are further analyzed to determine which combination methods are efficient to improve objective response rates (ORR) and reduce adverse effects, which will provide evidences for the clinical applications of TCM combinations with capitabine‐based regimen in treating CRC.

2. MATERIALS AND METHODS

The protocol for this systematic review was registered on INPLASY (Unique ID number) and was available in full on the inplasy.com (https://doi.org/10.37766/inplasy2021.3.0095) and was performed in accordance with the PreferredReporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) statement.

2.1. Eligibility criteria and outcome measures

According to the PICOS acronym, 12 the inclusion criteria were as follows: Participants (P): All included cases must be confirmed to be CRC after histopathological examination. No restriction on gender, race, or nation was found. Patients with non‐primary CRC or other tumors were excluded.

Intervention (I): The random clinical trials (RCTs) with TCMs combined with capecitabine‐based chemotherapy were included. No restrictions were in the types of TCM.

Comparison (C): In the control groups, the patients with CRC were treated with the capitabine‐based regime.

Outcomes (O): efficacy and safety of TCM.

Study design (S): RCTs.

Exclusion criteria: (i) no capecitabine‐based chemotherapy and (ii) non RCTs and (iii) with incomplete outcomes and (iv) lack in sufficient data. Primary outcomes included three efficacy measurements: short‐ and long‐term clinical efficacy, and adverse drug reactions (ADRs) according to world health organization (WHO) criteria and response evaluation criteria in solid tumors (RECIST). (I) Short‐term clinical efficacy: the short‐term tumor response included complete response (CR), partial response (PR), response rates in stable disease (SD), response rates in progressive disease (PD), ORR, and disease control rate (DCR). ORR was defined as the sum of CR and PR, and DCR was the sum of CR, PR, and SD; (II) Long‐term clinical efficacy: 1–5 year overall survival rate (OS); (III) quality of life (QOL), QOL is considered to be improved when Karnofsky performance status (KPS) score is higher than 10 points after treated. Secondary outcomes included ADRs, peripheral blood lymphocytes, tumor markers and related cytokines, transfer rate, and time to progress (TTP). According to WHO recommendations for grading of acute and subacute toxicity or NCI common terminology criteria for adverse events (CTCAE), ADRs are evaluated by testing hematotoxicity (neutropenia, anemia, thrombocytopenia, and leukopenia), gastrointestinal reaction (nausea and vomiting, diarrhea), liver/renal dysfunction, neurotoxicity, myelosuppression, and hand‐foot syndrome. T‐lymphocyte subsets such as the proportion of CD3+, CD4+, and CD8+ T cells, the ratio of CD4+/CD8+ T cells, and the proportion of natural killer cells (NK cells) are measured. Tumor markers and related factors tested include CEA, CA199, CA125, CA724, and TNF‐α.

2.2. Search strategy and study selection

Literature search in both international (Cochrane Library, PubMed, EMBASE, and Web of Science) and Chinese (CBM, CNKI, CQVIP, and Wanfang Database) databases will be systematically searched for eligible studies from their inception to March 2021, were independently conducted by two researchers (Hui‐zhong Jiang and Ya‐li Jiang). The retrieved keywords included TCM, CRC, capecitabine, and ADRs. The titles and abstracts were independently screened and then full texts of relevant publications for eligibility were read. Any discrepancy was discussed with a third researcher (Dong‐xin Tang). In addition, the references listed in original reports and previous reviews were reviewed, and manually selected for other available publications.

2.3. Data extraction

The following study and participant characteristics were extracted, including first author, year of publication, sample size, type of medications, mean age of participants, cancer staging system (TNM stage), Karnofsky performance status (KPS), TCM intervention (dosage and duration), drug delivery, capecitabine regimen (dose and cycles), and outcome measurements. Any disagreement was resolved by consensus.

2.4. Quality assessment and evidence level

The quality of studies were assessed by Cochrane risk of bias tool Review Manager 5.3 (Nordic Cochran aa). The review criteria cover seven areas included random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, other sources of bias. The included studies were evaluated to three degrees including low, unclear, and high risk of bias.

2.5. Statistical Analyses

Statistical analyses were performed using Review Manager 5.3 and R 4.0.5 software. The outcomes were mainly represented by risk ratio (RR) and standardized mean difference (SMD) with its 95% CIs. A two‐tailed p < 0.05 is considered to be statistically significant. Cochrane's Q‐test and I 2 statistics were used to assess heterogeneity between studies; p ≤ 0.1 or I 2 > 50% indicates statistical heterogeneity. A fixed‐effects model was used to calculate the outcomes when statistical heterogeneity was absent. Otherwise, the random‐effects model was used according to the DerSimonian and Laird method. Studies with zero events were included to avoid overestimation of effect. 13 When the same outcome was reported by more than 10 studies, publication bias was tested using funnel plots, Egger's regression test, and Begg's rank test. Sensitivity analysis was conducted to explore an individual study's influence on the pooled results by deleting one single study each time from pooled analysis.

Subgroup analyses were carried out based on the methods of the TCM administration. Meanwhile, only the TCMs with significant tumor responses were included in our analyses. Pooled ORRs were calculated for each group of studies that contained the same TCM. The same pairs of TCMs in three or more studies were identified. The pooled RRs were calculated. They were listed in descending order and any significant was highlighted.

3. RESULTS

3.1. Literature search and study characteristics

A total of 313 articles were initially identified. After screening the titles and abstracts, 119 articles were retrieved for full‐text review. Finally, 39 studies 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 with 1384 patients in the TCM combined with capecitabine group and 1367 patients in the capecitabine group were included for meta‐analyses (Figure 1). All the 39 studies were RCTs, and the characteristics are summarized in Table 1. All the 39 studies were conducted in China. Thirty‐five studies used the oral TCM, two studies used external TCM, and two studies used commercially available TCM injections (Table 1).

FIGURE 1.

FIGURE 1

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The flow charts of included studies.

TABLE 1.

Characteristics of randomized controlled trials of TCMs combined with capecitabine‐based regiments for CRC

First author (year) Design Sample size T/C; Age T/C TNM (T/C); KPS TCM intervention; Dosage and duration Drug delivery Capecitabine (Cap.) Regimen; Dose, Cycles (T/C) Outcome measures
Zhao 2017 14 RCT 30/30; (54.1 ± 4.9)/(53.3 ± 5.6) II‐III(all); NR

