- Review
- Open access
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Traditional Chinese medicine in treating upper digestive tract cancers
Molecular Cancer volume 23, Article number: 250 (2024)
Abstract
Upper digestive tract cancers, such as oral cavity, laryngeal, esophageal, and gastric cancers, account for 10% of cancer cases and 14.5% of cancer-related deaths worldwide. Conventional treatments often provide limited survival benefits and are frequently associated with adverse effects and drug resistance. Chinese herbal drugs (CHDs) are widely used in the Far East for managing these cancers. In this narrative review, we summarize current clinical studies (published up to June 2024) on the use of 138 CHDs in the treatment of cancers and precancerous lesions of the upper digestive tract. For cancer treatment, 126 CHDs were tested, all in combination with conventional therapies. Each CHD increased the clinical efficacy and/or reduced the adverse effects of conventional therapies. The five-year survival rate is a critical metric for evaluating the clinical benefits of cancer treatments. Four of the CHDs were reported to increase five-year survival rates of patients receiving conventional therapies. The four CHDs are Sishen Jiedu Decoction, Pingxiao Tablet, Fuzheng Guben Granule, and Buyang Huanwu Tang. For managing precancerous lesions, 12 CHDs were tested: six used alone and six in combination with conventional therapies. Zengshengping is one of the CHDs used alone and is the only one that has been proven to prevent the development of esophageal cancer with convincing evidence. This review provides information about the clinical benefits of CHDs and offers a reference for their rational application in treating upper digestive tract cancers. The reviewed studies have limitations: most trials had small sample sizes and were not multi-center; only one study investigated the mechanisms of action of the studied CHD; and the active components of CHDs were not explored. To promote international recognition of CHDs, rigorously designed studies on clinical outcomes, mechanisms of action, and active components are warranted. Moreover, the studied CHDs should be standardized.
Introduction
The upper digestive tract encompasses the oral cavity, pharynx, esophagus, and stomach [1]. In 2022, upper digestive tract cancers, including lip and oral cavity, salivary gland, hypopharyngeal, oropharyngeal, laryngeal, esophageal, gastroesophageal junction, and gastric cancers, accounted for approximately 10% of all cancer cases, and 14.5% of cancer-related deaths worldwide (Fig. 1A) [2, 3]. By 2050, the number of upper digestive tract cancer cases is expected to increase by 79%, with a projected 86% rise in associated deaths (Fig. 1B) [4, 5]. The 5-year survival rates among upper digestive tract cancer patients are generally low [6]. Conventional treatments offer limited survival benefits and come with numerous adverse effects and drug resistance [7, 8]. As a result, up to 40% of upper digestive tract cancer patients seek complementary and alternative medicines (CAMs) [9, 10]. Traditional Chinese medicine (TCM), an ancient practice popular in the Far East region, is a typical CAM [11, 12]. Although Chinese herbal drugs (CHDs) have been used to treat diseases, including upper digestive tract cancers, for over 2,000 years [13], the lack of convincing clinical evidence and a poor understanding of their modes of action have led to the perception that their therapeutic benefits are questionable. In this review, we collate and discuss the results from randomized controlled clinical trials and preclinical research that investigate the use of CHDs in the treatment of upper digestive tract cancers, aiming to discern their clinical efficacy and underlying mechanisms of action.
Global cancer statistics. A Pie chart showing the percentage of cases and deaths with respect to each tumor type in 2022, globally. Data shown in the panel was obtained from GLOBOCAN 2022 [3]. B Bar chart depicting the number of cases and deaths of upper digestive tract cancers in 2022 and 2050, globally. Data shown in the panel was obtained from the Global Cancer Observatory: Cancer Tomorrow (version 1.1) [4]
Methods
Data sources and search methods
Papers, published in English or Chinese, were retrieved from PubMed, MEDLINE, Embase, Web of Science, Scopus, Cochrane Central Register of Controlled Trials, China Academic Journals Full-text Database (CNKI), China Online Journals (WANFANG Data), Weipu Database, Traditional Chinese Medicine Database System, and Airiti Library (from 1950 to June 2024).
The search strategy was constructed using a combination of MeSH subject headings and keywords related to CHDs to manage upper digestive tract cancers (Supplementary 1). Here, the term “Chinese herbal drugs” refers to TCM formulas, single herbs, phytocompounds, and combinations of phytocompounds.
Eligibility criteria
Clinical studies: randomized controlled clinical trials involving patients with lip and oral cavity, salivary gland, hypopharyngeal, oropharyngeal, laryngeal, esophageal, gastroesophageal junction, or gastric cancer; the number of patients in each group was greater than 30; herbal drug compositions were clearly described, and not modified during the clinical trial period.
Preclinical studies: pharmacological studies involving rodent animal model(s) of an upper digestive tract cancer, involving CHDs that have undergone clinical studies for the evaluation of their anticancer efficacy and were used in the same form as in the clinical studies, using multiple doses, and having positive control(s); chemical analyses involving CHDs that have undergone clinical efficacy evaluations for managing precancerous lesions and/or cancer in the upper digestive tract.
Results
Description of reviewed studies
We identified 181 eligible randomized controlled clinical studies (Fig. 2). Tables 1 & 2 summarize the details of the reviewed studies. The eligible clinical trials studied 3 types of cancer (laryngeal cancer, esophageal cancer, and gastric cancer) and 3 types of precancerous lesions (oral leukoplakia, esophageal epithelial hyperplasia, and gastric precancerous lesions). In cancer treatment, 126 CHDs were used as adjuvant to conventional therapies (Table 1). Table 1 is divided into four sub-tables based on the type of conventional therapies: radiotherapy, chemotherapy, chemoradiotherapy, and targeted therapy. For the management of precancerous lesions, six CHDs were used alone, while six others were used in combination with conventional therapies (Table 2).
Flow diagram of the screening process. In total, 181 clinical studies were selected for review. Low-quality study: a study in which the results do not support the authors' claims, or a study that lacks a clear description of the herbal drug composition
No preclinical pharmacological or chemical studies were eligible.
Table 3 summarizes the compositions of the reviewed CHDs.
We introduce the clinical study results of CHDs listed in Table 1 & 2 under five subtitles.
Results of reviewed studies
In patients receiving radiotherapy
Thirty-one eligible reports studied 27 CHDs in patients receiving radiotherapy. Twenty-one CHDs were tested in esophageal cancer patients, four were tested in esophageal squamous cell carcinoma (ESCC) patients, and two were tested in gastric cancer patients.
Bruceae Fructus Oil Injection, prepared with the oil derived from the fruit of Brucea javanica, is a proprietary herbal drug (PHD) approved by the National Medical Products Administration (NMPA) of China for treating cancer. It has been used in the treatment of diverse cancers for several decades [195]. In middle- and late-stage esophageal cancer patients, Bruceae Fructus Oil Injection in combination with radiotherapy significantly increased 1-year survival rate compared to radiotherapy alone (76.3% vs. 56.9%). It was also observed that the combination treatment significantly improved immune function, evidenced by increased CD4+ T cells and CD4+/CD8+ratio, and significantly reduced occurrence rate of esophagitis, compared to the mono radiotherapy. Of 76 patients, only one experienced Bruceae Fructus Oil Injection-induced fever [14]. In another study designed to assess the efficacy and safety of Bruceae Fructus Oil Injection in combination with radiotherapy in advanced esophageal cancer patients, the combination therapy exhibited higher 1-year and 2-year survival rates than single radiotherapy (1-year survival rate: 63.3% vs. 46.7%; 2-year survival rate: 33.3% vs. 20%). The combined treatment group had a higher white blood cell (WBC) count than the radiotherapy group. Among the 30 patients, only two experienced drug-associated fever [15]. Bruceae Fructus Oil Oral Liquid is an oral form PHD prepared with Bruceae Fructus Oil. In esophageal cancer patients, Bruceae Fructus Oil Oral Liquid combined with radiotherapy exhibited a higher objective response rate (ORR) than radiotherapy alone (77.5% vs. 47.5%). Patients receiving the combined therapy had a higher Karnofsky Performance Scale (KPS) score than those receiving radiotherapy alone, indicating that this PHD improved patients’ quality of life (QOL). In addition, Bruceae Fructus Oil Oral Liquid co-treatment reduced the incidence of radiotherapy-induced adverse effects, including myelosuppression (12.5% vs. 30%), nausea/vomiting (20% vs. 42.5%), as well as radiation esophagitis and pneumonitis (27.5% vs. 32.5%) [16]. Findings of these studies demonstrate that Bruceae Fructus Oil-based drugs can enhance the efficacy, and reduce the toxicities of radiotherapy, and can improve patients’ QOL in treating esophageal cancer [14, 15].
Pingxiao Tablet, an NMPA-approved anticancer drug developed based on the TCM theory of regulating blood [196], in combination with radiotherapy, significantly increased 1-, 3-, and 5-year survival rates of middle- and late-stage esophageal cancer patients compared to mono radiotherapy (1-year survival rate: 49% vs. 39.6%; 3-year survival rate: 32.1% vs. 17%; 5-year survival rate: 18.9% vs 9.4%) [17].
Huisheng Koufuye (Oral Liquid) was initially approved for treating liver and lung cancers in China [197]. A clinical trial showed that, in patients with esophageal cancer, radiotherapy plus Huisheng Koufuye (Oral Liquid) resulted in higher complete remission (CR) and 1-year survival rate compared to radiotherapy alone (CR: 71.7% vs. 45.7%; 1-year survival rate: 67.4% vs. 43.5%) [18]. Drug administration-associated adverse events were not observed in any of the 46 patients.
Irisquinone Capsule is an NMPA-approved radiosensitizer [198]. One study showed that Irisquinone Capsule plus radiotherapy group had higher 1- and 3-year survival rates than the mono radiotherapy group (1-year survival rate: 73.8% vs. 47.7%; 3-year survival rate: 35.4% vs 18.5%) in esophageal cancer patients [19]. Another study showed that Irisquinone Capsule significantly sensitized radiotherapy in esophageal cancer patients, evidenced by increased CR (combined therapy 80% vs. radiotherapy alone 40%) and 1-year survival rate (75% vs. 56.7%) [20]. In both studies, only mild gastrointestinal (GI) side effects (without affecting treatment adherence) associated with the use of Irisquinone Capsule were observed [19, 20].
Fuzheng Kangai Jiedu Formula (a 19-herb prescription created by a TCM doctor) combined with radiotherapy resulted in significantly longer progression-free survival (PFS) and median overall survival (mOS) of esophageal cancer patients than single radiotherapy (PFS: 12 months vs. 8 months; mOS: 23 months vs. 19 months). After a 4-month treatment, the combination therapy showed significantly better effects in lowering the serum levels of the tumor markers cytokeratin 19 fragment (CYFRA21-1) and glycochain antigen 19-9 (CA19-9). Moreover, the formula enhanced the immune function of esophageal cancer patients receiving radiotherapy, evidenced by increased CD3+ and CD4+ T cells, and decreased CD8+ T cells in the combined treatment group compared to those in the mono radiotherapy group [21].
Fuzheng Guben Granule (based on a 13-herb prescription created by a TCM doctor) in combination with radiotherapy achieved significantly higher CR and 1-, 3-, and 5-year survival rates in patients with middle- and late-stage esophageal cancer, compared to single radiotherapy (CR: combined therapy 62.1% vs. radiotherapy 44.0%. 1-year survival rate: 63.8% vs. 41.4%; 3-year survival rate: 29.3% vs. 14.7%; 5-year survival rate: 19.0% vs 7.6%). Meanwhile, significantly increased WBC counts, haemoglobin (Hb) content, and platelete counts, as well as significantly reduced occurrence rate of esophagitis, were observed in the combined therapy group compared to the mono radiotherapy group [22].
Aiyishu Injection is an NMPA-approved anticancer drug comprising of sodium cantharidate and vitamin B6. Combining this drug with radiotherapy significantly increased disease control rate (DCR) in patients with esophageal cancer (combined therapy 81.39% vs. radiotherapy 58.14%) [23].
