Adjuvant role of traditional Chinese medicine in postoperative gastric cancer

Table 1 Clinical studies of traditional Chinese medicine for the treatment of postoperative gastric cancer

TCM	Compounds/constituents	Intervention	Intervention time	Postoperative condition	Study design	Outcome	Ref.
Sijunzi decoction	Radix Codonopsis (Dangshen), Poria cocos (Fuling), Rhizoma Atractylodis Macrocephalae (Baizhu), and Radix Glycyrrhizae (Gancao)	Sijunzi decoction + enteral nutrition vs enteral nutrition alone	8-10 days after operation	POCs after gastrectomy, Postoperative nutritional therapy	10 RCTs (688 participants), meta	Enhancing immune function, reducing the incidence of postoperative complications, and improving body nutrition status	[9]
Jianpi Yangzheng decoction	15 g Dangshen, 10 g Baizhu, 10 g Fuling, 15 g Shengyiren, 10 g Danggui, 15 g Shanyao, 10 g Muxiang, 10 g Baishao, 6 g Chenpi, 10 g Baqia, 15 g Shijianchuan and 3 g Zhigancao	TCM nursing intervention group (n = 520) vs the routine nursing intervention group (n = 512)	Every day after gastrectomy for at least 6 months	POCs after gastrectomy	Prospective, randomized controlled study	Improving POCs, mental status, long-term survival and reduces the recurrence	[25]
Yiqi Huayu Jiedu decoction	Astragalus membranaceus, 15 g; Codonopsis pilosula, 15 g; Atractylodes macrocephala, 10 g; Angelica, 10 g; Radices paeoniae alba, 10 g; Pericarpium citri reticulatae, 6 g; Pinellia, 10 g; Rhizoma sparganii, 10 g; Curcuma zedoary, 10 g; Chinese sage herb, 30 g; Hedyotis diffusa, 30 g; and Radix glycyrrhizae preparata, 5 g	Chemotherapy alone (n = 238) vs chemotherapy combined with Yiqi Huayu Jiedu decoction (n = 251)	More than 6 months	Stage II or III GC after radical gastrectomy	Multicenter, prospective, cohort study	Improve DFS rate in patients with GC stage III after radical gastrectomy and reduce the risk of recurrence and metastasis and improve the quality of life in patients with stage II or III GC after radical gastrectomy	[21]
Weifuchun	Radix Ginseng Rubra (Red Ginseng), Rabdosia amethystoides H. Hara (Xiangchacai), and fried Fructus Aurantii (Zhike)	Standard chemotherapy supplemented with Weifuchun tablets (n = 32) vs chemotherapy alone (n = 31)	6 months	Stages II and III GC and having undergonecurative resection within 8 weeks	Randomized, controlled, single-blind study	Reduce the 2-year recurrence and metastasis rates	[26]
TCM therapy	TCM therapies such as TCM decoction, moxibustion therapy, auricular-plaster therapy, hot ironing therapy, personalized food therapy, etc.	N/A	N/A	After the GC surgery	Meta-analysis (32 RCTs)	Reduce the risks of postoperative Wound infections and help shorten the time of wound healing; help patients rebuild a normal immune system and nutritional state	[38]
TCM therapy	The most common single herb prescriptions are Hwang-Chyi (Radix Hedysari; 11.8%), Dan-Shen (Radix Salviae Miltiorrhizae; 9.8%), Yan-Hu-Suo (Rhizoma Corydalis; 9.4%), Bai-Hua-She-She-Cao (Herba Hedyotidis Diffusae; 9.2%), and Hou-Pu (Cortex Magnoliae; 9.0%). The most common herbal formula prescriptions are Xiang-Sha-Liu-Jun-Zi-Tang (15.5%), Ping-Wei-San (12.6%), Ban-Xia-Xie-Xin-Tang (11.8%), Bu-Zhong-Yi-Qi-Tang (10.3%), and Shen-Lin-Bai-Zhu-San (10.2%)	Short-term TCM users (TCM use 30-179 days) (n = 1178) vs long-term TCM users (TCM use ≥ 180 days) (n = 523) vs nonusers (n = 5103)	N/A	Patients with GC following surgery and adjuvant chemotherapy	Nationwide matched cohort study	Short-term and long-term TCM users were independently associated with a decreased risk of death with HRs of 0.59 (95%CI: 0.55-0.65) in TCM users and 0.41 (95%CI: 0.36-0.47) in TCM nonusers	[100]
Zhipu Liujunzi decoction	Ginseng, solomonseal rhizome, figwort root, Ganoderma sinense, glabrous greenbrier rhizome, appendiculate cremastra pseudobulb and bamboo shavings (15 g each), 30 g of Mongolian milkvetch root, 20 g of large-head atractylodes rhizome, 6 g of villous amomum fruit, 6 g of finger citron, 12 g of dried tangerine peel, and 12 g of ginger processed pinellia	Early chemotherapy (oxaliplatin + capecitabine) (n = 50) vs Zhipu Liujunzi decoction + early chemotherapy (n = 50)	2 weeks	After radical gastrectomy	Retrospective analysis	Improve the immune function and quality of life for GC patients with higher safety	[15]
Decoction with Astragalus mongholicus and Semen Cuscutae	Radix Pseudostellariae 45 g, Rhizoma Atractylodis Macrocephalae 45 g, Rhizoma Zingiberis 45 g, Radix Glycyrrhizae Preparata 45 g, Rhizoma Pinellinae Praeparata 15 g, Fructus Amomi 15 g, Rhiizoma Dioscoreae 60 g, Astragalus mongholicus 120 g, Semen Cuscutae 60 g, Lignum Millettiae 60 g	Each N-of-1 trial consisted of two or three cycles with treatment decotion and control decotion assigned randomly	20-30 weeks (3-week standard chemotherapy and then used 3-day treatment periods)	After radical gastrectomy	A series of N-of-1 trials with randomization, double-blind, and controlled treatment	The QoL score after the trial was reported is a little higher than before	[101]
San Jie Pai Shi decoction	10 g of Codonopsis pilosula, 6 g of Radix glycyrrhiza, 12 g of the rhizome of Atrac_x005f tylodis macrocephalae, 9 g of the cortex of Magnoliae officinalis, 12 g of immature bitter orange, 12 g of the endothelium cor neum of Gigeriae galli, and 9 g of Rheum officinale	N/A	2 weeks	Gastric bezoar after Billroth II gastrectomy for GC	Case report	Gastroscopic examination showed that the gastric bezoar had dissolved	[22]