Changningyin, 150 ml, bid, 21 days/cycle, for 2

cycles

 Orally XELOX: Ox. 130 mg/m2, ivgtt, d1, capecitabine 1250 mg/m2, bid, po, 21 days/cycle (all) O2
Shi 2018 15 RCT 48/48; (57.26 ± 7.24)/(59.31 ± 7.97) II: 7/5, III: 32/35, IV: 9/8; KPS > 60 Erlingyiren decoction, bid, 1 month/cycle, for 3 cycles Orally XELOX:Ox. 130 mg/m2, ivgtt, d1, capecitabine 1250 mg/m2, bid, po, d1‐d14, 21 days/cycle, for 4 cycles (all) O2, 5
Chen 16 RCT 48/48; (61.07 ± 8.64)/(60.86 ± 8.57) II: 40/41, III: 8/7; NR Erlingyiren decoction, 300 ml, bid, continue for 2 weeks, stop for 1 week, 3 weeks/cycle, for 3 cycles Orally XELOX: Ox. 130 mg/m2, ivgtt, d1, capecitabine 1000 mg/m2, bid, po, d1‐d14, 21 days/cycle, for 3 cycles (all) O4, 5, 6
Gu 17 RCT 28/28; (56.5 ± 1.4)/(56.4 ± 1.3) NR; NR Erlingyiren decoction, 300 ml, bid, d1‐d14, 3 weeks/cycle orally XELOX: Ox. 130 mg/m2, ivgtt, day 1, capecitabine 1000 mg/m2, bid, po, d1‐d14, 21 days/cycle (all) O4, 5, 6
Zhang 18 RCT 30/30; (67 ± 11)/(63 ± 13) IV (all); KPS ≥70 Jianpijiedufang, 200 ml, bid, 21 days/cycle, for 2 cycles Orally Capecitabine 1000 mg/m2, bid, po, continue for 2 weeks, stop for 1 week, 3 weeks/cycle, for 2 cycles (all) O1, 4
Cui 19 RCT 20/20; 18–70 IV (all); KPS ≥60 Jianpiquyufang, 200 ml, bid, for 8 weeks Orally Xeloda+CPT‐11: Xeloda 1000 mg/m2, bid, for 14 days, CPT‐11 60 mg/m2, ivgtt for d1, d8, d15, 4 weeks/cycle, for 2 cycles(all) O2
Sun 20 RCT 29/29; (54.6 ± 4.8)/(56.0 ± 4.6) NR;NR Jianpiziyin decoction, 300 ml, tid, for 14 days Orally XELOX: Ox. 130 mg/m2, 3 hours ivgtt, capecitabine 1000 mg/m2, bid, po, d1‐d14 (all) O6
Ding 21 RCT 32/30; (35–76)/(37–78) III‐IV (all); KPS > 70 Kang'ai injection, 40 ml, ivgtt, qd, d1‐d14, 21 days/cycle Injection XELOX: capecitabine 1000 mg/m2, bid, 0.5 h p.c. po, d1‐d14, Ox. 130 mg/m2, 2 h ivgtt, d1, 21 days/cycle (all) O1, 2, 4
Min 22 RCT 41/41; (59.05 ± 6.42)/(59.89 ± 6.71) III (29), IV (12)/III (30), IV (11) Shiyiwei Shenqi Capsules, 5 pills, tid Orally XELOX: capecitabine 1250 mg/m2, bid, d1‐d14, Ox. 130 mg/m2, 6 hs ivgtt, d1, 3 weeks/cycle, for 6 cycles (all) O4, 6
Pan 23 RCT 32/32; (58.7 ± 3.2)/(59.2 ± 3.3) II (13), III (19)/II (12), III (20); KPS ≥60 Silingsan, 300 ml, bid, po, 3 weeks/cycle, for 4 cycles Orally XELOX: Ox. 130 mg/m2, 2 h ivgtt, d1, capecitabine 1000 mg /m2, bid, 3 weeks/cycle, for 4 cycles (all) O2, 5, 6
Yue 24 RCT 37/39; (51.65 ± 12.15)/(51.86 ± 12.05) IV (all); KPS ≥60 Tongtai decoction 150 ml, bid Orally XELIRI: irinoteca 100/m2, ivgtt, d1‐d14, capecitabine, po, bid, 21 days/cycle, for 2 cycles (all) O1, 2, 4, 6
Zhou 25 RCT 60/60; (57.9 ± 9.8)/(58.2 ± 9.6) NR; NR TCM, bid, 1 h p.c. d1‐d14, 21 days/cycle Orally Capecitabine 2000 mg/m2, bid, 0.5 h p.c. treatmeat for 2 weeks, stop 1 week (all) O4, 5
Gu 26 RCT 60/60; (53.62 ± 6.74) II (47), III (73); KPS ≥70 Xiaoaiping injection, p.r., qd, 2 weeks/cycle, for 4 weeks Enema XELOX: Ox.130 mg/m2, 2 h ivgtt, d1, capecitabine 1000 mg/m2, po, bid, d1‐d14, 21 days/cycle, for 2 cycles (all) O2, 4
Xiao 27 RCT 30/30; 37–74/39–72 NR; KPS ≥60 Guiqiliujun decoction, bid, 21 days/cycle, for 2 cycles Orally XELOX: Ox.130 mg /m2, 3 h ivgtt, d1, capecitabine 1000 mg /m2, po, d1‐d14, 21 days/cycle, for 2 cycles (all) O1, 2, 3, 5, 8
Bin 28 RCT 40/36; NR NR; KPS ≥70 Zhenxiang capsules, 6 pills, tid, 0.5 h p.c. Orally Capecitabine 2500 mg/m2, po, d1‐d14, 21 days/cycle, for 2 cycles (all) O5
Yao 29 RCT 21/21; (62.45 ± 9.64)/(57.5 ± 10.35) IV (all); KPS > 60 TCM, bid, po, for 6 cycles Orally XELOX: Ox.1350 mg/m2, d1, 2 h ivgtt, capecitabine 1000 mg/m2, po, d1‐d14, 21 days/cycle, for 2 cycles (all) O2, 4, 6
Guo 30 RCT 45/45; (55.1 ± 6.1) III (52), IV (28); KPS > 60 Fuzhengxiaoji decoction, bid or tid, d1, 14 days/cycle, for 3 cycles Orally Ox. 85 mg/m2, ivgtt, d1, capecitabine 1000 mg/m2, po, d1‐d14, 21 days/cycle, for 2 cycles (all) O1, 5, 6
Chen 31 RCT 28/28; 34–73 III (32), IV (24); KPS ≥60 Shenyi capsules, 20 mg, bid, 6 weeks/cycle, for 2 cycles Orally Capecitabine 2000 mg/m2, po, d1‐d14, 0.5 h p.c. Ox. 85 mg/m2, 2 h ivgtt, 21 days/cycle, for 4 cycles (all) O1, 2, 4, 5
Liu 32 RCT 40/40; (61.28 ± 5.05)/(61.85 ± 4.93) IV (all); KPS > 60 Shengxuefang, bid, for 6 weeks Orally XELOX: Ox.130 mg/m2, ivgtt, d1, capecitabine 1000 mg/m2, po, bid, d1‐d14, 21 days/cycle (all) O1, 2, 4, 5
Yao 33 RCT 45/40; 68–80 NR; KPS ≥70 TCM, bid, 0.5 h p.c. d3, 14 days/cycle Orally XELOX: capecitabine 1000 mg/m2, po, bid, d1‐d14, Ox. 130 mg/m2, ivgtt, d1, 28 days/cycle, for 4 cycles (all) O2, 3, 4
Li 34 RCT 30/30; 48–69 NR; NR TCM, 300 ml, pr, 30 min‐1 h, p.r. enema Capecitabine 1.5 g, po, bid, d1‐d14, 21 days/cycle (all) O1, 2, 4
Zhou 35 RCT 27/26; (59.19 ± 6.83)/(58.50 ± 7.62) IV (all); KPS ≥60 TCM, 90 ml, bid, p.c. for 4 cycles Orally XELOX: Ox. 130 mg/m2, ivgtt, d1, capecitabine 1000 mg/m2, bid, d1‐d14, 4 weeks/cycle, for 4 cycles (all) O2, 5, 6
Jiao 36 RCT 45/45; 55–78/45–75 IV (all); NR Zibu decoction, 100 ml, bid orally Capecitabine 1250 mg/m2, po, bid, d1‐d14, 21 days/cycle (all) O2, 4
Liu 37 RCT 23/22; (56 ± 12)/(59 ± 11)