Elemene Injection is an anticancer PHD comprising β-, γ-, and δ-elemene isolated from Curcumae Rhizoma. In two studies, combined use of Elemene Injection and radiotherapy resulted in a significantly higher ORR than single radiotherapy (97.5% vs. 80% [24] and 63.33% vs. 36.67% [25]) in patients with esophageal cancer. More CD4+ and CD3+ T cells, higher WBC count and CD4+/CD8+ ratio, as well as less CD8+ cells, were observed in the combined treatment group than in the mono radiotherapy group. The combination effectively lowered serum levels of the tumor markers CEA and CA19-9 more than radiotherapy alone. In addition, a higher KPS score was achieved in patients of the combination group, indicating that Elemene Injection improved QOL of patients undergoing radiotherapy [24, 25].
Fufang Danshen Injection was initially approved in China for treating coronary heart disease, angina pectoris and acute myocardial infarction. An article reported that Fufang Danshen Injection in combination with radiotherapy exhibited higher ORR than single radiotherapy in esophageal cancer patients (88.9% vs. 76.2%). It also increased the WBC count and improved the transcription activity of rDNA in the peripheral lymphocytes of patients receiving radiotherapy, indicating that it can enhance immune function of the patients [26].
Fufang Kushen Injection is an NMPA-approved anticancer adjuvant drug prepared with Sophorae Flavescentis Radix and Heterosmilacis Rhizoma. A clinical trial showed that, in patients with esophageal cancer, radiotherapy plus Fufang Kushen Injection resulted in higher CR compared to radiotherapy alone (33.3% vs. 10%). Patients in the combined treatment group exhibited better appetite, higher KPS score, and greater body weight gain than patients in the radiotherapy group, indicating that this injection improved the QOL of patients undergoing radiotherapy [27].
Fuzheng Yiliu Granule (based on a 4-herb prescription created by a TCM doctor), combined with radiotherapy resulted in a higher rosette rate of the red cell C3b receptor (RBC-C3bRR) and lower red blood cell immune complex rosette rate (RBC-ICRR) in esophageal cancer patients than single radiotherapy, indicating that it enhanced the immune function of cancer patients receiving radiotherapy. Moreover, this prescription significantly lowered the tumor metastatic marker CD44v6 in patients receiving radiotherapy [28].
Huachansu Capsule is a PHD prepared from the lipophilic components of Bufonis Corium. This drug in combination with radiotherapy achieved significantly higher ORR than single radiotherapy in treating esophageal cancer (89.47% vs. 68.42%). Meanwhile, the incidence of adverse effects (leukopenia, esophagitis, nausea, and myalgia) was lower in patients receiving the combined treatment compared to those receiving radiotherapy alone [29].
Kanglaite Injection is an NMPA-approved anticancer drug prepared from the oil of Coicis Semen. A study showed that the incidence of adverse reactions (fatigue, leukopenia and loss of appetite) caused by radiotherapy in esophageal cancer patients was significantly decreased by Kanglaite Injection [30].
Modified Liuwei Dihuang Decoction is an 8-herb prescription created by a TCM doctor. It improved the immune function of esophageal cancer patients receiving radiotherapy (CD4+/CD8+ ratio: combined therapy 1.4 vs. radiotherapy 1.2). Meanwhile, this prescription decreased the incidence of radiotherapy-induced adverse effects from 83.3% to 56.7%, and significantly improved the physical power of the patients [31].
Shenqi Liuwei Dihuang Decoction is an 8-herb prescription created by a TCM doctor. It has been shown to enhance the efficacy of radiotherapy in esophageal cancer patients. The ORR was higher in Shenqi Liuwei Dihuang Decoction plus radiotherapy group than in the mono radiotherapy group (81.8% vs. 75.5%). Patients in the combined treatment group had a lower probability of suffering from radiotherapy-induced adverse effects compared to patients in the mono-radiotherapy treatment group [32].
Si Jun Zi Tang, a classical TCM formula, is commonly used by TCM doctors for tonifying Qi. A study showed that this formula enhanced the clinical efficacy of radiotherapy in esophageal cancer patients, evidenced by an elevated ORR (combined therapy 62.5% vs. radiotherapy 37.5%) [33].
Xiangsha Bazhen Decoction is a 14-herb prescription created by a TCM doctor. This prescription has been proven to markedly increase CD4+ T cells and decrease CD8+ T cells in esophageal cancer patients receiving radiotherapy, suggesting that it enhanced the immune function of the patients. The incidence of adverse effects (vomiting and leukopenia) caused by radiotherapy was significantly reduced by the prescription [34].
In two reports, Sishen Jiedu Decoction (a 14-herb prescription created by a TCM doctor) combined with radiotherapy achieved significantly higher ORR (93.33% vs. 73.33% in one report, 92% vs. 75% in the other report) in the treatment of esophageal cancer compared to radiotherapy alone. Meanwhile, the prescription significantly reduced the occurrence rates of radiotherapy-induced adverse effects (radiation esophagitis, radiation pneumonitis, leukopenia and thrombocytopenia). QOL of patients receiving combined treatment was better than that of patients receiving radiotherapy only [35, 36].
Xuefu Zhuyu Decoction is a classical TCM formula that can protect esophageal cancer patients from radiotherapy-induced myelosuppression. Higher WBC, RBC and platelet counts were observed in the combined treatment group than in the mono radiotherapy group [37].
Yangzheng Xiaoji Capsule is a PHD that has been demonstrated to improve the QOL of esophageal cancer patients undergoing radiotherapy. The Quality of Life Questionnaire-Core 30 (QLQ-C30) and Quality of Life Questionnaire-Oesophageal Module 18 (QLQ-OES18) symptom scores were lower in the combination treatment group than in the radiotherapy group [38].
Antike Capsule, an NMPA-approved adjuvant drug for treating ESCC, combined with radiotherapy resulted in a significantly higher ORR in the treatment of ESCC than single radiotherapy (96.9% vs. 78.1%). Clinical symptoms of the ESCC patients, including eating disorders, chest pain and back pain, disappeared more quickly in the combined treatment group than in the mono radiotherapy group. Drug treatment-associated nausea was observed [39].
Liushen Pill is another PHD that can improve the efficacy of radiotherapy in ESCC treatment. Liushen Pill in combination with radiotherapy achieved significantly higher ORR than radiotherapy alone (75.76% vs. 50.0%). It also down-regulated vascular endothelial growth factor (VEGF) expression and reduced micro-vessel density in ESCC patients receiving radiotherapy, indicating that the combination therapy exhibited better anti-angiogenic effects in ESCC patients than radiotherapy alone [40].
Astragalus Polysaccharide Injection is a PHD prepared with the TCM herb Astragali Radix. It can increase ORR in ESCC patients receiving radiotherapy (76.6% vs. 50.0%). Patients receiving combined treatment had higher KPS score and greater body weight gain than patients receiving radiotherapy alone, indicating that the injection improved patients’ QOL [41].
Lianqi Capsule is a PHD used for treating lung, liver, and esophageal cancers. In advanced ESCC patients, the combination of Lianqi Capsule and radiotherapy significantly lowered serum levels of three tumor markers (CEA, SCC-Ag, and CYFRA21-1), and showed more potent effects than radiotherapy alone. Meanwhile, this PHD improved the immune function of ESCC patients receiving radiotherapy, indicated by higher CD4+ T cell count, lower CD8+ cell count and higher CD4+/CD8+ ratio in the combined treatment group compared to the radiotherapy group [42].
Modified Fuzheng Guben Quxie Decoction (a 13-herb prescription created by a TCM doctor) combined with radiotherapy achieved longer PFS and mOS, as well as higher 1-year survival rate in stage III-IV gastric cancer treatment compared to radiotherapy alone. In the combined treatment group, serum levels of the tumor markers CEA, CA19-9, and macrophage inflammatory protein 3α (MIP-3α, also known as CCL20), and the score of patient-generated subjective global assessment (PG-SGA, a patient-reported instrument for assessment of nutritional risk and nutritional deficit in patients with cancer) were lower compared to the radiotherapy group. It was also demonstrated that CD3+ and CD4+ T cells were more, and CD4+/CD8+ ratio was higher in the combined treatment group than in the mono radiotherapy group, indicating that this herbal prescription enhanced immune function of the gastric cancer patients receiving radiotherapy [43].
Yangzheng Sanjie Decoction is a 13-herb prescription created by a TCM doctor. This decoction in combination with radiotherapy resulted in a higher DCR than radiotherapy alone (97.56% vs. 82.50%). The combination therapy more effectively lowered serum levels of three tumor markers in gastric cancer patients: CEA, VEGF, and CD44v6, compared to radiotherapy alone. Higher serum motilin level, and lower serum D-lactic acid level were observed in the combination treatment group than in the radiotherapy group, indicating that this CHD improved the GI function of patients receiving radiotherapy [44].
In patients receiving chemotherapy
A total of 114 eligible clinical studies tested the clinical use of 104 CHDs as adjuvants to chemotherapies in cancer patients (22 studies on esophageal cancer, 90 on gastric cancer, and 2 on laryngeal cancer). In one of the clinical trials, potential anticancer mechanisms of Liu Jun Zi Tang were explored. Among the 104 CHDs, 28 are NMPA-approved PHDs.
In patients receiving fluoropyrimidine-based chemotherapeutics
5-fluorouracil (5-FU) and its oral prodrugs, such as tegafur, S-1, and capecitabine, are widely used in the treatment of various cancers including upper digestive tract cancers. Twelve eligible studies reported the combinational use of individual fluoropyrimidine-based chemotherapeutics and CHDs for treating gastric cancer.
Bo-Er-Ning Capsule (BENC), derived from an 11-herb prescription, is a PHD approved as an adjuvant to cancer therapies in China. It was reported that the ORR of stage IV gastric cancer patients was higher in the group treated with the combination of BENC and S-1 than in the group treated with S-1 alone (56.67% vs. 36.67%) [45]. Forty percent of patients in the combination therapy group showed a >10% increase in KPS score, compared to 13% in the S-1 monotherapy group. The incidence of myelosuppression (23.33% vs. 50%) and GI disorders (26.67% vs. 43.33%) was lower in the combined therapy group than in the S-1 monotherapy group. This study suggests that BENC can enhance the anti-gastric cancer effects of S-1, mitigate S-1-induced side effects, and improve QOL of the patients.
Another report showed that Yangzheng Xiaoji Capsule (a PHD), combined with capecitabine, lowered serum level of the tumor marker CEA in gastric cancer patients more effectively than capecitabine alone [46]. The patients in the combination group had a higher QLQ-C30 function score compared to patients in the capecitabine monotherapy group. These results indicate that the TCM capsule enhanced the anticancer efficacy of capecitabine, and enhanced QOL of the patients.
Two clinical trials tested Shenyi Jianzhong Decoction (an 11-herb prescription created by a TCM doctor) in combination with S-1 for treating gastric cancer [47, 48]. The ORR of patients was higher in the combination group than in the S-1 group. Patients in the combination group showed a greater increase in KPS score compared to the S-1 group, indicating that this herbal prescription enhanced the anti-gastric cancer efficacy of S-1 and improved patients’ QOL.
Fuzheng Jiedu Quyu Method-based Formula (FJQR) is a 6-herb prescription from the First Teaching Hospital of Tianjin University of Traditional Chinese Medicine. FJQR combined with capecitabine improved the ORR of patients with advanced HER-2 negative gastric cancer (9.4% vs. 6.2%). The incidence of grade III-IV adverse events, including leukopenia, anemia, and nausea/vomiting, was lower in the combination group compared to the capecitabine monotreatment group [49].
Xiaoai Decoction (a 5-herb prescription created by a TCM doctor) in combination with 5-FU increased the ORR of postoperative gastric cancer patients (combination therapy vs. 5-FU alone: 89.8% vs. 75.5%) [50]. The combination therapy group showed higher 1-year (87.2% vs. 76.1%) and 2-year (19.1% vs. 10.8%) survival rates, and longer PFS (20.98 months vs. 18.71 months) and mOS (18.41 months vs. 16.51 months) compared to the 5-FU monotherapy group, indicating that Xiaoai Decoction potentiates the anticancer efficacy of 5-FU.