Xuesaitong injection	Extract from the roots of Pannax notoginseng (Sanqi)	Conventional anti-infection and transfusion treatment + 400 mg Xuesaitong Injection (n = 25) vs conventional anti-infection and transfusion treatment (n = 25)	6 days from the first day after surgery	After laparoscopic surgery for gastric cancer	RCT	The occurrence rate of deep vein thrombosis on day 7 after operation in the Xuesaitong group was lower than that in the control group	[41]
Rikkunshito (Liujunzi decoction)	Dried Atractyloidis lanceae rhizoma, Ginseng radix, Pi_x005f nelliae tuber, Hoelen, Zizyphi fructus, Aurantii nobilis percarpium, Glycyrrhizae radix, and Zingiberis rhizome	Rikkunshito and then off treatment (n = 4) vs off treatment and then Rikkunshito (n = 7)	On treatment and off treatment for 4 weeks each	Underwent PPG for early GC more than 5 years ago	Crossover design study	Improved gastric emptying and ameliorated postoperative symptoms of patients who had undergone a PPG	[39]
Dai-kenchu-to (Dajianzhong decotion)	Dried ginger root, ginseng, and zanthoxylum fruit	Dai-kenchu-to and then off treatment (n = 10) vs off treatment and then Dai-kenchu-to (n = 7)	On treatment and off treatment for 2 weeks each	Underwent total gastrectomy with jejunal pouch interposition for GC	Crossover design study	Reduced stasis-related symptoms, accelerated emptying of both liquid and solid meals from the pouch, increased intestinal motility and decreased postoperative symptoms	[42]
Fuzheng Huoxue anticancer prescription	Codonopsis pilosula (Franch.) N annf (15 g), Astragalus membranaceus (Fisch.) Bge (15 g), Atractylodes macrocephala Koidz (12 g), Poria cocos (Schw.) Wolf (12 g), Rehmannia glutinosa (Gaertn.) Lib osch (12 g), Adenophoratetraphylla (Thunb.) Fisch (15 g), Salvia miltiorrhiza Bge (15 g), and Angelica sinensis (Oliv.) Diels (12 g)	Fuzheng Huoxue anticancer prescription (n = 35) vs control prescription (n = 34)	Five days, starting at one month after an operation	Mid- or late-stage (23 cases received palliative surgery and 11 cases radical surgery)	RCT	Replenish vital functions (Zhengqi), correct a hypercoagulatory state, improve immunologic function, and extend patient survival times, directly inhibit gastric tumor growth without producing toxic side effects	[13]
Powder of eight Noble Ingredients and cinnamon twig and Poria pills	Ginseng, white atractylodes rhizome, Poria, Pinellia, 4 g each; tangerine peel and Fructus ZiZiphi Jujubae, 2 g each; liquorice, 1 g; dried ginger, 0.5 g; cinnamon twig, Poria, Moutan bark, peach seed, peony root, 4 g each	FAP regimen (5-fluorouracil, 300 mg/m2 intravenous gutta for five consecutive days; adriamycin, 40 mg/m2 for the first day), or the CODP regimens (cyclophosphamide, vincristine, daunorubicin, prednisone) (n = 31) vs FAP regimen and TCM (n = 32)	6 months	Metastasis formation after surgery for GC	RCT	Metastatic relapse was reduced and the ornithine decarboxylase levels of the gastric mucosa were sharply reduced	[27]
Modified ShengYangYiwei decoction	30 g ginseng, 9 g atractylodes macrocephala, 9 g poria, 60 g astragalus, 15 g white peony, 30 g pinellia ternata, 6 g rhizoma coptidis, 9 g rhizoma alismatis, 12 g dried tangerine peel, 10 g magnolia officinalis, 9 g rhizoma Notopterygii, 9 g angelica pubescens, 9 g fangfeng, 9 g bupleurum chinense, 5 g ginger, 6 g jujube (denuded), 6 g cohosh, 9 g kudzu, 9 g pueraria lobata, 15 g Shijian Chuan, 12 g divine koji, and 6 g raw licorice	Modified ShengYangYiwei decoction one week before the examination (n = 56) vs routine gastrointestinal endoscopy (n = 50)	One week before the examination	GC patients after painless gastroscopy	Prospective, randomized controlled study	Optimize the anesthesia program during painless gastroscopy, improve the gastrointestinal function of patients after the operation, reduce the occurrence of examination-related complications	[102]
Acupuncture	Bilateral ST-36 (Zusanli), SP-6 (Sanyinjiao), LI-4 (Hegu), TE-6 (Ziagou), LV-3 (Taichong), LI-11 (Quchi), and unilaterally at GV-20 (Baihui), EX-HN3 (Yintang), GV-26 (Shuigou), and CV-24 (Chengjiang)	Acupuncture (n = 18) vs non-acupuncture (n = 18)	Once daily for 5 consecutive days starting at postoperative day 1	Postoperative Ileus after Distal Gastrectomy for GC	Prospective, randomized controlled, phase III study	Promoting the passage of sitz markers in small intestine; reducing the duration of POI after gastric cancer surgery, by earlier recovery of small bowel movement	[45]
	Acupuncture therapy including electroacupuncture, manual acupuncture, moxibustion, TEAS, warm needling, and ear acupressure	Acupuncture therapy vs standard perioperative care or sham/placebo acupuncture	N/A	Postoperative gastrointestinal dysfunction in patients with gastric and colorectal cancer	Umbrella review (six systematic reviews/meta-analyses)	Improve postoperative gastrointestinal function for postoperative GC patients	[44]
	Zusanli (ST 36), Shangjuxu (ST 37), Xiajuxu (ST 39), Gongsun (SP 4), Sanyinjiao (SP 6)	Acupuncture + routine treatment (n = 40) vs routine treatment (continuous gastrointestinal decompression) (n = 40)	30 minutes each time, once a day, 5 days as a course, 1-3 courses	Functional delayed gastric emptying after GC surgery	RCT	The first exhaust time, remove gastric tube time, liquid food intake time and hospital stay were shortened	[103]
	Baihui (GV 20), Zusanli (ST 36), Neiguan (PC 6), etc.	High-dose acupuncture (n = 19) vs low-dose acupuncture (n = 20) vs control group (n = 19)	Chemotherapy cycle of 21 days, 3 courses	Patients with GC during adjuvant chemotherapy after gastrectomy	RCT	The total score and the scores of feeling of non-well being, pain and shortness of breath of ESAS in the acupuncture group were lower than the control group	[104]