NR; KPS > 90

 Fuzheng shengbai orally liquid, 20 ml, tid, for 3 months Orally Capecitabine 1250 mg/m2, bid, for 14 days, Ox. 130 mg/m2, d1, 21 days/cycle, for 4 cycles (all) O1
Dong 38 RCT 64/58; (76 ± 5.27)/(57.76 ± 4.38) NR; KPS ≥60 Fufang tengligen preparation, 500 ml, bid Orally Irinoteca 180 mg/m2, ivgtt, d1, capecitabine 1000 mg/m2, po, bid, d1‐d14, 3 weeks/cycle, for 4 cycles (all) O1, 2, 4, 5
Sun 39 RCT 18/18; 38–72 NR; KPS ≥60 Pebenyiyang decoction, 200 ml, po, bid orally CapeOx: capecitabine 1250 mg/m2, po, bid, d1‐d14, Ox. 130 mg/m2, 2 hours ivgtt, 21 days/cycle (all) O1, 4
Xu 40 RCT 43/43; (59.24 ± 6.45)/(58.87 ± 7.21) NR; KPS ≥60 Shengxue decoction, 200 mL, qd, for 6 weeks Orally Xelox: Ox. 130 mg/m2, ivgtt, d1, capecitabine 1000 mg/m2, po, bid, d1‐d14, 21 days/cycles, for 2 cycles (all) O1, 2, 4, 5
Xu 41 RCT 50/50; (72.3 ± 5.9) II (25), III (75); NR TCM, bid, for 2 cycles orally Ox. 130 mg/m2, d1, 3 h ivgtt, capecitabine 1000 mg/m2, po, bid, d1‐d14, 21 days/cycle, for 2 cycles (all) O1, 7, 8
Ding 42 RCT 35/35; (47.5 ± 8.6)/(48.2 ± 7.5) II (13), III (22)/II (15), III (20); KPS ≥60 Aidi injection 100 ml, ivgtt, qd, d1‐d7, d15‐d21 Injection XELOX: Ox. 130 mg/m2, 3 h ivgtt, d1, capecitabine 1000 mg/m2, po, bid, d1‐d14, 21 days/cycle, for 3 cycles (all) O2, 4
Xie 43 RCT 32/32; 58.35 ± 1.32 II‐III (all); KPS ≥60 Boerning capsules, 0.6 g, tid, for 4 weeks Orally XELOX: Ox. 130 mg/m2, 2 hours ivgtt, d1, capecitabine 1000 mg/m2, po, bid, d1‐d14, 21 days/cycle, for 4 cycles (all) O1, 2, 4, 5
Ma 44 RCT 23/23; (53.28 ± 4.62)/(53.37 ± 4.83) II (4), III (19); KPS: 76.23 ± 7.93 Buqiyichangfang, bid Orally Ox. 130 mg/m2, capecitabine 1250 mg/m2, bid, d1‐d14, 3 weeks/cycle, for 6 cycles (all) O5, 6
Bian 45 RCT 20/20; 59.2 II (15), III (23), IV (2); NR Gubenyiliufang, qd, for 3 weeks orally Capecitabine 1250 mg/m2, bid, po, 3 weeks/cycle, for 4 cycles (all) O2, 5, 6
Li 46 RCT 40/40; (63.51 ± 5.63)/(62.47 ± 5.71) II‐IV (all); KPS ≥60 Jianpi Fuzheng Recipe, 300 ml, bid, 3 weeks/cycle, for 2 cycles Orally Ox. 130 mg/m2, 2 hours ivgtt, d1, capecitabine, 1000 mg/m2, po, bid, d1‐d14, 3 weeks/cycle, for 2 cycles (all) O2, 5
Xie 47 RCT 30/30; (65.7 ± 3.5)/(65.2 ± 2.8) NR; NR Jianpiyiqi, 300 ml, bid Orally Capecitabine 2000 mg/m2, bid, 0.5 h p.c. d1‐d14, 21 days/cycle (all) O2, 5
Qi 48 RCT 30/30; (54.1 ± 5.1)/(54.3 ± 5.8) II‐III (all); NR Ningchangyin, po, bid Orally XELOX: Ox. 130 mg/m2, 2 h ivgtt, d1, capecitabine 1250 mg/m2, po, bid, d1‐d14, 21 days/cycle, for 4 cycles (all) O4
Zhou 49 RCT 30/30; (53.63 ± 7.78)/(55.53 ± 8.12) II‐III (all); KPS ≥60

Sanmiao granules, tid, 21 days/cycle, for 3 cycles

 Orally XELOX: capecitabine 1.25 g/m2, 14 days/cycle, Ox. 85 mg/m2, 2 hours ivgtt, for 3 weeks (all) O2, 4, 5
Wu 50 RCT 40/40; (47.52 ± 5.11)/(48.03 ± 6.29) II (8), III (13), IV (19)/II (7), III (12), IV (21); KPS ≥60 Prunella vulgaris tablets, 6 pills, bid, 3 weeks/cycle, for 2 cycles orally XELOX: Ox. 130 mg/m2, 2 hours ivgtt, d1, capecitabine 800–1000 mg/m2, po, bid, d1‐d14, 21 days/cycle, for 2 cycles (all) O2, 4, 6
Xiao 51 RCT 30/30; NR II‐III (all); NR Tonifying Qi and nourishing Yin prescription, 150 ml, bid, p.c. for 2 weeks Orally XELOX: Ox. 130 mg/m2, 2 h ivgtt, d1, capecitabine 800–1000 mg/m2, po, bid, d1‐d14, 21 days/cycle, for 2 cycles (all) O6
Xiao 52 RCT 30/30; 60–71 II (18), III (42); NR Yiqi Yangyin Huatan Recipe, 150 ml, bid, 0.5 h p.c. Orally XELOX: Ox. 130 mg/m2, 2 h ivgtt, d1, capecitabine 800–1000 mg/m2, po, bid, d1‐d14, 21 days/cycle, for 2 cycles (all) O2,5
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Abbreviations: bid, twice per day; C, control group; d, day; ID, intravenous drip; ivgtt, injection venosa gutta; KPS, Karnofsky Performance Status; N, number; NR, not reported; O: outcomes, O1: tumor response including the objective response rate (ORR), and disease control rate (DCR); O2: quality of life (QOL), O3: Overall Survival rate (OS); O4: adverse drug reactions (ADRs); O5: the levels of peripheral blood lymphocytes; O6: tumor markers and related factors; O7:transfer rate,O8: time to progress (TTP); Ox., oxaliplatin; p.c., post cibum; po, per os; pr, per rectum; qd, once per day; T, treatment group; TCM, traditional Chinese medicine; tid, thrice per day; TNM, Tumor Node Metastasis (“T” for tumor, denotes the extent of invasion of the intestinal wall, “N” for lymphatic node, the amount of lymphatic node involvement, and “M” for the metastasis); Xel/Cap., capecitabine; XELOX, Ox. + capecitabine; XELIRI, irinoteca + capecitabine.