Some CHDs have also been shown to enhance the anticancer efficacy of fluoropyrimidines. For instance, Buyang Huanwu Tang (a classical TCM formula) combined with 5-FU resulted in a higher 5-year survival rate compared to 5-FU alone in gastric cancer patients (12.5% vs. 0%) [51]; Fufang Hongdoushan Capsule (a PHD approved as an adjuvant to cancer therapies) combined with S-1 showed increased ORR in gastric cancer patients compared to S-1 monotherapy (60% vs. 43.3%) [52]; Shenqi Jianwei Decoction (an 11-herb prescription created by a TCM doctor) combined with S-1 achieved a higher ORR in gastric cancer patients, compared to S-1 monotherapy (90% vs. 60%) [53]; and Jiawei Lizhong Decoction (a 5-herb prescription created by a TCM doctor) combined with S-1 resulted in a higher ORR compared to S-1 alone (82.22% vs. 62.22%) in gastric cancer patients, and the combination also reduced nausea and vomiting caused by S-1 [54]. The Japanese herbal medicine Hochu-ekki-to (whose composition is the same as the classical TCM formula Buzhong Yiqi Tang) was reported to reduce the occurrence of adverse events, including thrombocytopenia, nausea, vomiting, diarrhea, and appetite loss caused by S-1 treatment in stage II/III gastric cancer patients [55]. Jianpi Huazheng Decoction (a 19-herb prescription created by a TCM doctor) did not enhance the anticancer efficacy of tegafur in gastric cancer, but it was able to increase patient KPS score (the decoction + tegafur vs. tegafur alone: 72.12 vs. 65.98) [56], indicating a QOL benefit in patients.
In patients receiving CF regimen
Cisplatin in combination with 5-FU, commonly referred to as CF regimen, is one of the recommended therapies for locally advanced esophageal cancer. Six reports studied the combination of CHDs and CF regimen for treating esophageal cancer.
Sishen Jiedu Decoction combined with CF regimen resulted in a higher ORR in stage II-III esophageal cancer patients compared to CF regimen alone (90.48% vs 69.05%) [57]. The 1-year, 3-year, and 5-year survival rates of patients receiving the decoction-plus-CF regimen were 88.10%, 71.43%, and 52.38%, respectively, and those of patients who only received CF regimen were 66.67%, 45.24%, and 28.57%, respectively. The incidence of adverse effects such as leukopenia and thrombocytopenia was lower, and the KPS score was higher, in the combined treatment group than in the CF regimen group.
Another CHD that has been shown to enhance the efficacy of CF regimen is Tongguanteng Oral Solution [58], a PHD approved by the NMPA of China. Combination of this oral solution with CF regimen elevated the ORR of stage II-IV esophageal cancer patients (the oral solution + CF regimen vs. CF regimen: 75% vs. 52.5%). Patients receiving the oral solution-plus-CF regimen demonstrated a marked increase in peripheral NK cells and CD4+/CD8+ ratio, compared to the patients receiving CF regimen alone. In addition, the incidence of leukopenia, thrombocytopenia, and nausea/vomiting was significantly lower in the combined treatment group than in CF regimen group.
Xiaoaiping Tablet and Tongguanteng Oral Solution both are PHDs developed from the extracts of Caulis Marsdeniae Tenacissimae (Tongguanteng), the dry rattan stem of Marsdenia tenacissima (Roxburgh) Moon. Compared to the CF regimen alone, the combination of Xiaoaiping Tablet and CF regimen increased peripheral NK cells and CD4+/CD8+ ratio in patients with stage III-IV esophageal cancer. The tablet-plus-CF regimen decreased serum levels of tumor markers [cancer antigen 125 (CA125), CEA and CA19-9], and angiogenesis and metastasis-associated biomarkers [VEGF, transforming growth factor-β1 (TGF-β1), matrix metalloproteinase-9 (MMP-9), and neutrophil gelatinase-associated lipocalin (NGAL)] in these patients [59]. These findings [58, 59] indicate that drugs derived from Caulis Marsdeniae Tenacissimae enhance the anticancer efficacy and reduce the adverse effects of CF regimen, and may boost immune function of the esophageal cancer patients.
Some clinical studies revealed that combining certain CHDs with CF regimen may not enhance the efficacy of CF regimen in treating esophageal cancer, but could alleviate its side effects in patients. For instance, compared to the CF regimen, Fuzheng Guben Decoction (a 13-herb prescription created by a TCM doctor) combined with CF regimen significantly reduced the incidence of vomiting (combined treatment 25% vs. CF regimen 50%), thrombocytopenia (0% vs. 12.5%), and constipation or diarrhea (0% vs. 5.2%) [60]; Xuanfu Daizhe Tang, a classical TCM formula, combined with the CF regimen decreased the occurrence of severe GI reactions (3.3% vs. 30.0%) and serious myelosuppression (6.7% vs. 33.3%) [61]; Ye Ge Yin No.2 (a 10-herb prescription created by a TCM doctor) combined with CF regimen reduced the rates of vomiting (26.7% vs. 46.7%), hepatic and renal function impairment (3.3% vs. 6.7%), and leukopenia (20% vs. 30%) [62].
The CF regimen is also utilized for treating gastric cancer. Bo-Er-Ning Capsule (BENC) in combination with CF regimen significantly prolonged mOS of stage IV gastric cancer patients (BENC + CF regimen vs. CF regimen: 23.57 months vs. 18.75 months) [63]. Higher KPS score and greater body weight gain in the BENC-plus-CF regimen group than in the TC regimen group indicated that the adjuvant therapy with BENC improved the QOL of the patients. The researchers then explored the anticancer mechanisms of BENC using the bioinformatics tool BATMAN-TCM. Enrichment analysis indicated that BENC influenced various cellular processes, including cell proliferation, cell cycle arrest, and apoptosis, which were further validated in gastric cell and/or animal models. The molecular mechanisms underlying BENC's anti-gastric cancer effects and its ability to enhance the efficacy of the CF regimen remain unclear and warrant further investigation.
In patients receiving taxanes plus platinum-based regimens
Platinum-based agents (cisplatin, carboplatin, and oxaliplatin) combined with taxanes (paclitaxel and docetaxel) are commonly used chemotherapies for treating esophageal and gastric cancers.
Shidao Tongjie Formula (a 7-herb prescription created by a TCM doctor) combined with PC regimen (paclitaxel-plus-carboplatin) improved survival in patients with stage IIb-IV esophageal cancer, compared to PC regimen alone (3-year survival rate: 48.6% vs. 25.0%) [64]. This herbal prescription combined with PC regimen increased peripheral NK cells, CD3+ cells and CD4+/CD8+ ratio compared to PC regimen alone, indicating that the herbal prescription improved the immune function of patients receiving PC regimen.
Two reports tested Shidao Tongjie Granule (a PHD with a similar herbal composition to Shidao Tongjie Formula) in combination with TP regimen (docetaxel-plus-cisplatin) for treating stage IIb-IIIc and IIb-IVb esophageal cancer [65, 66]. Patients treated with the combination of the granules and TP regimen had longer median disease-free survival (mDFS) than those treated with TP regimen alone (34.6 months vs. 23.2 months). This combination therapy also improved the ORR of the patients with stage IIb-IVb esophageal cancer (combination therapy vs. TP regimen: 55.00% vs. 32.50%), reduced chemotherapy-related adverse effects, including leukopenia, thrombocytopenia, anemia, and nausea/vomiting, and increased peripheral CD3+ cells, CD4+ cells, CD4+/CD8+ ratio, and NK cells of the patients. These studies suggest that Shidao Tongjie Formula combined with TP regimen and Shidao Tongjie Granule combined with TP regimen can serve as preferential options for treating advanced esophageal cancer.
Esophageal Pingsan, a PHD approved by NMPA as an adjuvant for treating esophageal and gastric cancers, was shown to enhance the anticancer efficacy of TP regimen in patients with stage I-III esophageal cancer (ORR: Esophageal Pingsan + TP regimen 93.33% vs. TP regimen 63.33%) [67]. A lower QLQ-OES18 symptom score was observed in the group receiving the combination treatment than in the group receiving TP regimen monotreatment, indicating that Esophageal Pingsan improved the QOL of the patients.
One report showed that, when compared to TP regimen monotreatment, the combination of Lianqi Capsule (a PHD) with TP regimen not only increased ORR (Lianqi + TP regimen vs. TP regimen: 40% vs. 25%) but also enhanced DCR (75% vs. 53.33%) of stage IV esophageal cancer patients [68]. Patients in the Lianqi Capsule-plus-TP regimen group reported a higher QLQ-C30 function score and KPS score compared to patients in the TP regimen group. However, the incidence of adverse reactions between the two groups was not significantly different.
Yunzhitangtai Capsule, another approved PHD, combined with PC regimen [69] or combined with docetaxel-plus-nedaplatin regimen [70] has been reported to improve ORR and DCR of patients with advanced esophageal cancer. Higher QLQ-C30 and SF-36 (36-Item Short Form Survey) function scores in the two combination groups than in the corresponding chemotherapy group indicate that Yunzhitangtai Capsule improved the QOL of the patients receiving these chemotherapies.
The PHD Tongguanteng Oral Liquid (Solution) in combination with docetaxel-plus-nedaplatin regimen elevated ORR of stage III/IV esophageal cancer patients, compared to the docetaxel-plus-nedaplatin regimen alone (78.13% vs. 53.13%) [71]. The combination of the solution and the docetaxel-plus-nedaplatin regimen also improved KPS score and QLQ-C30 function score, increased peripheral NK cells and NKT cells, and reduced the occurrence rates of myelosuppression, hepatic and renal impairment, and GI disorders. This report further supports the clinical use of PHDs developed from the extracts of Caulis Marsdeniae Tenacissimae as adjuvants to chemotherapies for upper digestive tract cancers.
In addition to PHDs, some herbal prescriptions combined with platinum- and taxane-based chemotherapies, e.g. Jianpi Wenzhong Tang [72], Tongye Tang [73] and Liu Jun Zi Tang [74] respectively combined with cisplatin-plus-docetaxel, and Shenzhu Jiedu Tang [75] and Jianpi Tongluo Decoction [76] respectively combined with TP regimen, enhanced ORR of patients with gastric cancer or esophageal cancer compared to the corresponding mono chemotherapy. These combinations also mitigated chemotherapy-related side effects, i.e. nausea, vomiting, diarrhea, thrombocytopenia, and/or hepatic and renal toxicities. Mechanistic studies indicate that Liu Jun Zi Tang in combination with cisplatin-plus-docetaxel, lowered the serum levels of TGFβ1RI (transforming growth factor β1 type I receptor; related to cell proliferation) and TGFβ1RII, while upregulated the protein level of Smad7 (mothers against decapentaplegic homolog 7, a tumor suppressor) in the esophageal cancer patients, suggesting that the combination exerted anticancer effects potentially by regulating TGFβ1/Smad7 signaling [74].
In patients receiving DCF regimen
DCF regimen, comprising docetaxel, cisplatin, and 5-FU, is a first-line chemotherapy regimen for advanced gastric cancer.
The PHD Bruceae Fructus Oil Oral Liquid in combination with DCF regimen increased the ORR of gastric cancer patients compared to DCF regimen alone (56.3% vs. 38.8%) [77]. More patients in the oral liquid-plus-DCF regimen group showed a >10% increase in KPS score than in the DCF regimen group (56.3% vs. 34.7%), indicating that the PHD improved the QOL of patients receiving DCF regimen. Shenhu Banxia Decoction (a 5-herb prescription created by a TCM doctor) combined with DCF regimen resulted in lower EORTC QLQ-C30 symptom score and higher KPS score compared to the DCF regimen alone [78], indicating that the combination is superior to DCF regimen alone in improving patients’ QOL. Shenhu Banxia Decoction increased CR of patients receiving DCF regimen (the decoction + DCF regimen vs. DCF regimen: 53.13% vs. 28.13%) [78].