	Bilateral ST 36 (Zusanli), SP 6 (Sanyinjiao), LI 4 (Hegu), TE 6 (Ziagou), LV 3 (Taichong), LI 11 (Quchi), and unilaterally at GV 20 (Baihui), EX HN3 (Yintang), GV 26 (Shuigou), and CV 24 (Chengjiang)	Acupuncture (n = 5) vs nonacupuncture (n = 5)	5 consecutive days starting on postoperative day 1	POI after GC surgery	Prospective, randomized, controlled pilot study	Reduce duration of POI after GC surgery, by earlier recovery of small bowel movement	[105]
Simo decoction + acupuncture	Fructus aurantii (Zhike), Radix aucklandiae (Muxiang), Semen arecae (Binlang), Radix linderae (Wuyao)PC6 (Neiguan), ST36 (Zusanli), LV-3 (Taichong), SP-6 (Sanyinjiao)	Control group (n = 30) vs Simo decoction (n = 30) vs acupuncture + Simo decoction (n = 30)	10 days	After radical surgeries for GC	RCT	Accelerate early air exhaustion and defecation, improve clinical symptoms, bi-directional regulate peripheral white blood cells	[106]
TEAS	Hegu (LI4), Neiguan (PC6), Weishu (BL21), Xiaochangshu (BL27), Zusanli (ST36), Shangjuxu (ST37)	TEAS therapy on postoperative day 1-3 (n = 41) vs usual care (n = 40)	3 days	Patients underwent radical surgery for GC (laparoscopy/robot)	Unblinded randomized controlled trial	Relieve postoperative pain and promote the recovery of gastrointestinal function	[49]
Electro-acupuncture	Bilateral ST36, PC6, SP4, and DU20, EX-HN3, and selected Back-shu points	High-dose EA (seven times each chemotherapy cycle for three cycles) + adjuvant chemotherapy vs low-dose EA (three times each chemotherapy cycle) + adjuvant chemotherapy vs or adjuvant chemotherapy	3 chemotherapy cycles	During adjuvant chemotherapy following gastrectomy	Open-label, multicenter, parallel controlled trial	Improve HRQOL, controlling symptom burden, and reducing toxicity during adjuvant chemotherapy in GC patients	[107]
Fu’s subcutaneous needling	Erector spinae muscle and rectus abdominis muscle	N/A	Once a day for three days	Progressive nausea, vomiting and stomach fullness, with a bloating abdomen ten days after laparoscopic radical gastrectomy for GC	Case report	Gastrointestinal motility enhancement and gastric drainage volume decrement	[46]
Acupuncture and moxibustion	N/A	Experimental group (n = 638) vs control group (n = 621)	N/A	Undergone any type of surgical treatment (e.g., partial gastrectomy, and total gastrectomy) and/or any chemotherapy regimen	Meta-analysis (fifteen RCTs)	Aid in gastrointestinal function recovery, reduce the incidence of AEs of surgery and chemotherapy, and improve immune function	[47]
Acupoint injection	Zusanli (ST36) acupoint injection with Neostigmine	ST36 acupoint injection with neostigmine 05 mg per side (n = 67) vs gluteal intramuscular injection with 1.0 mg neostigmine (n = 67) vs ST36 acupuncture alone (n = 67) vs standard therapy (n = 67)	Once a day until recovery of peristalsis	Patients with paralytic POI following gastrectomy for GC	RCT	Shorter time to bowel sound recovery, shorter time to first flatus and first defecation	[48]
Auricular point-pressing with bean	Acupoints of the stomach, spleen, large intestine, endocrine, subcortex, and small intestine	Auricular point-pressing with bean plus 20 mg EM tablets (n = 41) vs routine EM tablets (n = 37)	The therapist conducted compression once every 6 hours	Gastrointestinal dysfunction after ESD	Retrospective study	Alleviate the gastrointestinal dysfunction of early GC patients after ESD and help them to maintain normal gastrointestinal function	[57]
	Spleen acupoint, large intestine acupoint, and gastrointestinal pain point	Acupoint patch combined with ear acupoint bean pressing burrowing (n = 41) vs conventional nursing methods (n = 41)	Postoperative until 1 day before patient discharge	After laparoscopic surgery for gastric cancer	Retrospective study	Better adapt to the treatment process, reduce anxiety, and improve the treatment effect and quality of life	[108]
Auricular acupuncture	Shenmen, sympathetic nerve, thalamus, point zero, and omega 2	Sham auricular acupuncture (n = 20) vs auricular acupuncture (n = 20)	6 days	Postoperative movement-evoked pain after open radical gastrectomy	Single-blind randomized controlled pilot trial	Have a certain relief effect on mild postoperative pain at rest with pain score below 3	[62]
Traditional Chinese medicine nursing	(1) TCM psychological care; (2) Syndrome differentiation nursing; (3) Dietetic nursing; and (4) Nursing of auricular-plaster therapy of TCM: Auricular points: Spleen, stomach, sympathy, endocrine, large and small intestines	TCM nursing (n = 52) vs routine nursing (n = 51)	Until the patient was discharged from hospital	Postoperative patients with GC after radical gastrectomy	Prospective, randomized controlled study	Improve postoperative gastrointestinal dysfunction, alleviate acute inflammation, improve postoperative unhealthy mental state, reduce the occurrence of postoperative complications	[58]

TCM: Traditional Chinese medicine; POI: Postoperative ileus; POC: Postoperative complication; GC: Gastric cancer; N/A: Not applicable; HRs: Hazard ratios; CI: Confidence interval; QoL: Quality of life; PPG: Pylorus-preserving gastrectomy; EA: Electro-acupuncture; EM: Esomeprazole magnesium; ESD: Endoscopic submucosal dissection; DFS: Disease-free survival; RCT: Randomized controlled trial; TEAS: Transcutaneous electrical acupoint stimulation; ESAS: Edmonton symptom assessment system; HRQOL: Health-related quality of life; FAP regimens: 5-fluorouracil, adriamycin, cisplatin; CODP regimens: Cyclophosphamide, vincristine, daunorubicin, prednisone; EA: Electro-acupuncture.