3.2. Methodological bias of the included studies

In 39 trials, the methods of random allocation were described clearly in only 18 trials. 14 , 15 , 16 , 22 , 26 , 30 , 37 , 38 , 39 , 40 , 42 , 44 , 45 , 47 , 48 , 49 , 50 , 52 This indicated that there was selectivity bias in the included studies. The random allocation concealment was unclear. Not all the included studies were described as blinding to patients and doctor. Therefore, it indicated that there were selective bias and implementation bias. All data were complete and selective report did not appear in all of the studies. Other bias was not clear. Characteristics and quality of all included studies are presented in Figure 2.

FIGURE 2.

FIGURE 2

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Risk of methodological bias of the included studies. (A) Risk of bias summary: review authors' judgments about each risk of bias item for each included study. (B) Risk of bias graph: review authors' judgment about each risk of bias item presented as percentages across all included studies.

3.3. Tumor response

According to the WHO 53 or RECIST 54 guidelines, 14 trials 18 , 21 , 24 , 27 , 30 , 31 , 32 , 34 , 37 , 38 , 39 , 40 , 41 , 43 containing 997 and 12 18 , 21 , 24 , 27 , 30 , 31 , 32 , 37 , 38 , 39 , 40 , 43 trials containing 837 cases evaluated ORR and DCR, respectively (Figure 3A,B). Cochran's χ 2 test and I 2 statistic showed no heterogeneity (ORR, I 2 = 0%; DCR, I 2 = 3%). Therefore, the data both using an FEM were synthesized. Compared with capecitabine alone, TCMs in combination with capecitabine significantly increased ORR (RR, 1.35 [1.45–1.88], p < 0.00001) and DCR (RR, 1.22 [1.12, 1.32], p < 0.00001).

FIGURE 3.

FIGURE 3

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Tumor response. (A) Forest plot displaying the results of the meta‐analysis for ORR. (B) Forest plot displaying the results of the meta‐analysis for DCR.

Two groups were divided for meta‐analyses to evaluate ORR: non‐oral group (2 studies) and oral group (12 studies). The non‐oral group has different ways (e.g., Kang'ai injection, and enema TCM) were tested in two studies (n = 122). Significant improvement in ORR (RR, 1.13 [0.80, 1.60], I 2 = 0%) was found in the non‐oral group. Twelve studies (n = 875) were included in the oral group, including decoctions, capsules, or tablets. The pooled ORR showed significant improvement in the oral group (RR, 1.39 [1.19, 1.61], I 2 = 0%).

One study and 11 studies were included to evaluate the DCR in the non‐oral and oral groups. Similarly, compared with capecitabine alone, the combined treatment significantly improved the pooled DCR in the non‐oral and oral groups (n = 62, RR, 1.07 [0.80, 1.41]; n = 775, RR, 1.23 [1.13, 1.34], I 2 = 9%), respectively.

3.4. Quality of life

The quality of life (QOL) changes on KPS were reported as two types of data in the included studies, the number of patients 21 , 23 , 33 , 34 , 36 , 38 , 42 , 43 , 45 who reported the improved or stable performance status based on KPS (10‐point cutoff) and the mean ± SD of KPS before and after treatment. 14 , 15 , 19 , 23 , 24 , 26 , 27 , 29 , 31 , 32 , 35 , 40 , 42 , 46 , 47 , 49 , 50 , 52 The results showed that compared with capitabine alone, the combined treatment significantly increased the number of improved patients based on KPS (RR, 1.71 [1.44, 2.03]; p < 0.0001, I 2 = 0%) (Figure 4A), and elevated KPS (SMD, 0.79 [0.51, 1.08]; p < 0.0001, I 2 = 82%) (Figure 4B). Taken together, the KPS in TCM combined with capecitabine group was significantly improved compared with the control group.

FIGURE 4.

FIGURE 4

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Quality of life. (A) Forest plot displaying the results of the meta‐analysis for KPS according to number of patients. (B) Forest plot displaying the results of the meta‐analysis for KPS according to mean ± SD.

3.5. Overall survival rate

Four trials 15 , 21 , 27 , 33 with 303 patients reported the 1‐year survival rate. The meta‐analysis showed significant difference between these two treatment groups (RR, 1.18 [1.04, 1.35]; p = 0.0126, I 2 = 0%; Figure 5A). Three trials 15 , 21 , 33 reported the 2‐year survival rate and indicated no statistically significant difference between the two treatment groups (RR, 1.48 [0.90, 2.43]; p = 0.1205, I 2 = 54%) (Figure 5B). Heterogeneity was present after one study (Ding, p. 2017) 21 was removed (RR, 1.89 [1.22, 2.94], p = 0.0047, I 2 = 3%). These results showed that TCM combined with capecitabine improved 1‐year/2‐year survival rate of CRC patients as compared with capitabine alone.

FIGURE 5.

FIGURE 5

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Overall survival rate. (A) Forest plot displaying the results of the meta‐analysis for 1‐year survival rate. (B) Forest plot displaying the results of the meta‐analysis for 2‐year survival rate.

3.6. Adverse drug reactions

Twenty‐one trials 16 , 17 , 18 , 21 , 22 , 24 , 25 , 26 , 29 , 31 , 32 , 33 , 34 , 36 , 38 , 39 , 40 , 42 , 43 , 48 , 49 , 50 with 1663 cases reported the ADRs (Table 2; Figure S1).Some studies described gastrointestinal reactions and hematological toxicity, but did not distinguish them in detail. Significant heterogeneity in gastrointestinal reaction (I 2 = 90%), nausea/vomiting (I 2 = 58%), hand‐foot syndrome (I 2 = 93%), and hematological toxicity (I 2 = 97%). The results also showed that TCM combined with capecitabine‐based chemotherapy had lower risks of neutropenia (RR, 0.67 [0.54, 0.85], p = 0.0006), thrombocytopenia (RR, 0.76 [0.58, 0.99], p = 0.0409), leukopenia (RR, 0.70 [0.60, 0.82], p < 0.0001), nausea/vomiting (RR, 0.67 [0.50, 0.88], p = 0.0049), diarrhea (RR, 0.61 [0.49, 0.74], p < 0.0001), liver/renal dysfunction (RR, 0.64 [0.47, 0.86], p = 0.0025), myelosuppression (RR, 0.67 [0.54, 0.82], p < 0.0001), anemia (RR, 0.69 [0.52, 0.92], p = 0.012), neurotoxicity (RR, 0.79 [0.64, 0.98], p = 0.0344) than those of chemotherapy alone. There were no significant differences in RR values and their 95% CI of gastrointestinal reaction (RR, 0.75 [0.50, 1.14], p = 0.18), hand‐foot syndrome (RR, 0.62 [0.23, 1.67], p = 0.3449), hematological toxicity (RR, 0.62 [0.09, 4.26], p = 0.6244) between the two groups.