Xiangsha Liujunzi Tang, a TCM formula, in combination with DCF regimen resulted in higher 1-year, 2-year, and 3-year survival rates compared to DCF regimen alone (1-year: 69.70% vs. 51.52%; 2-year: 48.48% vs. 33.33%; 3-year: 27.27% vs. 12.12%) [79]. The incidence of GI reactions was lower in the combination group than in the DCF regimen group. After treatment with the combination of Xiangsha Liujunzi Tang and DCF regimen, the QLQ-C30 function score of patients was significantly higher than those in the DCF regimen group, indicating that Xiangsha Liujunzi Tang improved the QOL of patients receiving the DCF regimen.
Matrine Injection (main active ingredient: matrine) is a PHD used to treat hepatitis and alleviate leukopenia caused by radiotherapy and chemotherapy. Compared to the DCF regimen alone, the combination of DCF regimen and the injection significantly mitigated myelosuppressive toxicity, reduced nausea, vomiting, hair loss, and hepatic and renal function impairment in the patients, and led to an increase in patient body weight, indicating that Matrine Injection can alleviate the toxicities associated with the DCF regimen [80].
In addition to treating gastric cancer, DCF regimen is also used clinically to treat laryngeal cancer. Two clinical studies tested the efficacy of Pingxiao Capsule, a PHD containing the same herbal components as Pingxiao Tablet, combined with DCF regimen for treating locally advanced laryngeal cancer [81, 82]. Post-treatment outcomes revealed that ORRs were markedly higher in the Pingxiao Capsule-plus-DCF regimen group than in the DCF regimen group (one study: 66.67% vs. 46.15%; the other study: 77.78% vs. 55.56%). Patients receiving the capsule plus DCF regimen had higher WHOQOL-BREF score than those receiving DCF regimen monotreatment, indicating that Pingxiao Capsule improved the QOL of patients receiving DCF regimen treatment. Serum levels of tumor markers [cancer antigen 72-4 (CA72-4), CA19-9, SCC-Ag, CYFRA21-1], and angiogenic and cell invasion factors [soluble tumor necrosis factor receptor I (sTNFRI), VEGF, MMP-9, β2-MG] were lowered, and peripheral CD4+ cells, CD3+ cells, and CD4+/CD8+ ratio were increased in patients receiving the capsule-plus-DCF regimen compared to those patients receiving DCF regimen. These findings demonstrated that Pingxiao Capsule enhanced the treatment outcomes of the DCF regimen in locally advanced laryngeal cancer, and improved QOL and boosted immune function of the patients.
Some chemotherapy regimens/combinations are derived from the DCF regimen, i.e. DOF regimen (docetaxel + oxaliplatin + 5-FU), TEX regimen (docetaxel + capecitabine + oxaliplatin) and the chemotherapy combination of paclitaxel, oxaliplatin, and 5-FU. Fuzi Lizhong Tang, a TCM formula, in combination with DOF regimen has been shown to decrease peripheral CD8+ cells and increase CD4+/CD8+ ratio, and lower incidence of adverse effects, such as anemia, vomiting/nausea, and thrombocytopenia, in gastric cancer patients compared to DOF regimen alone [83]. The combination of paclitaxel + oxaliplatin + 5-FU and a 15-herb prescription of Yunnan Provincial Hospital of Traditional Chinese Medicine has been shown to reduce the incidence of anorexia (16.28% vs. 48.84%), leukopenia (16.28% vs. 65.12%), and thrombocytopenia (20.93% vs. 67.44%) compared to the chemotherapy alone [84] in patients with gastric cancer. The anticancer PHD Kanglaite Injection in combination with TEX regimen increased the ORR of gastric cancer patients compared to TEX regimen alone (40% vs. 16.7%) [85]. The incidence of adverse events including leukopenia (50% vs. 63.3%), thrombocytopenia (30% vs. 43.3%), diarrhea (33.3% vs. 46.7%) and nausea/vomiting (53.3% vs. 66.7%) was lower in the injection-plus-TEX regimen group than in the TEX regimen group. Kanglaite Injection also improved the QOL of the patients receiving the TEX regimen, evidenced by higher KPS score in the combination group than in the TEX regimen group.
In patients receiving FOLFOX regimen
FOLFOX regimen, a chemotherapy combination that comprises 5-FU, leucovorin, and oxaliplatin, is widely used for treating cancer. Based on the differences in drug dosage and administration methods, the FOLFOX regimen can be divided into FOLFOX4, FOLFOX6, and mFOLFOX6 regimens. Twenty-six research articles have reported the therapeutic effects of the FOLFOX regimen in combination with 26 CHDs for the treatment of gastric cancer.
Thirteen CHDs improved the efficacy and reduced the adverse effects of FOLFOX regimen. Cidan Capsule, an NMPA-approved PHD, prolonged the mOS of patients treated with FOLFOX regimen (9.2 months vs. 8 months) [86]. Jianpi Hewei Ke’ai Tang [87] and Jianwei Sanjie Prescription [88], two multi-herb prescriptions created by TCM doctors, prolonged PFS of patients treated with FOLFOX regimen. Four multi-herb prescriptions created by TCM doctors (i.e. Shengxue Tang [89], Huazhuo Hewei Sanjie Tang [90], Wenyang Huazheng Tang [91] and Xinye County Hospital of Traditional Chinese Medicine-prepared Decoction [92]) and a combination of NMPA-approved PHDs (Huangqi Injection + Danshen Injection [93]) have been shown to prolong the OS of patients receiving FOLFOX regimen. FOLFOX regimen in combination with each of the eight multi-herb prescriptions created by TCM doctors, i.e. Shengxue Tang (64.4% vs. 51.2%) [89], Xiangsha Liujunzi Tang (48% vs. 57%) [94], Jianpi Huayu Tang (86.66% vs. 63.33%) [95], Buxu Jiedu Tang (89.4% vs. 72.3%) [96], Jianpi Yangwei Tang (51.19% vs. 35.71%) [97], Mianyang Hospital of Traditional Chinese Medicine-prepared Jianpi Huayu Tang (56.25% vs. 41.67%) [98], the PHD Cidan Capsule (65.6% vs. 52.9%) [86], or the PHD combination Huangqi Injection plus Danshen Injection (61.54% vs. 36.38%) [93], achieved significantly higher ORR than the FOLFOX regimen alone. FOLFOX regimen in combination with Huazhuo Hewei Sanjie Tang achieved significantly higher DCR than FOLFOX regimen alone (72.22% vs. 46.67%) [90]. All thirteen CHDs mentioned above can reduce the incidence of adverse effects caused by FOLFOX regimen, including GI reactions, myelosuppression, liver and kidney injury, and leukopenia.
Among the 13 CHDs, six (Jianpi Hewei Ke’ai Tang, Xiangsha Liujunzi Tang, Jianpi Huayu Tang, Jianwei Sanjie Prescription, Buxu Jiedu Tang and Mianyang Hospital of Traditional Chinese Medicine-prepared Jianpi Huayu Tang) improved the QOL of patients undergoing FOLFOX regimen. In addition, FOLFOX regimen in combination with Huangqi Injection + Danshen Injection was able to effectively down-regulate the serum levels of VEGF and CEA [93]; and in combination with Jianwei Sanjie Prescription had better effects in down-regulating serum levels of the tumor markers CA19-9, CA72-4, and CEA compared to FOLFOX regimen alone [88].
Two TCM prescriptions (Fuzheng Xiaozheng Tang and Modified Xuezheng Decoction) improved the efficacy of FOLFOX regimen without relieving the adverse effects induced by the FOLFOX regimen. Fuzheng Xiaozheng Tang in combination with FOLFOX regimen achieved higher ORR than single chemotherapy (24% vs. 13%) [99, 100]. Modified Xuezheng Decoction in combination with FOLFOX regimen, achieved significantly higher ORR than single chemotherapy (57.69% vs. 36.54%) [101]. The QLQ-C30 function score was higher in the Fuzheng Xiaozheng Tang-plus-FOLFOX regimen group than in the FOLFOX regimen group, indicating that it enhanced the QOL of patients receiving FOLFOX regimen [99, 100].
Five CHDs improved immune function of patients receiving FOLFOX regimen. Elemene Injection increased CD3+, CD4+ T cells and CD4+/CD8+ ratio [102]; Huayu Jianpi Tang [103] and Mianyang Hospital of Traditional Chinese Medicine-prepared Jianpi Huayu Tang increased CD3+ and CD4+ T cells [98]; Shiyiwei Shenqi Tang increased CD4+/CD8+ ratio [104] in patients receiving FOLFOX regimen. One of the five CHDs (Shiyiwei Shenqi Tang), in combination with FOLFOX regimen, achieved significantly higher ORR than single FOLFOX regimen (94.12% vs. 67.65%) [104]. Combined FOLFOX regimen with Elemene Injection or Modified Shenling Baizhu Tang reduced the occurrence rate of chemotherapy-induced adverse effects (erythropenia, leukopenia and thrombocytopenia for Elemene Injection; GI reactions for Modified Shenling Baizhu Tang). Meanwhile, co-treatment with FOLFOX regimen and Elemene Injection, Huayu Jianpi Tang or Modified Shenling Baizhu Tang significantly enhanced patients’ QOL. Moreover, one of the five CHDs, Huayu Jianpi Tang, has been shown to down-regulate serum levels of tumor marker: CEA, CA19-9, and CA125, in patients receiving FOLFOX regimen [103].
Six TCM prescriptions (Fuzheng Jianpi Tang + Jianpi Hewei Tang [106], Jianpi Bushen Yiqi Yangxue Prescription [107], Liujunzi + Tengligen Tang [108], Qingdao Tumor Hospital-prepared Decoction [109], Weifu Tang [110], and Zibo Hospital of Traditional Chinese Medicine-prepared Prescription [111]) markedly improved the QOL of gastric cancer patients undergoing the FOLFOX regimen. Meanwhile, four of them (i.e. Fuzheng Jianpi Tang + Jianpi Hewei Tang, Liujunzi + Tengligen Tang, Weifu Tang, and Zibo Hospital of Traditional Chinese Medicine-prepared Prescription) reduced the incidence of adverse effects caused by chemotherapy (e.g. GI reactions, myelosuppression, leukopenia, weak and neurotoxicity). Zibo Hospital of Traditional Chinese Medicine-prepared Prescription down-regulated serum levels of the tumor markers CEA, CA19-9, and pepsinogen I (PGI) in gastric cancer patients receiving chemotherapy [111].
A research article has reported the effects of Modified Shenling Baizhu Tang in regulating gut microbiota and improving intestinal barrier function. FOLFOX regimen in combination with this CHD exhibited better effects in down-regulating serum levels of intestinal barrier markers (Diamine oxidase, D-lactate, and endotoxin) compared to mono chemotherapy. This CHD in combination with FOLFOX regimen also increased the numbers of Lactobacillus and Bifidobacterium, as well as reduced the numbers of Enterococcus, Staphylococcus and Peptostreptococcus in faeces of patients compared to FOLFOX regimen alone [105].
In patients receiving SOX regimen
SOX regimen, a chemotherapy combination comprising S-1 and oxaliplatin, is widely used for treating cancers, especially gastric cancer. Recently, 18 research articles have reported the effects of combining each of the 17 CHDs with a SOX regimen in treating gastric cancer.