Table 2 Anti-gastric cancer effects and corresponding mechanisms of traditional Chinese medicine formulae

TCM formulae	Compounds/constituents	Functions	Clinical stage	Experimental model	Effect	Specific mechanisms (pathways/targets)	Ref.
Sijunzi decoction	Radix Glycyrrhiizae (Gancao), Radix Ginseng (Renshen), Poria cocos Schw. (Fuling) and Rhizoma Atractylodes (Baizhu)	Nourishing spleen and enrich qi	GC tumor recurrence and treatment resistance	In vitro (MKN74 cellsand MKN45 cells)	Anti-tumor	Inhibit the nuclear accumulation and DNA-binding of β-catenin	[14]
Fuzheng Huoxue anticancer prescription	Codonopsis pilosula (Franch.) N annf Astragalus membranaceus (Fisch.) Bge, Atractylodes macrocephala Koidz, Poria cocos (Schw.) Wolf, Rehmannia glutinosa (Gaertn.) Lib osch, Adenophoratetraphylla (Thunb.) Fisch, Salvia miltiorrhiza Bge, and Angelica sinensis (Oliv.) Diels	Replenish vital functions (Zhengqi), improve blood stasis and circulation	Mid- or late-stage GC	In vitro (SGC-7901). In vivo (female nude mice)	Correct a hypercoagulatory state, improve immunologic function, extend patient survival times, and inhibit gastric tumor growth	NS	[13]
SRRS	Atractylodes macrocephala koidz (Baizhu), Poria cocos Schw. (Fuling), Sargentodoxa cuneata (Oliv.) Rehd. Et Wils. (Daxueteng), Prunella vulgaris L. (Xiakucao) and etc	Nourishing spleen	Advanced GC	In vitro (SGC-7901). In vivo (female BALB/C-nu/nu mice)	Inhibition of gastric cancer cell growth	Decrease the expression of bcl-2 mRNA inducing apoptosis	[109]
Composed Chinese medicine of Huachansu	Arenobufagin (11.14%), bufalin (18.67%), bufotalin (7.33%), cinobufagin (16.67%), cinobufotalin (16.74%), gamabufotalin (8.45%), resibufogenin (12.03%), and telocinobufagin (8.97%)	Anticancer	Advanced GC	In vitro (SGC7901, MGC803 and NCM460)	Suppression of proteasome activities and increase of ROS levels	Regulating PI3K/AKT and MAPK signaling pathways	[110]
Xiaojianzhong decoction	cassia twigs, paeonia, roasted licorice, ginger, jujube, and maltose sugar	Nourishing spleen and stomach, anticancer	GC	In vitro (AGS, HGC-27, and GES-1)	Suppressing the viability of GC cells, inducing apoptosis, arresting these cells in the G0/G1 phase, and inhibiting cell clone formation	Inhibiting the expression of IL6, PTGS2, MMP9, MMP2, and CCL2 proteins and promoted the expression of the heme oxygenase-1 protein	[111]
Yiqi Huayu decoction	Huangqi, Dangshen, Chenpi, Banxia, Baizhu, Baishao, Danggui, Sanleng, Ezhu, Sheshecao, Shijianchuan, Fulin, Muxiang, Sharen, and Gancao	Invigorating qi and invigorating spleen and removing blood stasis	GC after stage II and III operations	In vitro (AGS)	Anti-recurrence and metastasis of GC	Affecting the JAK2-STAT3 pathway and the expression of ACSL4, and induction of ferroptosis	[35]
Weifuchun	Radix Ginseng Rubra (red ginseng), Rabdosia amethystoides H. Hara (Xiangchacai), and fried Fructus Aurantii (Zhike)	Strengthen the spleen and replenish qi, promote blood circulation and detoxification, and alleviate flatulence and phlegm	GC	In vitro (AGS, MKN45, and SGC7901)	Inhibiting proliferation, migration, and inducing apoptosis in GC cells	Targeting candidate genes (TNFa, IL6, VEGFA, NFKB, MAPK1, and BAX)	[26]
				In vitro (NCI-N87, SNU-5, SNU-16, GES-1 cells, and Hs.738. St/Int cells)	Suppressing the malignant cellular phenotypes of GC cells	miR-26a-5p-mediated KPNA2 destabilization and the disruption of the MAPK pathway also enhances the repression of KPNA2	[32]
Daikenchuto	Zanthoxylum fruit (Huajiao), processed dried ginger (Ganjiang), ginseng (Renshen), and malt sugar (Maiyatang)	Stimulates intestinal motility	POI following abdominal surgery	In vivo (male BALB/c mice)	Recovery of the delayed intestinal transit	Inhibited the infiltration of neutrophils and CD68-positive macrophages, and inhibited mRNA expressions of TNF-α and MCP-1 may be partly mediated by activation of α7nAChR	[40]
Jianpi Yangzheng decoction	Astragali Radix (Huang Qi) (60 g), Codonopsis Radix (Dang Shen) (30 g), Sparganii Rhizoma (San Leng) (15 g), Curcumae Rhizoma (E Zhu) (15 g), Atractylodis Macrocephalae Rhizoma (Bai Zhu) (10 g), Angelicae Sinensis Radix (Dang Gui) (10 g), Paeoniae Alba Radix (Bai Shao) (10 g), Aucklandiae Radix (Mu Xiang) (10 g), Citri Reticulatae Pericarpium (Chen Pi) (10 g), and Glycyrrhizae Radix (Gan Cao) (5 g)	Anticancer, anti-metastasis	GC after chemotherapy	In vitro (MFC murine GC cell). In vivo (615-strain mice)	Impeding pre-metastatic niche formation and exhibiting anti-tumor metastasis effect	Reshaping the gut microbiota structure, enhancing SCFA production, and inhibiting the formation of the pre-metastatic microenvironment	[30]