TABLE 2.

Meta‐analysis results of ADRs

Outcomes Trials Experimental group (Events/Total) Control l group (Events/Total) SM RR,95% CI I 2 (%) p PB
Myelosuppression 9 81/302 121/300 FEM 0.67 (0.54, 0.82) 0 <0.0001 No
Gastrointestinal reaction 8 81/288 121/286 REM 0.75 (0.50, 1.14) 90 0.18 Unclear
Anemia 5 49/217 71/213 FEM 0.69 (0.52, 0.92) 0 0.012 Unclear
Thrombocytopenia 10 70/431 92/428 FEM 0.76 (0.58, 0.99) 0 0.0409 No
Liver/Renal dysfunction 11 52/446 83/442 REM 0.64 (0.47, 0.86) 0 0.0025 No
Neurotoxicity 13 94/432 119/429 FEM 0.79 (0.64, 0.98) 0 0.0344 No
Nausea/vomiting 12 111/447 169/443 REM 0.67 (0.50, 0.88) 58 0.0049 Yes
Neutropenia 3 53/139 77/133 FEM 0.67 (0.54, 0.85) 25 0.0006 Unclear
Hand‐foot syndrome 8 64/281 90/276 REM 0.62 (0.23, 1.67) 93 0.3449 Unclear
Diarrhea 12 93/452 151/443 FEM 0.61 (0.49, 0.74) 0 <0.0001 No
Leukopenia 11 133/435 189/432 FEM 0.70 (0.60, 0.82) 32 <0.0001 Yes
Hematological toxicity 3 40/88 53/88 REM 0.62 (0.09, 4.26) 97 0.6244 Unclear
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Note: Forest of all results are in Figure S1.

Abbreviations: CI, confidence interval; FEM, fixed‐effects model; PB, Publication bias; REM, random‐effects model; RR, relative ratio; SM, statistical method.

3.7. The levels of peripheral blood lymphocytes

Twenty trials 15 , 16 , 17 , 23 , 25 , 27 , 30 , 31 , 32 , 35 , 38 , 40 , 43 , 44 , 45 , 46 , 47 , 49 , 52 with 1465 cases reported the levels of peripheral blood lymphocytes (Table 3; Figure S2). There was statistical heterogeneity in CD3+ T cells (I 2 = 93%), CD4+ T cells (I 2 = 91%), CD8+ T cells (I 2 = 97%), CD4+/CD8+ T cells ratio (I 2 = 92%), and excluded medium heterogeneity in NK cells (I 2 = 45%). Therefore, the data of CD3+ T cells, CD4+ T cells, CD8+ T cells, and CD4+/CD8+ T cells ratio and the NK cells were calculated by using a FEM. The meta‐analysis results showed that TCM plus capecitabine‐based chemotherapy improved the CD3+ T cells (RR, 1.47 [0.96, 1.98], p < 0.0001), CD4+ T cells (RR, 1.70 [1.27, 2.13], p < 0.0001), CD4+/CD8+ T cells ratio (RR, 1.47 [1.05, 1.89], p < 0.0001), and NK cells (RR, 0.87 [0.69, 1.06], p < 0.0001) compared with those of chemotherapy alone. No significant differences were found in RR values and their 95% CI of CD8+ T cells (RR, −0.22 [−0.99, 0.54], p = 0.565) between the two groups.

TABLE 3.

Meta‐analysis results of the levels of peripheral blood lymphocytes

Outcomes Trials SM SMD, 95% CI I 2 (%) p PB
CD3+ T cells 16 REM 1.47 (0.96, 1.98) 93 <0.0001 Yes
CD4+ T cells 17 REM 1.70 (1.27, 2.13) 91 <0.0001 Yes
CD8+ T cells 15 REM −0.22 (−0.99, 0.54) 97 0.565 No
CD4+/CD8+ T cells ratio 19 REM 1.47 (1.05, 1.89) 92 <0.0001 Yes
NK cells 7 FEM 0.87 (0.69, 1.06) 45 <0.0001 Unclear
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Note: Forest of all results are in Figure S2.

Abbreviations: CI, confidence interval; FEM, fixed‐effects model; PB, Publication bias; REM, random‐effects model; SM, statistical method; SMD, standardized mean difference.

3.8. Tumor markers and related factors

Thirteen trials 15 , 16 , 17 , 23 , 25 , 27 , 28 , 30 , 31 , 32 , 35 , 38 , 40 , 43 , 44 , 45 , 46 , 47 , 49 , 52 with 843 cases reported the tumor markers and related factors (Table 4 and Figure S3). In the studies, result showed that there was a significant difference in the level of CEA, CA199, and CA125 between the two groups, and the TCM with chemotherapy group was found to have lower CEA, CA199, and CA125 (RR, −1.83 [−2.69, −0.96], I 2 = 96%, p < 0.0001; −0.86 [−1.32, −0.40], I 2 = 81%, p = 0.0003; −1.73 [−3.14, −0.32], I 2 = 96%, p = 0.0162). But about CA724 and TNF‐α, the result indicated no statistical differences between the two groups (RR, −2.39 [−7.14, 2.36], I 2 = 99%, p = 0.3246; RR, 0.13 [−2.65, 2.91], I 2 = 98%, p = 0.9262).

TABLE 4.

Meta‐analysis results of tumor markers and related factors

Outcomes Trials SM SMD, 95% CI I 2 (%) p PB
CEA 12 REM −1.83 (−2.69, −0.96) 96 <0.0001 Yes
CA199 7 REM −0.86 (−1.32, −0.40) 81 0.0003 Unclear
CA125 4 REM −1.73 (−3.14, −0.32) 96 0.0162 Unclear
CA724 2 REM −2.39 (−7.14, 2.36) 99 0.3246 Unclear
TNF‐α 2 REM 0.13 (−2.65, 2.91) 98 0.9262 Unclear
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Note: Forest of all results are in Figure S3.

Abbreviations: CI, confidence interval; FEM, fixed‐effects model; PB, Publication bias; REM, random‐effects model; SM, statistical method; SMD, standardized mean difference.

3.9. Transfer rate and TTP

Of the 39 trials, only two studies 15 , 41 reported the tumor transfer rate, and no significant difference was found between the two groups(RR, 0.55 [0.29, 1.03], I 2 = 0%, p = 0.0647) (Figure 6A). And three trials 25 , 27 , 41 reported TTP (RR, 1.33 [0.05, 2.60], I 2 = 95%, p = 0.0419), with a significant difference between the two groups (Figure 6B).

FIGURE 6.

FIGURE 6

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Transfer rate and TTP. (A) Forest plot displaying the results of the meta‐analysis for transfer rate. (B) Forest plot displaying the results of the meta‐analysis for TTP.