Thirteen CHDs improved the efficacy of the SOX regimen. Huosu Yangwei Oral Liquid, an NMPA-approved PHD, prolonged mOS of patients receiving SOX regimen (combined treatment 8.8 months vs. SOX regimen treatment 7.4 months) [112, 113]. Putuo Hospital Affiliated to Shanghai University of Traditional Chinese Medicine-prepared Jianpi Jiedu Tang, a 7-herb prescription, combined with SOX regimen, resulted in a higher 1-year survival rate compared to SOX regimen alone (32.3% vs. 9.6%) [114]. Two NMPA-approved PHDs, i.e. Aidi Injection (DCR: 87% vs. 67%, 93.75% vs. 68.65%; ORR: 57% vs. 27%, 68.75% vs. 40.63%) [115, 116] and Huosu Yangwei Oral Liquid (DCR: 60.6% vs. 40.8%; ORR: 64.71% vs. 14.29%) [112, 113], and the multi-herb prescription Kuerle Hospital-prepared Decoction (DCR: 84.32% vs. 73.88%; ORR: 61.16% vs. 47.76%) [117], combined with SOX regimen achieved higher DCR and ORR in treating gastric cancer compared to chemotherapy alone. Buzhong Xiaowei Decoction (88.89% vs. 70.37% [118]), Chanpi Ezhu Tang (77.50% vs. 51.28%) [119], and Guangshan County People's Hospital-prepared Shenyi Jianzhong Tang (88.89% vs. 68.89%) [120], three multi-herb prescriptions created by TCM doctors, combined with SOX regimen achieved higher DCR in treating gastric cancer than chemotherapy alone. Modified Bazhen Tang (45.1% vs. 25.49%) [121], Fuzheng Xiaoliu Tang (83.72% vs. 65.12%) [122], The First Affiliated Hospital of China Medical University-prepared Shenyi Jianzhong Tang (90.7% vs. 69.77%) [123], Jiawei Xiaoxianxiong Tang (83.72% vs. 65.12%) [124], Zisheng Xiexin Tang (86.7% vs. 56.7%) [125], and The Second Hospital of Jiaxing-prepared Decoction (64.7% vs. 45.1%) [126], six multi-herb prescriptions created by TCM doctors, combined with SOX regimen attained higher ORR in treating gastric cancer compared to chemotherapy alone.
Seven of the 13 mentioned CHDs (i.e. Aidi Injection, Chanpi Ezhu Tang, Huosu Yangwei Oral Liquid, Jiawei Xiaoxianxiong Tang, Kuerle Hospital-prepared Decoction, The Second Hospital of Jiaxing-prepared Decoction and Putuo Hospital Affiliated to Shanghai University of Traditional Chinese Medicine-prepared Jianpi Jiedu Tang) decreased the incidence of adverse effects caused by the SOX regimen, including GI reactions, liver and kidney injury, leukopenia and myelosuppression. Meanwhile, six of the 13 mentioned CHDs (Buzhong Xiaowei Tang, Guangshan County People's Hospital-prepared Shenyi Jianzhong Tang, Huosu Yangwei Oral Liquid, Putuo Hospital Affiliated to Shanghai University of Traditional Chinese Medicine-prepared Jianpi Jiedu Tang, The Second Hospital of Jiaxing-prepared Decoction, and The First Affiliated Hospital of China Medical University-prepared Shenyi Jianzhong Tang) significantly enhanced the QOL of patients receiving the SOX regimen.
One NMPA-approved PHD (Kanglaite Injection [127]) and two multi-herb prescriptions created by TCM doctors (Gansu Provincial Cancer Hospital-prepared Jianpi Huayu Tang [128] and Shanxi Hospital of Traditional Chinese Medicine-prepared Jianpi Quyu Tang [129]) markedly improved the QOL of gastric cancer patients undergoing the SOX regimen. These three CHDs also protected gastric cancer patients from SOX regimen-induced adverse effects.
Seven of the 17 CHDs described in this section, including Aidi Injection (CEA, CA125, CA199, and CA242) [115, 116], Modified Bazhen Tang [CEA, CA19-9, insulin-like growth factor 1 (IGF-1) and platelet endothelial cell adhesion molecule (PECAM-1)] [121], Chanpi Ezhu Tang (CA19-9) [119], Kanglaite Injection (CEA and CA19-9) [127], Kuerle Hospital-prepared Decoction (CEA, CA19-9, CA125, CA242, and VEGF) [117], Sanleng Ezhu Decoction (CA125, CA72-4, CEA, and VEGF) [130], and The Second Hospital of Jiaxing-prepared Decoction (VEGF, TIMP1, and MMP-9) [126], in combination with SOX regimen respectively exerted better effects in down-regulating serum levels of tumor markers than SOX regimen alone.
Among the 17 CHDs described in this section, six CHDs improved the immune function of patients receiving SOX regimen. Modified Bazhen Tang [121], Fuzheng Xiaoliu Tang [122], Guangshan County People's Hospital-prepared Shenyi Jianzhong Tang [120], The Second Hospital of Jiaxing-prepared Decoction [126], and Sanleng Ezhu Decoction [130] markedly increased CD3+ and CD4+ T cells, and CD4+/CD8+ ratio in patients receiving SOX regimen. Putuo Hospital Affiliated to Shanghai University of Traditional Chinese Medicine-prepared Jianpi Jiedu Tang significantly increased NK cells in patients receiving SOX regimen [114].
In patients receiving XELOX regimen
XELOX regimen, a chemotherapy combination comprising capecitabine and oxaliplatin, is widely used for treating cancers, especially colorectal cancer. Fifteen research articles have reported the combinational use of the individual 15 CHDs with XELOX regimen in treating gastric cancer or esophageal cancer.
Ten CHDs improved the efficacy of the XELOX regimen. In gastric cancer patients, Bruceae Fructus Oil Injection combined with XELOX regimen resulted in higher 1-year and 2-year survival rates compared to XELOX regimen alone (1-year survival rate: 75% vs. 59.4%; 2-year survival rate: 21.9% vs. 15.6%) [131]. Shenzhu Jianyun Tiaoqi Tang, a 15-herb prescription created by a TCM doctor, increased the 1-year survival rate of esophageal cancer patients receiving XELOX regimen (59.09% vs. 34.09%) [132]. Yiqi Jiedu Tang (an 11-herb prescription created by a TCM doctor) combined with XELOX regimen achieved higher DCR and ORR in treating gastric cancer compared to chemotherapy alone (DCR: 93.88% vs. 79.59%; ORR: 65.31% vs. 42.68%) [133]. Fuzheng Huayu Tang (a 13-herb prescription created by a TCM doctor) combined with XELOX regimen achieved higher ORR in treating gastric cancer compared to chemotherapy alone (83.3% vs. 60%) [134]. Two PHDs, i.e. Astragalus Polysaccharide Injection (85.71% vs. 59.52%) [135] and Bruceae Fructus Oil Injection (68.7% vs. 53.1%) [131], and four multi-herb prescriptions created by TCM doctors, i.e. Jianpi Guben Huadu Tang (77.5% vs. 55%) [136], Buzhong Yiqi Tang (97.5% vs. 87.5%) [137], Jianpi Quyu Tang (97.5% vs. 87.5%) [138] and Jianpi Yishen Tang (85% vs. 52.5%), [139] combined with the XELOX regimen accomplished higher ORR in the treating gastric cancer compared to chemotherapy alone. A PHD, i.e. Huachansu Capsule (61.76% vs. 50%) [140], and a 15-herb prescription created by a TCM doctor, i.e. Shenzhu Jianyun Tiaoqi Tang (27.27% vs. 18.18%) [132], combined with XELOX regimen achieved higher ORR in treating esophageal cancer compared to chemotherapy alone.
Five of the ten CHDs mentioned above (i.e. Astragalus Polysaccharide Injection, Bruceae Fructus Oil Injection, Fuzheng Huayu Tang, Huachansu Capsule, and Jianpi Guben Huadu Tang) reduced the incidence of adverse effects caused by the XELOX regimen, including GI reactions, liver and kidney injury, leukopenia, myelosuppression and fragility. Five of the ten CHDs mentioned above (Bruceae Fructus Oil Injection, Buzhong Yiqi Tang, Huachansu Capsule, Jianpi Guben Huadu Tang, and Jianpi Yishen Tang) significantly enhanced the QOL of patients receiving the XELOX regimen.
Three multi-herb prescriptions created by TCM doctors (Qizhu Fuzheng Tang [141], Shenling Baizhu Tang [142], and The Second People's Hospital of Luxian County-prepared Decoction [143]) did not affect the efficacy of the XELOX regimen, however, the QOL of gastric cancer patients undergoing the XELOX regimen was significantly improved. Three multi-herb prescriptions created by TCM doctors (Huangqi Jianzhong Tang [144], Jianpi Yangxue Tang [145] and Shenling Baizhu Tang [142]) protected gastric cancer patients against adverse effects caused by the XELOX regimen.
Among the 15 CHDs mentioned in this section, three CHDs improved the immune function of gastric cancer patients receiving the XELOX regimen. Fuzheng Huayu Tang significantly increased CD4+ T cells, decreased CD8+ T cells, and increased CD4+/CD8+ ratio in patients receiving the XELOX regimen [141]. Jianpi Yishen Tang [145], and Yiqi Jiedu Tang [133] significantly increased CD3+, CD4+ T cells, and decreased CD8+ T cells in patients receiving the XELOX regimen.
Six of the 15 CHDs described in this paragraph, including Buzhong Yiqi Tang (CA199, CA724, CEA, and TPS) [137], Jianpi Guben Huadu Tang (CEA and CA19-9) [136], Jianpi Yangxue Tang (CEA and CA19-9) [145], Qizhu Fuzheng Tang (CEA, CA19-9, and CA72-4) [141], Shenzhu Jianyun Tiaoqi Tang (VEGF and CYFRA21-1) [132], and Yiqi Jiedu Tang (CEA, CA19-9, CA72-4, and CA125) [133], in combination with the XELOX regimen respectively demonstrated better effects in down-regulating serum levels of tumor markers than the XELOX regimen alone.
Astragalus Polysaccharide Injection in combination with XELOX regimen exhibited better effects in up-regulating the serum level of interferon-γ (IFN-γ) and down-regulating the serum level of interleukin 4 (IL-4) than the XELOX regimen alone [135]. These findings indicated that this injection in combination with the XELOX regimen had stronger anti-inflammatory effects than mono-chemotherapy in patients with gastric cancer.
In patients receiving FAM regimen
The combination of 5-FU, doxorubicin, and mitomycin (known as FAM regimen) has been used for treating gastric cancer since the 1980s [199]. Four research articles reported the combinational use of each of the four CHDs with the FAM regimen in treating gastric cancer.
Compound Danshen Dripping Pill is a PHD comprising extracts of Salviae Miltiorrhizae Radix et Rhizoma, Notoginseng Radix et Rhizoma, and Borneolum Syntheticum. It has been demonstrated that combining this drug with the FAM regimen significantly improved DCR in patients with gastric cancer (67.4% vs. 43.2%). Patients in the FAM regimen + Compound Danshen Dripping Pill treatment group had higher KPS score and greater body weight gain compared to patients in the FAM regimen group, indicating that this herbal drug improved the QOL of patients undergoing the FAM regimen. This herbal drug also decreased the occurrence rates of leukopenia and nausea/vomiting caused by chemotherapy in the gastric cancer patients [146].
Shenqi Fuzheng Injection plus FAM regimen resulted in higher ORR compared to FAM regimen alone (58.33% vs. 33.33%). Meanwhile, the incidence of adverse effects (leukopenia, nausea/vomiting, weakness and insomnia, and thrombocytopenia) in patients receiving the combined treatment was lower compared to patients receiving the FAM regimen alone [147].
Weining Granule is prepared based on a 4-herb prescription created by a TCM doctor. In a clinical trial assessing the efficacy of Weining Granule + FAM regimen in treating gastric cancer, 180 patients with stage II/III gastric cancer were randomly assigned to receive Weining Granule + FAM regimen or FAM regimen alone. After a 6-month treatment, the combined therapy showed significantly better effects in lowering serum levels of the tumor markers VEGF and MMP-9. In the combined therapy arm, 6 patients had recurrence, and 14 patients experienced metastasis within one year, which is significantly less than that observed in the FAM regimen arm where 10 patients experienced recurrence and 19 experienced metastasis [148].
Xiangsha Yangwei Wan in combination with the FAM regimen significantly increased the 1-year survival rate of advanced gastric cancer patients compared to the FAM regimen alone (38.7% vs. 6.4%) [149].