				In vitro (MKN28, AGS, HGC-27, MKN74, MKN45 and MFC). In vivo (male BALB/c-nude mice)	Inhibitory effect on GC growth and metastasis	Elevates the abundance of CLDN18.2 in gastric cancer, suppresses the activity of YAP/TAZ signaling	[31]
				In vitro (AGS, HGC -27). In vivo (BALB/c nude mice)	Inhibit the invasion and migration of GC	Regulating TAM-exos miR-513 b-5p mediated PTEN/AKT signaling	[29]
Modified Jian-pi-yang-zheng decoction	-	Qi-invigorating, spleen-strengthening and stasis-removing	Advanced GC	In vitro (HGC-27 and THP-1 monocytes). In vivo (mice (615-strain)	Suppressed GC growth and metastasis	Inhibit GC cell EMT via PI3Kγ-dependent TAM reprogramming	[28]
Modified Gexia-Zhuyu Tang	Peach kernel (9 g), Safflower (9 g), Angelica sinensis (9 g), Chuanxiong (6 g), Red peony (6 g), Peony bark (6 g), YanhuSuo (3 g), Wulingzhi (6 g), Wuyao (6 g), Fructus Aurantii (4.5 g), Xiangfu (4.5 g), Licorice (9 g), Rhizoma atractylodis macrocephalae (12 g), Rhizoma curcumae (9 g), Hedyotis diffusa (15 g), and Scutellaria barbata (15 g)	Anticancer	GC	In vitro (MFC). In vivo (BALB/c male mice)	Inhibited GC tumor progression	Inhibits the growth, proliferation, metastasis, and invasion of GC by regulating the intestinal flora and promotes pyroptosis of GC	[43]
Xiaotan Sanjie recipe	Rhizoma Arisaematis, Pinellia Ternata, Atractylodes Macrocephala, Poria Cocos, Fritillaria sichuanensis, White Mustard Seed, Fructus aurantii, Pericarpium Citri Reticulatae, Radish Seed, Galli Gigerii Endothelium Corneum and Medicated Leaven (5:5:4:4:3:3:3:3:2:2:1)	Anti-metastasis	Advanced GC	In vitro (GC-7901, HGC-27, MKN-28, MKN-45, MGC80-3, BGC-823, MKN-7 and KAO-II). In vivo (Female BALB/c-nude mice)	Prevented GC metastasis	Inhibits the GnT-V-mediated E-cadherin glycosylation and promotes the E-cadherin accumulation at cell-cell junctions	[17]
				In vitro (SGC-7901 cells and HUVEC)	Inhibit angiogenesis in GC	Inhibit angiogenesis in gastric cancer through IL-8-linked regulation of the VEGF pathway	[18]
Banxia Xiexin decoction	Pinellia ternata (Thunb.) Makino 12 g, Zingiber officinale Roscoe 9 g, Scutellaria baicalensis Georgi 9 g, Coptis chinensis Franch. 3 g, Panax ginseng C.A.Mey. 9 g, Ziziphus jujuba Mill 12 g, and Glycyrrhiza uralensis Fisch 9 g	Protecting the gastrointestinal mucosa, improving gastrointestinal diseases, regulating human endocrine metabolism	Advanced GC	In vitro (AGS and GES-1)	Inhibits invasion, metastasis, and epithelial mesenchymal transition in GC	Inhibition of lncRNA TUC338 expression	[37]
Compound kushen injection	Kushen (Radix Sophorae Flavescentis) and Baituling (Rhizoma Heterosmilacis)	Anticancer, improve body immunity, relieve of cancer pain and bleeding	Advanced GC	In vitro (AGS, HGC-27, MKN-45, MKN-74, GES-1). In vivo (male mice)	Inhibit GC growth and metastasis, improve body's immunity, and protect normal tissues from damage	Regulating VCAM1 induced by the TNF signaling pathway to inhibit epithelial-mesenchymal transition of GC	[34]
				In vitro (BGC-803/MKN-28)	Inhibited GC cell growth and migration and induced GC cell apoptosis	Regulating the EMT process in GC cells through the PI3K/AKT signalling pathway	[33]
Yiwei decoction	Astragalus Membranaceus, Pinellia Ternate, Tetrastigma Hemsleyanum Diels et Gilg, Actinidia chinensis Planch, Ophiopogon Japonicus, Taraxacum mongolicum Hand, Paeonia lactiflora Pall, Coix lacryma-jobi L.var.ma-yuen (Roman.) Stapf, and Rabdosia amethstoides (Benth.) Hara	Anticancer, supplementing qi and strengthening the body	GC recurrence and metastasis	In vitro (HGC-27 , MFC, S180 cells). In vivo (Wistar rats)	Inhibit the proliferation of tumor cells	Inhibition of GC cell proliferation by spleen-derived exosomes inducing apoptosis	[11]
Ziyin Huatan recipe	Lilii Bulbus (Baihe.), Pinelliae Rhizoma (Fabanxia) and Hedyotis Diffusa (Baihuasheshecao)	Anti-metastasis	Advanced GC	In vitro (MGC-803 and SGC-790). In vivo (male BALB/c nude mice)	Inhibit migration and invasion of GC	Relate to the upregulation of RUNX3 expression	[19]
				In vitro (HGC27 and MGC803). In vivo (male BALB/c nude mice)	Inhibit cell proliferation and promote apoptosis in GC	Decrease the expression of Bcl-2 and Cyclin D1, modulate PI3K/AKT signaling pathway by inhibiting PI3K expression	[20]