3.10. Publication bias analysis

More than 10 studies reported the same outcomes, including ORR, DCR, KPS, thrombocytopenia, liver/renaldysfunction, neurotoxicity, nausea/vomiting, diarrhea, leukopenia, CD3+ T cells, CD4+ T cells, CD8+ T cells, CD4+/CD8+ T cells ratio, and CEA. Publication bias was tested using funnel plots (Figure 7) and Egger's regression test (Figure 8). Other publication bias is shown in the previous tables (Tables 2 and Table 3).

FIGURE 7.

FIGURE 7

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Funnel plots displaying the results of the meta‐analysis for Publication bias analysis. (A) ORR. (B) DCR. (C) KPS (mean ± SD). (D) Thrombocytopenia. (E) Liver/Renal dysfunction. (F) Neurotoxicity. (G) Nausea/Vomiting. (H) Diarrhea. (I) Leukopenia. (J) CD3+ T cells. (K) CD4+ T cells. (L) CD8+ T cells. (M) CD4+/CD8+ T cells. (N) CEA.

FIGURE 8.

FIGURE 8

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Egger's analysis for Publication bias analysis. (A) ORR. (B) DCR. (C) KPS (mean ± SD). (D) Thrombocytopenia. (E) Liver/Renal dysfunction. (F) Neurotoxicity. (G) Nausea/Vomiting. (H) Diarrhea. (I) Leukopenia. (J) CD3+ T cells. (K) CD4+ T cells. (L) CD8+ T cells. (M) CD4+/CD8+ T cells. (N) CEA.

3.11. Sensitivity analysis

Thirty‐nine trials were included for sensitivity analysis, excluding the poor/over/ underestimated trials. The result demonstrated that except for CA724, TNF‐α, and transfer rate, no heterogeneities were found in other parameters tested (Table 5 and Figures S4 and S5). Although excluding the trials, 16 , 17 , 22 , 24 , 29 , 30 , 35 , 45 , 50 , 51 heterogeneity was also found in CEA (Table 5).

TABLE 5.

Sensitivity analysis by excluding the poor/over/underestimated trials

Outcomes Trials SM RR/SMD, 95% CI I 2 (%) Excluded trials (Reference number) Trials SM RR/SMD, 95% CI I 2 (%)
(a)
ORR 14 FEM 1.35 (1.17, 1.55) 0 1 39 13 FEM 1.31 (1.13, 1.52) 0
DCR 12 FEM 1.22 (1.12, 1.32) 3 1 32 11 FEM 1.19 (1.09, 1.29) 0
KPS(number) 9 FEM 1.71 (1.44, 2.03) 0 1 34 8 FEM 1.80 (1.49, 2.18) 0
KPS(mean ± SD) 18 REM 0.79 (0.51, 1.08) 82 1 26 17 REM 0.65 (0.53, 0.77) 33
1‐year Survival rate 4 FEM 1.18 (1.04, 1.35) 0 1 27 3 FEM 1.13 (0.98, 1.30) 0
2‐year Survival rate 3 REM 1.48 (0.90, 2.43) 54 1 21 2 FEM 1.89 (1.22, 2.94) 3
b)
Myelosuppression 9 FEM 0.67 (0.54, 0.82) 0 1 21 8 FEM 0.72 (0.58, 0.88) 0
Gastrointestinal reaction 8 REM 0.75 (0.50, 1.14) 90 1 31 7 FEM 0.71 (0.59, 0.85) 32
Anemia 5 FEM 0.69 (0.52, 0.92) 0 1 38 4 FEM 0.76 (0.57, 1.03) 0
Thrombocytopenia 10 FEM 0.76 (0.58, 0.99) 0 1 24 9 FEM 0.72 (0.54, 0.97) 0
Liver/Renal dysfunction 11 REM 0.64 (0.47, 0.86) 0 1 24 10 FEM 0.56 (0.40, 0.79) 0
Neurotoxicity 13 FEM 0.79 (0.64, 0.98) 0 1 25 12 FEM 0.84 (0.67, 1.05) 0
Nausea/Vomiting 12 REM 0.67 (0.50, 0.88) 58 1 15 11 FEM 0.70 (0.59, 0.84) 41
Neutropenia 3 FEM 0.67 (0.54, 0.85) 25 1 40 2 FEM 0.56 (0.37, 0.85) 0
Hand‐foot Syndrome 8 REM 0.62 (0.23, 1.67) 93 1 16 7 FEM 0.58 (0.40, 0.82) 0
Diarrhea 12 FEM 0.61 (0.49, 0.74) 0 4 16 , 29 , 38 , 44 8 FEM 0.55 (0.43, 0.70) 0
Leukopenia 11 FEM 0.70 (0.60, 0.82) 32 1 33 10 FEM 0.73 (0.63, 0.86) 18
Hematological toxicity 3 REM 0.62 (0.09, 4.26) 97 1 31 2 FEM 0.48 (0.27, 0.86) 0
c)

CD3+ T cells

 16 REM 1.47 (0.96, 1.98) 93 12 15 , 16 , 17 , 23 , 31 , 43 , 44 , 47 , 49 , 52 4 FEM 1.26 (1.01, 1.50) 0
CD4+ T cells 17 REM 1.70 (1.27, 2.13) 91 8 16 , 28 , 30 , 32 , 40 , 43 , 45 , 47 9 FEM 1.74 (1.56, 1.93) 32
CD8+ T cells 15 REM −0.22 (−0.99, 0.54) 97 8 15 , 23 , 30 , 44 , 45 , 46 , 47 , 52 7 FEM −0.06 (−0.23, 0.11) 40
CD4+/CD8+ T cells ratio 19 REM 1.47 (1.05, 1.89) 92 13 15 , 16 , 23 , 25 , 27 , 28 , 35 , 38 , 40 , 43 , 46 , 49 , 52 6 FEM 1.24 (1.01, 1.48) 17
NK cells 7 FEM 0.87 (0.69, 1.06) 45 1 49 6 FEM 0.80 (0.61, 0.99) 5
d)
CEA 12 REM −1.83 (−2.69, −0.96) 96 10 16 , 17 , 22 , 24 , 29 , 30 , 35 , 45 , 50 , 51 2 REM −1.45 (−2.19, −0.71) 67
CA199 7 REM −0.86 (−1.32, −0.40) 81 3 17 , 44 , 45 4 FEM −0.63 (−0.86, −0.39) 48
CA125 4 REM −1.73 (−3.14, −0.32) 96 2 22 , 35 2 FEM −1.23 (−1.58, −0.88) 45
CA724 2 REM −2.39 (−7.14, 2.36) 99 2 22 , 35 0 NO NO NO
TNF‐α 2 REM 0.13 (−2.65, 2.91) 98 2 20 , 44 0 NO NO NO
e)
Transfer rate 2 FEM 0.55 (0.29, 1.03) 0 2 15 , 41 0 NO NO NO
TTP 3 REM 1.33 (0.05, 2.60) 95 1 41 2 FEM 0.64 (0.34, 0.94) 0
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Abbreviations: CI, confidence interval; FEM, fixed‐effects model; ORs, odds ratios; Over or Under, over or underestimated trial which the result had significant difference and was beneficial to TCMs use; Poor trial (Poor) that had at least one domain being considered as high risk of bias; SM, statistical method; SMD, standardized mean difference.