In patients receiving ECF regimen
ECF regimen is the chemotherapy combination of 5-FU, cisplatin, and epirubicin. In stage IIIB/IV gastric cancer patients, ECF regimen plus Fufang Kushen Injection significantly increased 0.5-, 1-, 2-year survival rates compared to the ECF regimen alone (0.5-year survival rate: 87.5% vs. 65.6%; 1-year survival rate: 75.0% vs. 59.4%; 2-year survival rate: 40.6% vs. 21.9%). Patients receiving combined therapy had a higher KPS score than those receiving chemotherapy alone, indicating that Fufang Kushen Injection improved the QOL of the patients. In addition, Fufang Kushen Injection ameliorated chemotherapy-induced adverse effects including leukopenia and liver injury in the patients [150]. In another study designed to assess the efficacy and safety of Fufang Kushen Injection in combination with the ECF regimen in advanced gastric cancer patients, the combined treatment exhibited higher ORR than chemotherapy alone (65% vs. 37.5%). Fufang Kushen Injection co-treatment reduced the incidence of chemotherapy-induced adverse effects, including leukopenia and erythrocytopenia [151]. These studies demonstrate that Fufang Kushen Injection improves the effectiveness and reduces the adverse effects of the ECF regimen in treating patients with gastric cancer, while also enhancing the QOL of the patients.
In patients receiving other regimens
Apart from the regimens mentioned above, there are also other combinations of different chemotherapy drugs. In this section, we describe the effects of combining each of the 12 CHDs with various multi-drug chemotherapy for the treatment of gastric and esophageal cancers.
For treating esophageal cancer, Xianchan Tablet, a PHD used as an adjuvant for cancer therapies, combined with a multi-drug chemotherapy (cisplatin + leucovorin + paclitaxel) resulted in a higher DCR (91.2% vs. 70.6%) than single chemotherapy. This PHD also improved the immune function and QOL of patients receiving the chemotherapy [152]. Shenyi Capsule, another adjuvant anti-cancer PHD, combined with chemotherapy (cisplatin + gemcitabine) resulted in a higher 1-year survival rate (66.7% vs. 36.7%) and lower serum levels of the tumor marker VEGF in esophageal cancer patients compared to chemotherapy alone. Meanwhile, this PHD protected patients against chemotherapy-induced adverse effects (GI reactions, thrombocytopenia, and myelosuppression) and improved the QOL of the patients [153].
An article reported that combined use of 5-FU, bleomycin, cisplatin and Compound Danshen Dripping Pill resulted in a significantly higher DCR than single chemotherapy in esophageal cancer patients (80.6% vs. 52.9%). A higher KPS score was observed in patients of the combined treatment group, indicating that Compound Danshen Dripping Pill improved the QOL of patients undergoing the chemotherapy. In addition, the incidence of adverse effects (leukopenia and nausea/vomiting) was lower in patients receiving the combined treatment than those receiving chemotherapy alone [154].
5-FU + hydroxycamptothecin + cisplatin combined with Huohua Kaitong Capsule, prepared based on a 12-herb prescription created by a TCM doctor, achieved significantly higher 1-, 2-, and 3-year survival rates and longer mOS in patients with stage III/IV esophageal cancer compared to chemotherapy alone (1-year survival rate: 78.3% vs. 53.7%; 2-year survival rate: 63.2% vs. 33.3%; 3-year survival rate: 39.6% vs 16.7%; mOS: 19 months vs. 9.5 months). A higher KPS score was observed in patients of the combined treatment group, indicating that this herbal drug improved the QOL of patients undergoing the chemotherapy. In addition, Huohua Kaitong Capsule co-treatment reduced the incidence of chemotherapy-induced adverse effects, including leukopenia, nausea/vomiting, and thrombocytopenia [155].
For the treatment of gastric cancer, Fuzi Lizhong Tang, a classical TCM formula, in combination with cisplatin-plus-vinorelbine increased ORR (combined treatment 58.71% vs. chemotherapy 59.52%), and down-regulated serum levels of tumor markers [Pentraxin-3, CYFRA21-1, thyroid transcription factor-1 (TTF-1) and human epididymis protein 4 (HE4)] in patients compared to the chemotherapy alone. In addition, Fuzi Lizhong Tang reduced the incidence of adverse effects caused by the chemotherapy from 52.38% to 23.81% [156].
Jianpi Jiedu Decoction prepared by Jiangsu Province Hospital of Traditional Chinese Medicine is a 12-herb prescription. In gastric cancer patients, this prescription combined with a chemotherapy (5-FU + cisplatin + epirubicin + leucovorin) significantly increased ORR and DCR compared to chemotherapy alone (ORR: 55% vs. 47.5%, CDR: 75% vs. 62.5%). It also increased CD3+ cells, CD4+ cells, and NK cells, and elevated CD4+/CD8+ ratio, in patients receiving the chemotherapy, indicating that it enhanced the immune function of the patients. This prescription also lowered the occurrence rate of chemotherapy-induced adverse effects [157].
Fuzheng Yiai Tang, a 9-herb prescription created by a TCM doctor, increased the ORR (53.1% vs. 46.7%) of paclitaxelin in patients with gastric cancer. In addition, this prescription reduced paclitaxelin-induced adverse effects and improved the QOL of the patients [158].
Guishao Liujun Tang, a 14-herb prescription created by a TCM doctor, combined with paclitaxel-plus-S-1 resulted in a significant increment in ORR in patients with advanced gastric cancer compared to the chemotherapy alone (98% vs. 70%). Moreover, a higher KPS score was observed in the combined treatment group than in the paclitaxel-plus-S-1 therapy group, indicating that this prescription improved QOL of patients receiving the chemotherapy [159].
Modified Xiangsha Liujunzi Decoction is an 11-herb prescription of a TCM doctor. It enhanced QOL of gastric cancer patients undergoing a chemotherapy (cisplatin + paclitaxel + leucovorin). Meanwhile, this prescription significantly reduced the chemotherapy-induced adverse effects including GI reactions, leukopenia, thrombocytopenia, liver injury, alopecia, anemia, and stomatitis in the patients [160].
Two reports studied 2 PHDs in gastric cancer patients receiving 5-FU + cisplatin + leucovorin. Bruceae Fructus Oil Injection enhanced immune function of gastric cancer patients receiving chemotherapy, evidenced by more CD3+ and CD4+ T cells, and fewer CD8+ T cells in the combined treatment group than in the mono chemotherapy group [161]. Fufang Kushen Injection in combination with 5-FU + cisplatin + leucovorin achieved significantly higher DCR than single chemotherapy in treating gastric cancer (81.3% vs. 70.8%). Patients receiving combined therapy had a higher KPS score than those receiving single chemotherapy, indicating that this PHD improved the QOL of the patients. Meanwhile, the incidence of adverse effects (myelosuppression and GI adverse reactions) in patients receiving the combined treatment was lower than that observed in patients receiving chemotherapy alone. Higher CD4+ T cells, CD3+ T cells and CD4+/CD8+ ratio, as well as lower CD8+ cells, were observed in the combined treatment group than in the mono chemotherapy group [162].
A 12-herb prescription created by a TCM doctor combined with 5-FU + etoposide + leucovorin resulted in significantly longer mOS in gastric cancer patients compared to single chemotherapy (25.6 months vs. 17.3 months). The QOL of patients receiving the combined treatment was better than that of patients receiving chemotherapy alone [163]. A 14-herb prescription created by a TCM doctor combined with 5-FU + etoposide + leucovorin increased the ORR of gastric cancer patients compared to chemotherapy alone (94% vs. 85.3%) [164].
In patients receiving chemoradiotherapy
Ten eligible reports studied six CHDs in patients receiving chemoradiotherapy. Five CHDs were tested in esophageal cancer patients; one was tested in gastric cancer patients.
Bazhen Tang, a classical TCM formula, increased the ORR of II-IV-stage esophageal cancer patients receiving paclitaxel-plus-radiotherapy. This formula enhanced the immune function of the patients (CD4+ T cells and CD4+/CD8+ ratio increased; CD8+ T cells decreased), and improved patients’ QOL (KPS score increased; QLQ-C30 symptom score decreased) [165, 166]. In addition, this formula ameliorated chemoradiotherapy-induced adverse effects including radiation esophagitis, radiation pneumonitis, myelosuppression, liver injury, and kidney injury [165, 166]. When combined with the CF regimen and radiotherapy, this formula increased the ORR of chemoradiotherapy in esophageal cancer patients from 37.8% to 67.6% [167]. Moreover, Bazhen Tang increased CD4+ T and NK cells, decreased CD8+ T cells, and enhanced the QOL of esophageal cancer patients receiving the chemoradiotherapy [167].
Shenmai Injection is a PHD prepared with Ginseng Radix et Rhizoma Rubra and Ophiopogonis Radix. It is commonly used as an adjuvant drug for treating cancer in China. In late-stage esophageal cancer patients, Shenmai Injection combined with chemoradiotherapy (CF regimen + radiotherapy) significantly increased ORR compared to chemoradiotherapy alone [168, 169]. It also significantly reduced the occurrence rates of chemoradiotherapy-induced leukemoid reaction and GI adverse reactions in the patients. Another report showed that Shenmai Injection significantly improved ORR in advanced ESCC patients treated with chemoradiotherapy (capecitabine + radiotherapy) (83.33% vs. 76.67%). Meanwhile, Shenmai Injection elevated KPS score in these patients, indicating an improvement in patients' QOL. It also decreased the occurrence rates of leukopenia, GI adverse reactions, radiation esophagitis, and radiation pneumonitis caused by chemoradiotherapy, in ESCC patients [170].
Shenqi Fuzheng Injection, a PHD used as an adjuvant to cancer therapies, reduced the toxicities of chemoradiotherapy (CF regimen + radiotherapy) in esophageal cancer patients [171]. Patients in the combined treatment group had a lower probability of suffering from severe radiation esophagitis, granulocytopenia, nausea, and vomiting compared to patients in the mono-chemoradiotherapy treatment group [171].
Huachansu Capsule combined with chemoradiotherapy (CF regimen + radiotherapy) resulted in a longer mOS (15 months vs. 12 months) and a higher ORR (75% vs. 62.5%) in esophageal cancer patients compared to chemoradiotherapy alone. Meanwhile, the incidence of adverse reactions induced by chemoradiotherapy (leukopenia, esophagitis, nausea, and myalgia) was lower in the combined therapy group than in the chemoradiotherapy group [172].
Xiao’aiping Injection is another adjuvant anti-cancer PHD. It was prepared from the TCM herb Marsdeniae Tenacissimae Caulis. The drug improved the clinical efficacy of chemoradiotherapy (mFOLFOX6 regimen + radiotherapy) in esophageal cancer patients, evidenced by an elevated DCR (43.3% vs. 33.3%). Patients receiving combined therapy had a higher KPS score than patients receiving chemoradiotherapy, indicating that the injection improved patients’ QOL. In addition, the occurrence rates of chemoradiotherapy-induced GI adverse reactions and leukopenia in the patients were markedly reduced by the addition of Xiao’aiping Injection treatment [173].
Huaier Keli is an NMPA-approved drug developed from Trametes robiniophila. In the treatment of gastric cancer, patients receiving Huaier Keli plus chemoradiotherapy (capecitabine + radiotherapy) had better QOL (lower symptom score, higher function score of QLQ-C30) than those receiving chemoradiotherapy alone. In addition, Huaier Keli enhanced the immune function of gastric cancer patients receiving chemoradiotherapy. Higher WBC count, CD4+ T cells, NK cells and CD4+/CD8+ ratio, as well as lower CD8+ cells were observed in the combined therapy group than in the chemoradiotherapy group [174].
In patients receiving targeted therapy
There are six eligible reports regarding the benefits of five CHDs in gastric cancer patients receiving targeted therapies.
Kanglaite Injection in combination with apatinib prolonged the PFS of gastric cancer patients compared to apatinib alone (median PFS: 11.4 months vs. 6.2 months). The TRR of patients was significantly higher in the combined treatment group than in apatinib group (86.67% vs. 66.67%). Kanglaite Injection decreased the incidence of apatinib-induced adverse effects, including leukocyte reduction, liver injury and anemia; and elevated the KPS score of patients receiving apatinib. These findings indicated that Kanglaite Injection improved the QOL of these patients. In addition, the upregulation of serum inflammatory cytokines (IL-2, TNF-α and INF-γ) induced by the targeted therapy was significantly diminished by Kanglaite Injection [175, 176].