Qi Ling decoction	Astragalus, Smilacisglabrae, Atractylodesmacrocephalae, Scutellariabarbata, Salvia chinensis, Benth, Eupolyphagasteleophaga, Agrimonia, and Forsythia suspense	Anti-metastasis, anti-tumor	Advanced GC	In vitro (BGC-823 and SGC-7901)	Inhibit the invasion, migration, and adhesion of GC cells	Inhibition of MMP-9 expression through the PI3K/AKT signaling pathway	[24]
Babao Dan	Natural bezoar, snake gall, antelope horn, pearl, musk, and Panax notoginseng	Anti-metastasis, anti-tumor	Advanced GC	In vitro (AGS and MGC80-3)	Inhibits the migration and invasion of GC cells	Inhibit TGF-β-induced EMT and inactivating TGF-β/Smad signaling in GC cells	[36]

TCM: Traditional Chinese medicine; GC: Gastric cancer; NS: Not stated CAG: Chronic atrophic gastritis; MAPK: Mitogen-activated protein kinase; KPNA2: Karyopherin subunit Alpha 2; POI: Postoperative ileus; SCFA; Short-chain fatty acids; VACM1: Vascular cell adhesion molecule 1; TNF: Tumor necrosis factor; MMP: Matrix metalloproteinases; TAM: Tumor-associated macrophages; HUVEC: Human umbilical vein endothelial cells; VEGF: Vascular endothelial growth factor; SGC: Stem cell growth factor; ROS: Reactive oxygen species; PI3K: Phosphoinositide 3-kinase; AKT: Protein kinase B; IL6: Interleukin 6; PTGS2: Prostaglandin-endoperoxide synthase 2; CCL2: C-C motif chemokine ligand 2; JAK2: Janus kinase 2; STAT3: Signal transducer and activator of transcription 3; ACSL4: Acyl-CoA synthetase long-chain family member 4; VEGFA: Vascular endothelial growth factor A; NF-κB: Nuclear factor kappa B; BAX: BCL2-associated X protein; MCP-1: Monocyte chemoattractant protein-1; YAP: Yes-associated protein; TAZ: Transcriptional coactivator with PDZ-binding motif; PTEN: Phosphatase and tensin homolog; EMT: Epithelial-mesenchymal transition; PI3Kγ: Phosphoinositide 3-kinase gamma; TAM: Tumor-associated macrophages; GnT-V: N-acetylglucosaminyltransferase V; VEGF: Vascular endothelial growth factor; RUNX3: Runt-related transcription factor 3; TGF-β: Transforming growth factor beta; Smad: Sma and mad related protein.

Table 3 Effects and specific mechanisms of single herbs and their ingredients for the treatment of gastric cancer

Herb	Active component/extract	Functions	Clinical stage	Experimental model	Effect	Specific mechanism	Ref.
Peel and pulp of citrus grandis, citrus paradise and orange (Zhike, Chenpi)	Naringin	Anti-tumor	GC	In vitro (MGC803 and MKN45 GC cells). In vivo (BALB/c female nude mice)	Block the cell-cycle of GC cells	Induce cancer cell apoptosis, and inhibit the epithelial mesenchymal transition process by inhibiting the PI3K-AKT/Zeb1 pathway	[66]
Poria cocos (Fuling)	Pachymic acid	Anti-tumor	GC	In vitro (SGC-7901, AGS, and GES-1). In vivo (BALB/c nude mice)	Ferroptosis in GC cells	Suppressing the PDGFRB-mediated PI3K/AKT pathway	[67]
	Poria acid			In vitro (AGS and MKN-28)	Inhibit the invasion and metastasis of GC cells	Inhibit the EMT process and expressions of metastasis-related proteins matrix metalloproteinase in GC cells	[68]
Cimicifugae Rhizoma (Shengma)	Cimifugin	Anti-tumor	GC	In vitro (MKN28)	Inhibits GC cell proliferation, invasion, and migration	Interacts with AKR1C2, MAOB and PDE2A to modulate various metabolic pathways	[69]
the roots of Plumbago zeylanica (Banlangen)	Plumbagin	Anti-tumor	GC	In vitro (SGC-7901 cells)	Inhibits cell apoptosis in human GC cells	Suppressed the expression of BAX, BCL-2, pro-caspase-3, and cleaved-caspase-3; restrained the expression and phosphorylation of STAT3 and decreased the phosphorylation of AKT1	[70]
Eremias multiocellata	N/A	Removing blood stasis, eliminating nodules	Cisplatin-resistant GC	In vitro (MKN45/DDP). In vivo (BALB/c nude mice)	Reversing DDP resistance and increasing the sensitivity of gastric cancer drug-resistant cells to DDP	Regulating the NF-κB/Snail signaling pathway, PI3K/AKT/mTOR signaling pathway, and the expression of drug resistance-related proteins and genes	[112]
Salvia miltiorrhiza Bunge (Danshen)	Diterpenoid tanshinones	Activating blood circulation and removing blood stasis	GC	In vitro (SGC-7901, HUVECs). In vivo (BALB/c-nu nude mice)	Inhibit tumor growth and angiogenesis	Affecting the expression of the angiogenic factor VEGF through the PI3K/AKT/mTOR pathway	[73]
Celastrus orbiculatus Thunb (Leigongteng)	Triptonoterpene	Anti-metastasis, anti-tumor	Advanced GC	In vitro (BGC-823, MKN-28)	Inhibit the migration and invasion of GC cells	Inhibit the changes in EMT-related and invasion and metastasis-related proteins	[71]