3.12. The effects of multi‐ingredient TCM in the oral administration group

The multi‐ingredient TCM formulae had similarity in their main ingredients and functional approximation. In order to identify the most comparable subgroups of studies and potential synergistic effects, a series of planned sensitivity analyses were made. Only the TCMs with significant ORR results have been reported in our analyses. In Table 6, all significant RR results (excluding those with heterogeneity >30%) were ranked in order according to descending RR.

TABLE 6.

Effects of specific orally administered TCMs on tumor response: single TCMs and combinations

Level Traditional Chinese medicine RR 95% CI No. of Studies, References No. Part I 2 (%)
1 Yiyiren 1.5682 1.2038, 2.0428 3 24 , 30 , 38 288 0.0
1 Fuling 1.5195 1.1890, 1.9419 4 27 , 30 , 38 , 39 298 0.0
1 Gancao 1.5195 1.1890, 1.9419 4 27 , 30 , 38 , 39 262 0.0
1 Baizhu 1.4720 1.1948, 1.8136 8 18 , 24 , 28 , 30 , 32 , 38 , 39 , 40 600 0.0
1 Sheshecao 1.4705 1.0849, 1.9932 3 24 , 28 , 30 226 0.0
1 Dangshen 1.4602 1.1655, 1.8294 5 28 , 30 , 37 , 38 , 39 307 0.0
1 Banxia 1.4324 1.0436, 1.9661 3 18 , 28 , 30 200 0.0
1 Nvzhenzi 1.3954 1.0500, 1.8545 3 30 , 37 , 43 189 0.0
1 Huangqi 1.3767 1.1082, 1.7103 8 18 , 24 , 28 , 30 , 32 , 37 , 40 , 43 551 0.0
1 Taizishen 1.3636 0.8420, 2.2086 3 18 , 32 , 40 226 0.0
1 Jixueteng 1.3439 0.9411, 1.9189 4 24 , 32 , 37 , 40 287 0.0
2 Baizhu+yiyiren 1.5682 1.2038, 2.0428 3 24 , 30 , 38 258 0.0
2 Baizhu+dangshen 1.5195 1.1890, 1.9419 4 28 , 30 , 38 , 39 278 0.0
2 Baizhu+fuling 1.5195 1.1890, 1.9419 4 28 , 30 , 38 , 39 278 0.0
2 Baizhu+gancao 1.5195 1.1890, 1.9419 4 28 , 30 , 38 , 39 278 0.0
2 Dangshen+gancao 1.5195 1.1890, 1.9419 4 28 , 30 , 38 , 39 278 0.0
2 Fuling+gancao 1.5195 1.1890, 1.9419 4 28 , 30 , 38 , 39 298 0.0
2 Huangqi+sheshecao 1.4705 1.0849, 1.9932 3 24 , 28 , 30 216 0.0
2 Baizhu+sheshecao 1.4705 1.0849, 1.9932 3 24 , 28 , 30 216 0.0
2 Huangqi+banxia 1.4324 1.0436, 1.9661 3 18 , 28 , 30 200 0.0
2 Huangqi+baizhu 1.4324 1.1048, 1.8572 6 18 , 24 , 28 , 30 , 32 , 40 442 0.0
2 Banxia+baizhu 1.4324 1.0436, 1.9661 3 18 , 28 , 30 200 0.0
2 Baizhu+jixueteng 1.4324 0.9202, 2.2296 3 24 , 32 , 40 242 0.0
2 Huangqi+nvzhenzi 1.3954 1.0500, 1.8545 3 30 , 37 , 43 189 0.0
2 Huangqi+dangshen 1.3902 1.0350, 1.8672 3 28 , 30 , 37 185 0.0
2 Baizhu+taizishen 1.3636 0.8420, 2.2086 3 18 , 32 , 40 226 0.0
2 Huangqi+taizishen 1.3636 0.8420, 2.2086 3 18 , 32 , 40 226 0.0
2 Huangqi+jixueteng 1.3439 0.9411, 1.9189 4 24 , 32 , 37 , 40 287 0.0
3 Dangshen+fuling+gancao 1.5195 1.1890, 1.9419 4 28 , 30 , 38 , 39 298 0.0
3 Huangqi+banxia+baizhu 1.4324 1.0436, 1.9661 3 18 , 28 , 30 200 0.0
7 h + b + b + s + d + f + gancao 1.4828 1.0506, 2.0927 2 28 , 30 140 0.0
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Abbreviations: 95% CI, 95% confidence interval; I 2%, measure of heterogeneity; RR, risk ratio for tumor response; No. Part., number of participants; 7.h + b + b + b + d + f(huangqi+banxia+baizhu+ sheshecao+dangshen+fuling).

Level 1: Single TCM. Sixty ingredients in the formulae have been included in this review. Among them, there are 11 ingredients that have been used in three or more formulae. The Chinese name in pin yin of each ingredient was used to represent the TCMs. According to their frequency in the formulae, TCMs were listed as follows: Huangqi (n = 8), baizhu (n = 8), dangshen (n = 5), jixueteng (n = 4), fuling (n = 4), gancao (n = 4), yiyiren (n = 3), sheshecao (n = 3), banxia (n = 3), taizishen (n = 3), and nvzhenzi (n = 3). Then, the RR values were calculated, which are listed in descending order in Table 2. The pooled RR values were divided into two groups. The RR values in the first group were equal to or greater than the total pool. In the second group, the RR values were less than the total pool.

The first group included eight TCMs: yiyiren (n = 3), fuling (n = 4), gancao (n = 4), baizhu (n = 8), sheshecao (n = 3), dangshen (n = 5), banxia (n = 3), and nvzhenzi (n = 3). In the second group there were only three TCMs, huangqi (RR, 1.3767 [1.1082, 1.7103]), taizishen (RR, 1.3636 [0.8420, 2.2086]), and jixueteng (RR, 1.3439 [0.9411, 1.9189]), which had a lower value than the total pool (RR, 1.3881 [1.1932, 1.6148]) (Table 6).

Level 2: Combinations of two TCMs. Compared with the total pool, at this level, the RR values of 14 pairs including baizhu+yiyiren (n = 3), baizhu+dangshen(n = 4), baizhu+fuling (n = 4), baizhu+gancao(n = 4), dangshen+gancao (n = 4), fuling+gancao (n = 4), huangqi+sheshecao (n = 3), baizhu+sheshecao (n = 3), huangqi+banxia (n = 3), huangqi+baizhu (n = 6), banxia+baizhu (n = 3), baizhu+jixueteng (n = 3), huangqi+nvzhenzi (n = 3), huangqi+dangshen (n = 3) were equal to or greater. Three pairs were lower than the total pool (baizhu+taizishen, huangqi+taizishen, huangqi+jixueteng) (Table 6).