Huosu Yangwei Oral Liquid is a PHD that has been demonstrated to ameliorate apatinib-induced adverse effects. Co-treatment with Huosu Yangwei Oral Liquid significantly reduced the incidence of apatinib-induced adverse effects from 90.0% to 66.7%. Huosu Yangwei Oral Liquid also improved the QOL of patients receiving apatinib treatment. The KPS score was higher in the combined treatment group than in the apatinib mono-treatment group [177].
Buzhong Xiaowei Decoction, an 11-herb prescription created by a TCM doctor, combined with apatinib-plus-S-1 therapy achieved significantly higher DCR in the treatment of stage III-IV gastric cancer compared to apatinib-plus-S-1 therapy (91.55% vs. 70.42%). The immune function of patients in the combined treatment group was better than that of the apatinib-plus-S-1 therapy group. The decoction markedly increased CD3+ and CD4+ T cells, and decreased CD8+ T cells in patients receiving apatinib-plus-S-1 therapy. In addition, the incidence of adverse reactions (dizziness, weakness, nausea, vomiting, and stomachache) caused by apatinib-plus-S-1 therapy was significantly decreased by the decoction [178].
Guben Xiaoai Decoction is a 23-herb prescription created by a TCM doctor. It also enhanced the efficacy and reduced the toxicities of apatinib-plus-S-1 therapy. This decoction increased the DCR of gastric cancer patients undergoing apatinib-plus-S-1therapy by 11.43% (82.86% vs. 71.43%). The combined therapy more effectively down-regulated serum levels of three tumor markers: CEA, CA125, and CA19-9, compared to apatinib-plus-S-1 therapy alone. This decoction enhanced the immune function of patients receiving apatinib-plus-S-1 therapy, evidenced by higher CD3+, CD4+ T cell counts, and CD4+/CD8+ ratio, and lower CD8+ T cell count in the combined treatment group than in apatinib-plus-S-1 therapy group. Moreover, a higher KPS score and a lower incidence of adverse effects (myelosuppression, GI adverse reactions, liver and kidney injury) were observed in the combined treatment group than in apatinib-plus-S-1 therapy group [179].
Combining Yiyang Jianpi Formula (a 12-herb prescription created by a TCM doctor) with apatinib-plus-S-1 therapy resulted in a significant increment in the DCR of patients with advanced gastric cancer (82.86% vs. 65.71%). The combined therapy was more effective in lowering serum levels of the tumor markers CEA and CA125 compared to apatinib-plus-S-1 therapy alone. Meanwhile, this formula decreased the occurrence rates of adverse effects (nausea, vomiting, myelosuppression, hepatotoxicity) induced by apatinib-plus-S-1 therapy [180].
In patients with precancerous lesions
Across 14 eligible reports, the clinical efficacy of 12 CHDs was evaluated. One CHD was tested in patients with oral leukoplakia, one in patients with laryngeal precancerous lesions, one in patients with oral leukoplakia and patients with esophageal epithelial hyperplasia, and nine in patients with gastric precancerous lesions.
A seven-herb prescription created by a TCM doctor combined with Transfer Factor Capsule-plus-local Vitamin A and D Drop increased the DCR of patients with oral leukoplakia compared to Transfer Factor Capsule-plus-Vitamin A and D Drop alone (91.67% vs. 72.92%). After a 30-day treatment, patients treated with combination therapy had a higher serum IgG level and lower serum IgA and IgM levels compared to patients treated with Western medicine only. Among the 48 patients in the Western medicine group, three experienced mild nausea and vomiting, and one experienced mild headache. Only one of the 48 patients in the combined therapy group experienced mild nausea and vomiting [181].
Modified Sanjiasan (a prescription created by a TCM doctor) combined with local recombinant human P53 adenovirus resulted in a significantly higher ORR in patients with laryngeal precancerous lesions compared to single adenovirus treatment (85.71% vs. 66.67%). After a 6-week treatment, the combination treatment showed significantly better effects in lowering serum levels of the tumor markers VEGF and β2-microglobulin (β2-MG) compared to the adenovirus treatment alone. Moreover, the prescription enhanced the immune function of patients, evidenced by a higher number of CD4+ T cells and lower number of CD8+ T cells in the combined treatment group than in the mono adenovirus treatment group [182].
Zengshengping (also called Antitumor B) is a PHD for treating esophageal and cardiac epithelial hyperplasia. A clinical study assessed the efficacy of a 6-month Zengshengping treatment in severe esophageal dysplasia. Compared to the placebo group, a significantly higher proportion of patients from the Zengshengping group reported the disappearance or alleviation of symptoms such as dry mouth, dry throat, acid reflux, and bloating (disappearance of symptoms: 34.3% vs. 4.7%; alleviation of symptoms: 51.3% vs. 8.1%). The results from endoscopy and histopathology of the esophagus showed that patients treated with Zengshengping had a significantly higher reversal of dysplasia rates compared to the placebo group (endoscopy: 59% vs. 38.7%; histopathology: 64.3% vs. 22.8%). Of 300 patients who received Zengshengping treatment, seven experienced temporary adverse effects. Five patients experienced increased bowel movements and two patients experienced nausea and rashes. All adverse effects resolved after the medication was stopped [183]. In a 5-year study, the efficacy of Zengshengping in preventing the progression of severe esophageal dysplasia to esophageal cancer was assessed. A total of 2,523 patients were randomly assigned to receive Zengshengping, retinamide (an apoptosis-inducing agent), or placebo treatment. Four hundred seventy-nine persons in the Zengshengping group, 506 persons in the retinamide group, 507 persons in the placebo group completed the 5-year study. Results of esophageal cytological examination showed that Zengshengping, similar to retinamide, significantly reduced the incidence of esophageal cancer (Zengshengping vs. retinamide vs. placebo: 7.7% vs. 8.3% vs. 14.6%) [184]. The efficacy of Zengshengping in treating oral leukoplakia was also tested. In oral leukoplakia patients, Zengshengping exhibited a higher ORR than the placebo (67.8% vs. 17.0%) [185]. In the Zengshengping group, patients had lower levels of the oral leukoplakia biomarkers [argyrophilic nucleolar organizer region (AgNOR) and proliferating cell nuclear antigen (PCNA)] compared to those in the placebo group [185].
Astragali Radix decoction significantly lowered the recurrence rate of gastric precancerous lesions in patients within 6 months, compared to amoxicillin + metronidazole + omeprazole treatment (3.1% vs. 25%). After a 3-month treatment, the herbal decoction group had a significantly higher DCR compared to the Western medicine group (96.9% vs. 75.0%) [186].
Echan Jianwei Formula, a prescription created by a TCM doctor, demonstrated significantly better efficacy compared to vitacoenzyme in managing gastric precancerous lesions. In the herbal formula group, the DCR of patients was significantly higher compared to the vitacoenzyme group (73.4% vs. 60.4%). The results from gastroscopy and histopathology of the stomach showed that ORRs were higher in the herbal formula group than in the vitacoenzyme group (gastroscopy: 73.4% vs. 66.6%; histopathology 79.5% vs. 68.7%) [187].
In a 3-arm study, Fuwei Kangyi Formula, an herbal prescription created by a TCM doctor, and vitacoenzyme showed similar efficacy in treating chronic atrophic gastritis, while their combination achieved better results (ORR of Fuwei Kangyi Formula vs. vitacoenzyme vs. combination: 85% vs. 77.5% vs. 97.5%). Results from gastroscopy and histopathology showed that, after a 3-month treatment, the lesions regressed in all three groups, and the combination therapy group had the best result. B-cell lymphoma 2 (Bcl-2), cyclooxygenase-2 (COX-2), survivin, and p16 are molecules involved in the development of gastric cancer. The combination treatment upregulated p16 level and lowered Bcl-2, COX-2, and survivin levels in the lesions, and the effects of the combined treatment were the best among the three treatments [188].
Huatan Xiaoyu Formula, a 10-herb prescription created by a TCM doctor, combined with rabeprazole achieved a better response rate in treating gastric precancerous lesions compared to rabeprazole alone (ORR: 90.90% vs. 71.87%). The combined therapy was also better in alleviating epigastric pain, gastric fullness, and loss of appetite compared to rabeprazole alone. In the combined treatment group, serum levels of the GI hormones gastrin and motilin were higher, and the tumor markers CEA, CA19-9, CA125, and CA72-4 were lower compared to the rabeprazole group [189].
Huatan Xiaoyu Granule (based on an 11-herb prescription created by a TCM doctor) in combination with vitacoenzyme showed better efficacy in alleviating symptoms (epigastric pain, acid reflux, and nausea and vomiting) in patients with intestinal metaplasia compared to vitacoenzyme alone. The combined treatment was more effective in regulating the expression of two miRNAs involved in the development and progression of gastric cancer. In the combined treatment group, gastric-juice miR-133a level was higher and miR-421 level was lower compared to the vitacoenzyme treatment group. Results of gastroscopy showed that the combined therapy was better at reversing gastric mucosal atrophy, intestinal metaplasia, and dysplasia [190].
Weifuchun Tablet is a PHD approved by the NMPA in 1982. It has been widely used for treating gastric precancerous lesions and as a postoperative adjuvant in the treatment of gastric cancer in China [200]. A clinical trial showed that, in patients with gastric precancerous lesions, Weifuchun Tablet treatment was better at alleviating clinical symptoms, and improving gastroscopy and histopathology results compared to vitacoenzyme treatment alone. Weifuchun Tablet treatment achieved higher rates of reversal of both atrophy and intestinal metaplasia compared to vitacoenzyme treatment alone (gastric mucosal atrophy: 80% vs. 23.33%; intestinal metaplasia: 73.33% vs. 26.67%). The study also found that the increase of Parabacteroides, a member of intestinal microbiome, contributes to the development of gastric precancerous lesions. Weifuchun Tablet treatment decreased Parabacteroides to the level of the healthy group, while vitacoenzyme treatment had no impact on the abundance of Parabacteroides [191].
Jiawei Huangqi Jianzhong Formula, a TCM prescription, combined with celecoxib achieved a better impact on inflammation and immune homeostasis, evidenced by higher serum levels of IL-10, IL-17A, and IFN-γ compared to celecoxib treatment alone. Jiawei Huangqi Jianzhong Formula decreased anaemia caused by celecoxib. Serum Hb levels were higher in the combination therapy group than in the celecoxib group [192].
Moluodan is an NMPA-approved over-the-counter drug for treating chronic atrophic gastritis and stomachache. In 2019, Moluodan was included in the Management of Epithelial Precancerous Conditions and Lesions in the Stomach (MAPS II) for managing chronic atrophic gastritis with dysplasia [201]. A clinical study demonstrated that Moluodan had the highest efficacy in reversing low-grade dysplasia compared to folic acid and the combination of Moluodan and folic acid. Dysplasia disappearance rates in patients who received Moluodan, folic acid, and their combination were 82.8%, 53.9%, and 61.1%, respectively. No Moluodan-related adverse effects were reported [193].
Weiyanfu Formula, a prescription created by a TCM doctor, exerted higher efficacy than omeprazole in treating gastric precancerous lesions (ORR: 98.2% vs. 94.6%) [194].