				In vitro (BGC-823 and AGS). In vivo (nude mice)	Inhibit the metastasis and EMT of GC cells	Inhibited the remodeling of the actin skeleton of gastriccancer cells by promoting the degradation of CFL1	[72]
Trametes robiniophila Murr. (Huaier)	Huaier n-butanol extract	Anti-metastasis, anti-tumor	Advanced GC	In vitro (GES-1, MGC803, MKN74, AZ-521, and MKN28). In vivo (nude mice)	Inhibits GC growth and hepatic metastasis	Inhibiting the syntenin/STAT3 signaling pathway and reversing EMT	[76]
Rhizoma coptidis (Chaihu)	Berberine	Anti-inflammatory, anti-tumor	Advanced GC	In vitro (MKN-45 and HGC-27 and GES-1). In vivo (male BALB/C nude mice)	Inhibits GC cell proliferation	Modulating the signaling pathways related to IL-6/JAK2/STAT3	[77]
Paeonia suffruticosa Andr. (Mudanpi)	Paeonol	Anti-tumor, anti-inflammation, immune regulation	Apatinib-resistant GC	In vitro (BGC-823 and MGC-80). In vivo (female BALB/C nude mice)	Inhibit the malignancy of Apatinib-resistant GC cells	Regulating the LINC00665/miR-665/MAPK1 axis	[81]
Brucea javanica (Yadanzi)	Brusatol	Antitumor	Advanced GC	In vitro (SGC-7901)	Suppress GC cell proliferation, migration, invasion, and EMT formation	Inhibit LPS-induced EMT via the deactivation of the PI3K/AKT/NF-кB signaling pathway	[83]
Curcuma (wenyujin)	β-Elemene	Anti-metastasis, anti-tumor	Multidrug resistant GC	In vitro (SGC7901, SGC7901/ADR). In vivo (male BALB/C nude mice)	Inhibits the metastasis of multidrug resistant GC cells	Modulating the miR-1323/Cbl-b/EGFR signaling axis	[86]
Highly toxic beetles of the family Meloidae	Cantharidin	Anti-metastasis, anti-tumor	Advanced GC	In vitro (MGC803 and BGC823)	Suppress GC cell growth and migration/invasion	Inhibited the activation of the PI3K/AKT signaling pathway by downregulating CCAT1 targeting	[89]
Arachis hypogaea Linn. and Vitis vinifera Linn.	Resveratrol	Anti-metastasis, anti-tumor	Advanced GC	In vitro (SGC7901, BGC823 and GES1)	Suppress the invasion and migration of human GC cells	Inhibition of MALAT1-mediated epithelial-to-mesenchymal transition	[92]
			Interleukin-6 induced GC metastasis	In vitro (SGC-7901). In vivo (male NOD/SCID mice)	Prevent the IL-6 induced GC metastasis	Block the IL-6 induced invasion through the blocking of Raf-MAPK signaling pathway	[93]
Radix Angelica Sinensis (danggui)	N-butylidenephthalide	Anti-metastasis, anti-tumor	Advanced GC	In vitro (AGS, NCI-N87 and TSGH-9201). In vivo (NOD-SCID mice)	Inhibit proliferation and induces mitochondrial-dependent apoptosis in GC cells	Activation of mitochondria-intrinsic pathway and induced the REDD1 expression leading to mTOR signal pathway inhibition in GC cells	[94]
Venenum Bufonis (Chan Su)	Bufalin	Anti-invasion, anti-metastasis	Advanced GC	In vitro (AGS). In vivo (male BALB/c mice)	Arrests GC invasion and metastasis	Down-regulation of the Wnt/β-catenin signaling pathway, followed by the inhibition of ASCL2 expression and EMT	[95]
Ginseng	Ginsenoside Rg3	Anti-metastasis, anti-tumor	Metastatic GC	In vitro (NUGC-4). In vivo (female BALB/c mice)	Inhibite tumor growth and reduced lymphatic metastasis	Suppress expression of VEGF-C, VEGF-D and VEGFR-3	[96]

GC: Gastric cancer; GPL: Gastric precancerous lesions; STAT3: Signal transducer and activator of transcription 3; AKT: Protein kinase B; DDP: Cisplatin; VEGF: Vascular endothelial growth factor; HUVEC: Human umbilical vein endothelial cell; EMT: Epidermal mesenchymal transition; LPS: Lipopolysaccharide; MALAT1: Metastasis-associated lung adenocarcinoma transcript 1; ASCL2: Achaete-scute-like 2; PI3K: Phosphoinositide 3-kinase; Zeb1: Zinc finger E-box-binding homeobox 1; PDGFRB: Platelet-derived growth factor receptor beta; AKR1C2: Aldo-keto reductase family 1 member C2; MAOB: Monoamine oxidase B; PDE2A: Phosphodiesterase 2A; AX: Axin; BCL-2: B-cell lymphoma 2; STAT3: Signal transducer and activator of transcription 3; NF-κB: Nuclear factor kappa B; Snail: Snail family transcriptional repressor 1; mTOR: Mechanistic target of rapamycin; VEGF: Vascular endothelial growth factor; CFL1: Cofilin-1; IL-6: Interleukin-6; JAK2: Janus kinase 2; MAPK1: Mitogen-activated protein kinase 1; Cbl-b: Casitas B-lineage lymphoma b; EGFR: Epidermal growth factor receptor; CCAT1: Colon cancer-associated transcript 1; REDD1: Regulated in development and DNA damage responses 1.