Level 3: Combinations of 3 TCMs. At this level, there were two significant pairs from level 2 that were combined with other TCMs that showed significant RRs compared with single TCM group. At this level, the RR values of all pairs including dangshen+fuling+gancao (n = 4), huangqi+banxia+baizhu (n = 3) were greater than the total pool (Table 6).

Levels 4 to 7: Combinations of 4 to 7 TCMs. There were no combinations of 4, 5, 6 TCMs, and there was one combination of 7 which showed an RR equal to the pool: huangqi+banxia+baizhu+sheshecao+dangshen+fuling+gancao (n = 2) (Table 6).

3.13. TCMs potential synergistic effects selection

Compared with TCM alone, 10 TCM pairs showed higher RR values and potential synergistic effects in group 1, including baizhu+yiyiren (n = 3), baizhu+dangshen (n = 4), baizhu+fuling (n = 4), baizhu+gancao (n = 4), dangshen+gancao (n = 4), fuling+gancao (n = 4), huangqi+sheshecao (n = 3), baizhu+sheshecao (n = 3), huangqi+banxia (n = 3), huangqi+nvzhenzi (n = 3), while the RR values of two combinations in levels 3–7 with were lower than the level 1, such as huangqi+banxia+baizhu (n = 3), huangqi+banxia+baizhu+sheshecao+ dangshen+fuling+gancao (n = 2). In all levels, dangshen, fuling, and gancao showed significant ORRs equal or higher than the totalpool at each level.

4. DISCUSSION

TCM's essential components are being studied constantly, and more and more research has proven that TCM may assist with tumor treatment. 55 , 56 Capecitabine, a 5‐FU prodrug, is an effective first‐line therapy for CRC due to its ease of use and low frequency of ADRs. 57 Though oxaliplatin‐ or 5‐FU‐based chemotherapy combined with TCM was shown to be more effective than TCM alone in two studies, 58 , 59 the efficiency of capecitabine‐based chemotherapy combined with TCM in CRC is yet unknown.

Thirty‐nine studies including 2751 patients were included in meta‐analyses to evaluate the therapeutic CRC regimen capitabine‐based coupled with TCMs clinical effectiveness and ADRs. As a consequence, capecitabine‐based chemotherapy regimens were shown to be more effective when combined with TCM. The ORR and DCR of the oral TCM or non‐oral group (e.g., injection, enema) were shown to be substantially greater than those utilizing capitabine alone, as a consequence of which we exhibited. Improving immunological function and overall well‐being is critical for cancer patients undergoing treatment. We compared the QOL and the number of peripheral blood lymphocytes in each group as part of our research. According to the findings, combining capecitabine‐based chemotherapy with TCM improved CD3+ T cells, CD4+ T cells, CD4+/CD8+ T cells ratio, and NK cells, as well as overall QOL. In addition, it has the potential to decrease tumor marker expression levels (CEA, CA199, and CA125). This will assist the patient's immune system, allowing him or her to fight off tumor recurrence and metastasis in the future. T‐lymphocyte expression is linked to poor prognosis and tumor metastasis, 60 such as CD3+, 61 CD4+, 62 CD4+/CD8+ T cell ratio, 63 and NK cells, 64 increasing immune function to inhibit tumor growth. 65 An important clinical biomarker for gastrointestinal malignancies is a cell surface glycoprotein called carcinoembryonic antigen (CEA) 66 . There has been an increase in CEA overexpression in 90% of gastrointestinal cancers, including CRC tumor recurrence is predicted by an increase in postoperative CA125 and CA199 levels, and this information is critical for the diagnosis of digestive system cancer. 67 , 68

TCMs used orally or intravenously showed promise in the treatment of CRC. Specific plant‐based TCMs were further analyzed and shown to have substantially greater contributions to the RR value, including yiyiren, fuling, gancao, baizhu, sheshecao, dangshen, banxia, and nvzhenzi. Dangshen, fuling, and gancao all contributed considerably more to the RR value than the others at all levels. Capecitabine‐based chemotherapy for CRC may benefit from the addition of TCMs.

5. CONCLUSION

Our research found that the combination of TCM and capecitabine‐based chemotherapy was more effective than the capecitabine‐only regimen. Additionally, it has the potential to decrease adverse responses in patients, enhance survival rates, and the body's capacity to fight off infection, lower tumor marker expression levels, and even slow tumor development. Specific TCMs may have the potential to improve the efficacy of capecitabine‐based chemotherapy for CRC.

AUTHOR CONTRIBUTIONS

Hui‐Zhong Jiang and Ya‐Li Jiang conceived of and designed the study. They had full access to all data in the study and took responsibility for the integrity of the data, the accuracy of the data analysis, and the writing of the report. Yang Bing, Feng‐Xi Long, Zhu Yang, and Dong‐Xin Tang critically revised the report. Hui‐Zhong Jiang and Ya‐Li Jiang performed the statistical analyses. All the authors contributed to the data acquisition and analyses. The authors have reviewed and approved the final version of the manuscript.

CONFLICT OF INTEREST

The authors declare that they have no competing interests.

Supporting information

Figure S1

Figure S2;

Figure S3;

Figures S4‐S5

Click here for additional data file. (4MB, pdf)

Appendix S1

Click here for additional data file. (88.3KB, pdf)

Jiang H‐Z, Jiang Y‐L, Yang B, Long F‐X, Yang Z, Tang D‐X. Traditional Chinese medicines and capecitabine‐based chemotherapy for colorectal cancer treatment: A meta‐analysis. Cancer Med. 2023;12:236‐255. doi:  10.1002/cam4.4896

Funding information

This work was financially supported by the Key Research on “TCM Modernization” of National Key Research and Development Plan (2019YFC1712500, 2019YFC1712504), National Natural Science Foundation of China (nos. 81760814, 81860819, 81960818), Guizhou Traditional Chinese Medicine Tumor Inheritance and Science and Technology Innovation Talent Base (No. Deaf leader‐[2018] No. 3), Yang Zhu, Guizhou Province, “Traditional Chinese Medicine Oncology” Graduate Tutor Studio (no. Teaching and research GZS‐[2016]08), Guizhou high‐level innovative talent training plan (100 levels) (no. Yankehe Talents [2016] no. 4032), TCM graduate schoolworkstation (No. Teaching and research JYSZ‐[2014]018), The Big Health Science and Technology Cooperation Project of the First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine (No. Building branch [2019] 9–2, No. Building branch [2019] 9‐2‐35), Guizhou Province Traditional Chinese Medicine Oncology Inheritance and Scientific and Technological Innovation Talent Team (Qian Kehe Platform Talents [2020] 5013), Guizhou Provincial Science and Technology Plan Project (Qianke Foundation [2020] 1Y368).

Contributor Information

Zhu Yang, Email: yangzhu20150426@163.com.

Dong‐Xin Tang, Email: tangdongxin@sina.com.

DATA AVAILABILITY STATEMENT

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

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Associated Data

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Supplementary Materials

Figure S1

Figure S2;

Figure S3;

Figures S4‐S5

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Appendix S1

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Data Availability Statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

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