Summary and future perspectives
For managing cancers and precancerous lesions in the upper digestive tract, CHDs were mainly used as adjuvants (132 CHDs: 126 CHDs for cancer treatment, 6 CHDs for precancerous lesions management) to conventional therapies, and in some cases, they were used as monotherapy (6 CHDs, for precancerous lesions management). As adjuvants, all 132 CHDs enhanced the efficacy, particularly increased survival rates or prolonged mOS, and/or reduced the toxicities of conventional therapies. Specifically, 68 CHDs enhanced ORR, 30 CHDs increased DCR, 34 CHDs increased survival rates and/or prolonged mOS, 70 CHDs improved QOL, and 38 CHDs improved immune function of patients compared to mono-conventional therapies. Seventy-five CHDs reduced adverse effects/toxicities of the conventional therapies: 16 CHDs reduced liver injury and 10 CHDs reduced kidney injury induced by chemotherapies, 62 CHDs reduced myelosuppression and 64 CHDs reduced GI reactions caused by conventional therapeutics, six CHDs reduced radiation pneumonitis and nine CHDs reduced radiation esophagitis induced by radiotherapy, 11 CHDs reduced neurotoxicity induced by chemotherapies, two CHDs ameliorated pain of gastric cancer patients, and nine CHDs relieved patients’ symptoms of fatigue. When used alone, some CHDs slowed disease progression from precancerous lesions to malignant tumors. The reviewed clinical trials include 104 studies on gastric cancer, 61 on esophageal cancer, two on laryngeal cancer, two on oral leukoplakia, one on esophageal epithelial hyperplasia, and 11 on gastric precancerous lesions. None of the clinical studies evaluated the efficacy of CHDs with respect to oral lip cancer, salivary gland cancer, hypopharyngeal cancer, oropharyngeal cancer, or gastroesophageal junction cancer. Only one clinical study explored the mechanisms of action of the studied CHD. Our work has limitations, such as only studies published in Chinese or English were included. Nevertheless, the collected evidence indicates that CHDs, either administered in combination with conventional therapies or as standalone agents, show clinical benefits for the treatment of upper digestive tract cancers.
Five-year survival rate is the most important index for assessing clinical benefits of cancer treatments. In the reviewed studies on cancer treatment, the combinations of Sishen Jiedu Decoction and the CF regimen [57], Pingxiao Tablet with radiotherapy [17], and Fuzheng Guben Granule with radiotherapy [22] all resulted in increased 5-year survival rates for patients with esophageal cancer compared to conventional therapy alone. Additionally, Buyang Huanwu Tang combined with 5-FU [51] improved 5-year survival rates for patients with gastric cancer compared to 5-FU alone. Notably, Sishen Jiedu Decoction, when paired with the CF regimen, not only enhanced the 5-year survival rate of stage II-III esophageal cancer patients but also reduced the incidence of adverse effects compared to the CF regimen alone [57]. Sishen Jiedu Decoction has also been used in combination with radiotherapy for treating esophageal cancer [35, 36]; however, this combined treatment was not reported to increase the 5-year survival rate of patients. Although the mechanisms underlying the improved clinical outcomes are not yet understood, these studies suggest that the combination of Sishen Jiedu Decoction and CF regimen is an ideal option for treating esophageal cancer.
The primary goal of cancer prevention is to reduce cancer incidence. In the reviewed studies for managing precancerous lesions, Zengshengping is the sole CHD demonstrated to reduce cancer incidence in subjects with severe esophageal dysplasia [184]. The study involved two centers and a large sample size of 2,523 participants [184]. The clinical benefits of Zengshengping in preventing esophageal cancer have been validated by compelling evidence.
Despite their positive roles in treating diseases, including upper digestive tract cancers, CHDs have not yet achieved global acceptance. The primary barriers hindering the international recognition of CHDs are: 1) a lack of convincing clinical evidence, 2) unclear mechanisms of action, and 3) indistinct active components. To provide compelling clinical evidence, standardized clinical trials are necessary. Although many efforts have been made, studies regarding the use of CHDs for the treatment of upper digestive tract cancers still require significant improvements. Initially, we screened 1,492 clinical trials, however only 659 were randomly controlled trials, and merely 181 met our inclusion criteria (Fig. 2). Sample size calculations are important for avoiding the rejection of true findings and the approval of false results. However, only two of the reviewed clinical studies conducted power analysis in the sample size calculation step. Sample sizes of the eligible trials are between 60 to 2,247. Most of the trials included fewer than 200 subjects, with only five trials having sample sizes greater than 200. Only seven of the eligible studies were multi-center trials, while the remaining trials were conducted in a single hospital. The majority of eligible clinical reports were published in Chinese, and only seven reports were in English, making it challenging for non-Chinese speakers to access the information. Clinical studies on CHDs should include a power analysis for sample size calculation, aim for a substantial sample size, and be conducted in multiple centers, thereby reinforcing the reliability and replicability of the results in different populations. Moreover, to broaden the audience and enhance accessibility, it is advisable to publish research findings in multiple languages.
Well-designed preclinical pharmacological studies can help verify and explain the clinical benefits of CHDs. The studies should include multiple doses and positive controls. The biggest problem is that no eligible preclinical pharmacological studies were related to clinical trials. Preclinical pharmacological studies should be designed based on clinical findings. If a CHD is used as an adjuvant to chemotherapy in the treatment of cancer, the mechanisms of action of the CHD in combination with the chemotherapy drug should be studied using proper pharmacological models. To understand the mechanisms of action of CHDs, either used alone or in combination with conventional therapies, patient samples should be collected from clinical trials and analyzed using artificial intelligence-aided methods, followed by confirmation in animal and/or cell models.
Identification of the active components in CHDs is essential for understanding their mechanisms of action. Regrettably, we did not find any studies that had conducted chemical analyses of CHDs to explore their active components in managing upper digestive tract cancers. The clinical efficacy of CHDs relies on their chemical constituents and/or the constituents’ metabolites in the circulation [202]. Therefore, chemical identification of compounds in human circulation, followed by validation in pharmacological models, is an effective strategy for identifying bioactive compounds of CHDs. Although challenging, with the aid of modern technology, some researchers have conducted studies using this strategy. In a single-center, randomized, open-label, and multiple-dose clinical trial, Chen et al. analyzed the components of Lianhuaqingwen Capsule, a PHD for treating COVID-19 pneumonia [203]. They further identified active components of the drug using biochromatography [203]. We recommend using our proposed strategy to identify compounds in CHDs, either alone or in combination with conventional therapeutics, for treating upper digestive tract cancers.
In clinical, pharmacological and chemical studies, it is essential to standardize the studied CHD preparations. CHDs often exhibit variability in composition due to differences in raw material sources and preparation protocols, which can lead to inconsistent study results. To achieve standardization, it is critical to establish stringent quality control measures, such as using high-performance liquid chromatography (HPLC) for chemical fingerprinting and setting content standards for their active constituents [204].
With advancements in demonstrating clinical efficacy, clarifying mechanisms of action, and identifying active constituents, it is anticipated that CHDs will assume an increasingly critical role in the management of upper digestive tract cancers.
In summary, our review of the literature has confirmed that CHDs indeed offer benefits to patients with upper digestive tract cancers and to individuals with precancerous conditions in the upper digestive tract, although their mechanisms of action and anticancer components are not fully understood. We have outlined specific recommendations aimed at enhancing the methodological design and reproducibility of clinical and preclinical studies. We anticipate that our contributions will: 1) facilitate a deeper understanding of the role of CHDs in managing precancerous and malignant conditions of the upper digestive tract; 2) assist researchers specializing in upper digestive tract cancer in designing high-quality clinical, pharmacological, and chemical studies that aim to demonstrate the clinical efficacy, elucidate the mechanisms of action, and identify the bioactive compounds of CHDs; and 3) enable physicians to develop evidence-based therapeutic regimens, incorporating CHDs as adjunctive or alternative treatments for upper digestive tract malignancies.
Data availability
No datasets were generated or analysed during the current study.
Abbreviations
- 5-FU:
-
5-Fluorouracil
- AgNOR:
-
Argyrophilic nucleolar organizer region
- Bcl-2:
-
B-cell lymphoma 2
- BENC:
-
Bo-Er-Ning Capsule
- CA125:
-
Cancer antigen 125
- CA19-9:
-
Carbohydrate antigen 19-9
- CA72-4:
-
Cancer antigen 72-4
- CAM:
-
Complementary and alternative medicine
- CAPOX:
-
Capecitabine + 5-FU
- CEA:
-
Carcinoembryonic antigen
- CF:
-
Cisplatin + 5-FU
- CHD:
-
Chinese herbal drug
- CNKI:
-
China Academic Journals Full-text Database
- COX-2:
-
Cyclooxygenase-2
- CR:
-
Complete remission
- CX:
-
Cisplatin + capecitabine
- CYFRA21-1:
-
Cytokeratin 19 fragment
- DCF:
-
cisplatin + docetaxel + 5-FU
- DCR:
-
Disease control rate
- DFS:
-
Disease-free survival
- DOF:
-
Docetaxel + oxaliplatin + 5-FU
- D-LA:
-
D-lactic acid
- ECF:
-
Cisplatin + epirubicin + 5-FU
- ECX:
-
Cisplatin + epirubicin + capecitabine
- EOX:
-
Epirubicin + oxaliplatin + capecitabine
- ESCC:
-
Esophageal squamous cell carcinoma
- FAM:
-
5-FU + doxorubicin + mitomycin
- FJQR:
-
Fuzheng jiedu Quyu Method-based Formula
- FLOT:
-
5-FU + leucovorin + oxaliplatin + docetaxel
- FOLFOX:
-
Leucovorin + 5-FU + oxaliplatin
- FP:
-
Cisplatin + 5-FU
- FU-LV:
-
5-FU + leucovorin calcium
- GI:
-
Gastrointestional
- Hb:
-
Haemoglobin
- HE4:
-
Human epididymis protein 4
- IFN-γ:
-
Interferon-γ
- IGF-1:
-
Insulin-like growth factor 1
- IL-4:
-
Interleukin 4
- KPS:
-
Karnofsky Performance Scale
- β2-MG:
-
β2-Microglobulin
- MAPS II:
-
Management of Epithelial Precancerous Conditions and Lesions in the Stomach
- MIP-3α:
-
Macrophage inflammatory protein 3α
- mOS:
-
Median overall survival
- MMP-9:
-
Matrix metalloproteinase-9
- MVD:
-
Micro-vessel density
- NGAL:
-
Neutrophil gelatinase-associated lipocalin
- NMPA:
-
National Medical Products Administration
- ORR:
-
Objective response rate
- PC:
-
Carboplatin/Paclitaxel
- PCNA:
-
Proliferating cell nuclear antigen
- PECAM-1:
-
Platelet endothelial cell adhesion molecule
- PFS:
-
Progression-free survival
- PGI:
-
Pepsinogen I
- PG-SGA:
-
Patient-generated subjective global assessment
- PHD:
-
Proprietary herbal drug
- QLQ-C30:
-
Quality of Life Questionnaire-Core 30
- QLQ-OES18:
-
Quality of Life Questionnaire-Oesophageal Module 18
- QOL:
-
Quality of life
- RBC-C3bRR:
-
Red cell C3b receptor
- RBC-ICRR:
-
Red blood cell immune complex rosette rate
- S-1:
-
Tegafur + gimeracil + oteracil
- SCC-Ag:
-
Squamous cell carcinoma antigen
- Smad7:
-
Mothers against decapentaplegic homolog 7
- SOX:
-
S-1 + oxaliplatin
- TCM:
-
Traditional Chinese medicine
- TEX:
-
docetaxel + capecitabine + oxaliplatin
- TGF-β1:
-
Transforming growth factor-β1
- TGFβ1RI:
-
Transforming growth factor β1 type I receptor
- TP:
-
cisplatin + paclitaxel
- TTF-1:
-
Thyroid transcription factor-1
- VEGF:
-
Vascular endothelial growth factor
- WBC:
-
White blood cell
- XELOX:
-
capecitabine + oxaliplatin
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Acknowledgements
We thank Miss Yunfan Xi for helping collecting references.
Funding
This study was financially supported by Food and Health Bureau (HK) (HMRF, No.19200791) and Research Talent Hub for ITF Projects (ITF, No.PiH/107/24).
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Alexis SY Huang and JY Wu contributed equally to this work. ZL Yu conceived and designed the review; ZL Yu, Alexis SY Huang, JY Wu, XQ Fu wrote the manuscript; Alexis SY Huang prepared figures and tables; A AMIN edited the manuscript; ZL Yu and XQ Fu finalized the manuscript. All authors have reviewed the manuscript.
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Huang, A.S., Wu, J., AMIN, A. et al. Traditional Chinese medicine in treating upper digestive tract cancers. Mol Cancer 23, 250 (2024). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12943-024-02149-x
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DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12943-024-02149-x