Table 4 Planned and ongoing clinical studies of traditional Chinese medicine for the treatment of gastric cancer

TCM	Compounds/constituents	Condition	Intervention	Study design	Time frame	Phase	Status	Primary outcome	Secondary outcomes	NCT number
TCM collaborative model	Radix Pseudostellariae (12 g), Rhizoma Atractylodis Macrocephalae (12 g), Poria (30 g), Rhizome Pinelliae Preparata (9 g), green tangerine peel (4.5 g), Concha Ostreae (30 g), and Prunella vulgaris (9 g)	Stage IIIb and IIIc gastric cancer who undergo radical surgery for D2 lymphadenectomy	Adjuvant chemotherapy (oxaliplatin plus capecitabine or S-1; or docetaxel plus S-1; docetaxel plus oxaliplatin plus 5-FU) (n = 130) vs adjuvant chemotherapy + TCM formula + auricular acupressure and acupoint therapy (n = 130)	Prospective, multicenter, randomized, open-label trial	36 months	Phase 2, phase 3	Completed	3-year DFS rate	Quality of life, side effects caused by chemotherapy, and safety-related measures	NCT03607656
Yiqi Wenyang Jiedu prescription	Astragalus membranaceus (30 g), Codonopsis pilosula (15 g), Angelica dahurica (10 g), Curcuma zedoary (9 g), Rhizoma nardostachyos (10 g), Polygonum cuspidatum (10 g), Radix Actinidiae chinensis (15 g), and Paris polyphylla (9 g)	Completed adjuvant chemotherapy within 8 months of radical gastrectomy	YWJP (n = 106) vs YWJP placebo (n = 106)	Multicenter, randomized, double-blind, placebo-parallel-controlled clinical trial	24 weeks	Phase 4	Unknown	DFS rate 2 years after surgery	DFS time, overall survival, annual cumulative recurrence and rate of metastasis after 1-3 years, cumulative annual survival after 1-3 years, fat distribution-related indicators, tumor markers, peripheral blood inflammatory indicators, prognostic nutritional index, symptoms and quality of life evaluation, medication compliance, and adverse reaction rate	NCT05229809
Hou Gu Mi Xi (modified Shen Ling Bai Zhu San)	Ginseng, tuckahoe, baked licorice, coixenolide, Chinese yam, lotus seed, shrinkage fructus amomi, white hyacinth bean, dried orange peel, and perilla leaf	Spleen qi deficiency status in GC patients after radical gastrectomy	Dietary supplement: Hou Gu Mi Xi (n = 65) vs Other: Placebo (n = 65)	Multicenter, randomized, double-blinded, parallel-group, placebo-controlled trial	104 weeks	N/A	Terminated (high attrition rate)	Spleen Qi deficiency symptoms grading and quantifying scale	Quality of life assessed by the Short Form 36 scale, performance status as assessed by the Eastern Cooperative Oncology Group Performance Status scale, body weight, and body mass index	NCT03025152
Modified Banxia Xiexin decoction	N/A	Stage IV GC	Modified Banxia Xiexin decoction combined chemotherapy (n = 73) vs placebo granules combined chemotherapy (n = 73)	Randomized clinical trial	18 weeks	Early phase 1	Completed	Overall survival	Progression-free survival, solid tumor efficacy, TCM syndrome score, quality of life score, tumor markers, Immune function and adverse reactions	NCT05908838
Huaier granule	N/A	Patients with stage II or III gastric adenocarcinoma who undergo radical gastric adenocarcinoma within 2 months of surgery	Huaier granule (n = 351) vs SOX regimen (n = 351)	Prospective, multi-center, open-label, randomised controlled study	3 years	Phase 4	Not yet recruiting	3-year DFS rate	1-, 2-, 3-year OS rate, 1-, 2-, 3-year local recurrence-free survival rate, 1-, 2-, 3-year distant metastasis-free survival rate, quality of life score	NCT05498766
Weifichun	N/A	Gastric adenocarcinoma patients undergoing chemotherapy	Weifichun combined chemotherapy (n = 36) vs chemotherapy (n = 36)	Randomized clinical trial	24 weeks	Early phase 1	Completed	OS rate	Progression-free survival, EuroPean organization for Research and Treatment Quality of Life Scale, clinical symptoms, tumor markers, immune function	NCT05888675
Acupuncture	Acupuncture at back-shu points according to heat-pain threshold measurement at 24 well-points, combining with electro-acupuncture at fixted acupoints	GC patients after R0 resection and D2 lymph node dissection	High-dose acupuncture + chemotherapy vs low-dose acupuncture + chemotherapy vs none-acupuncture	Randomized, open label, pilot study	3 cycles of adjuvant chemotherapy	N/A	Completed	FACT-gastric trial outcome index, C-ESAS	Incidence of treatment-emergent adverse events, adherence to chemotherapy, concentration of inflammatory factors in plasma, circulating myeloid-derived suppressor cells, circulating CD8+ T lymph cells, circulating tumor cells	NCT03753399
	N/A	POI after gastrectomy in patients with GC	Acupuncture vs none-acupuncture	Prospective randomized pilot study	5 postoperative days	N/A	Completed	Remnant sitz markers in small intestine	Time to first flatus, start of water intake, start of soft diet, hospital stay	NCT02480361
	For participants with abdominal distension: LI4, PC6, ST36, SP6. For participants with post-operative ileus: LI4, SJ6, ST36, ST37	Underwent abdominal surgery within one month	Electroacupuncture combined with metoclopramide vs metoclopramide	Non-randomized, parallel assignment	3 days	N/A	Unknown	Visual Analogue Scale, daily feeding volume, gastric residual volume	Acute Physiology and Chronic Health Evaluation II score, Sequential Organ Failure Assessment score, Physiological and operative severity scores for the enumeration of mortality and morbidity score, blood examination	NCT04467528
	Electroacupuncture at Baihui, Nei guan, bilateral Zu sanli and bilateral Tian shu	Patients with gastric cancer who undergoing gastrectomy	Electroacupuncture vs Sham electroacupuncture	Randomized, parallel assignment	7 days	N/A	Unknown	Gastrointestinal function score	Physical fitness index	NCT03291574

N/A: Not applicable; YWJP: Yiqi Wenyang Jiedu prescription; DFS: Disease-free survival; OS: Overall survival; POI: Postoperative ileus; C-ESAS: Chinese version of edmonton symptom assessment scale; GC: Gastric cancer; 5-FU: 5-Fluorouracil; TCM: Traditional Chinese medicine; SOX: Sry-related HMG-box; FACT: Facilitates chromatin transcription.