Association of Sijunzi decoction plus chemotherapy with gastrointestinal function and serum markers in patients after gastric carcinoma surgery

Abstract

BACKGROUND

The deleterious effects of surgical trauma and subsequent postoperative complications pose significant challenges to the smooth recovery of patients after gastric cancer (GC) resection despite the substantial curative benefits provided by surgical interventions for GC. Hence, the investigation of more optimal and efficacious treatment approaches has become an urgent necessity in the medical community.

AIM

To investigate the association of Sijunzi decoction plus chemotherapy with the gastrointestinal function and serum markers of patients after GC surgery.

METHODS

This study included patients who underwent GC surgery from June 2022 to February 2024. The control group included 45 patients who received chemotherapy (oxaliplatin + calcium folinate + 5-fluorouracil), whereas the research group consisted of 54 patients who received Sijunzi decoction therapy in addition to the treatment administered in the control group. Comparative analyses were conducted from the following perspectives: Gastrointestinal function (defecation time, intestinal gas discharge time, and hospitalization time), serum markers [carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 125, and CA199], nutritional indicators [total protein (TP) and transferrin (TRF), traditional Chinese medicine (TCM) syndrome score, and grades III–IV adverse events (gastrointestinal reactions, renal/liver function impairment, and myelosuppression).

RESULTS

The two groups demonstrated similar defecation time (P > 0.05), but the intestinal gas discharge time and hospitalization time were significantly shortened in the research group (P < 0.05). Further, the research group exhibited significant CEA, CA125, and CA199 reductions after treatment, which were lower compared to the control group, as well as notable increases in TP and TRF that were statistically higher than the control group (all P < 0.05). Furthermore, the research group demonstrated an evident decrease in TCM syndrome scores in areas, such as poor appetite, epigastric distension and pain, fatigue and weakness (P < 0.01), and abdominal distension after eating, which are notably lower than those in the control group (P < 0.01), with a comparable incidence of grades III–IV adverse events (P > 0.05).

CONCLUSION

Our research results indicate that Sijunzi decoction plus chemotherapy exerts a good rehabilitation-promoting effect on gastrointestinal function in patients after GC surgery and significantly downregulates abnormally increased CEA, CA125, and CA199 levels.

Key Words: Sijunzi decoction; Chemotherapy; Gastric carcinoma; Gastrointestinal function; Serum markers

Core Tip: Considering the scarcity of existing research regarding the association of the combination of Sijunzi decoction and chemotherapy with the gastrointestinal function and serum markers of patients after gastric cancer (GC) surgery, this investigation has meticulously conducted a comprehensive, multi-faceted comparative analysis of the clinical efficacy between the therapeutic approach of Sijunzi decoction combined with chemotherapy and chemotherapy alone in such patient populations. The assessment covers a wide array of aspects, including gastrointestinal function, serum markers, nutritional parameters, traditional Chinese medicine syndrome scores, and adverse events. The research results confirmed that the combined Sijunzi decoction and chemotherapy treatment effectively alleviated symptoms, such as poor appetite, epigastric distension and pain, fatigue and weakness, and abdominal distension after eating, besides its remarkable capacity to improve gastrointestinal function, optimize nutritional status, and rectify abnormally increased serum tumor markers in patients after GC surgery. These results will provide novel perspectives and valuable guidance for the clinical management of patients after GC surgery.

INTRODUCTION

Gastric cancer (GC), a cancer with complex etiologies and heterogeneity, is a crucial primary epithelial malignancy that originates from the stomach[1]. Race, diet, genetic alterations, smoking, alcohol abuse, and Helicobacter pylori infection are prevalent pathogenic factors for GC[2]. Global statistics report nearly 1.1 million new GC cases and approximately 800000 deaths annually despite the decline in the incidence and mortality risks of GC[3]. Surgery remains the most crucial and predominantly used approach among the various treatment modalities for GC, including surgery, radiotherapy, chemotherapy, and basic supportive treatment[4,5]. Factors, such as surgical trauma, postoperative complications, and patients’ insufficient disease awareness, affect the recovery of gastrointestinal function in patients after GC surgery despite the good efficacy of surgery[6-8]. Hence, the primary emphasis of contemporary research should be firmly focused on exploring innovative therapeutic modalities, with the overarching objective of expediting patient recovery.

Previous evidence has indicated that chemotherapy for patients during GC surgery helps improve the prognosis and survival outcomes of those with resectable gastroesophageal adenocarcinoma[9]. The FOLFOX regimen, consisting of oxaliplatin + calcium folinate + 5-fluorouracil (5-Fu), is a predominant chemotherapy option for patients during GC surgery, with its definite efficacy documented in patients with advanced GC[10,11]. Previous studies have revealed that the FOLFOX regimen plays a pivotal role in augmenting the long-term survival rate of patients diagnosed with localized GC. However, it exerts certain detrimental effects on patients’ quality of life. Moreover, it may result in a certain degree of chemotherapy tolerance as well as potential toxic and side effects[12,13]. Sijunzi decoction, a traditional Chinese medicine (TCM) with the effect of invigorating the spleen, can eliminate tumor cells and exert a certain inhibitory effect on tumor metastasis, demonstrating a certain therapeutic potential for tumor diseases[14]. A rat experiment revealed that the use of Sijunzi decoction significantly inhibited the growth of GC side population cells and induced their apoptosis[15]. Moreover, literature has exhibited that Sijunzi decoction plays a certain therapeutic role in intestinal metaplasia of gastric mucosa, thereby providing a new therapeutic direction for treating precancerous lesions and preventing GC[16].

However, the current research on the effects of Sijunzi decoction combined with chemotherapy on the gastrointestinal function and serum markers of patients after GC remains relatively limited. We believe that analyzing this aspect is beneficial to filling the relevant gaps and expanding the treatment options for such patients.

MATERIALS AND METHODS

General information

This retrospective study included 99 patients with GC who underwent surgery at the Affiliated Hospital of Liaoning University of TCM from June 2022 to February 2024. Patients were categorized into distinct groups based on the variance in treatment regimens. Of them, 45 cases in the control group received chemotherapy (oxaliplatin + calcium folinate + 5-Fu); whereas, 54 cases in the research group were treated with Sijunzi decoction in addition to the treatment administered in the control group. The inclusion of patients in each group is identified with strict adherence to the following inclusion and exclusion criteria to ensure representativeness. Meanwhile, the number of patients in each group is meticulously confirmed to meet the minimum thresholds established through sample size estimation methodologies.

Patient selection criteria

Inclusion criteria: Conforming to the relevant diagnostic criteria specified in the diagnostic criteria for GC[17]; TCM diagnosis: Spleen-qi deficiency diagnosis based on the Guide to Diagnosis and Treatment of Digestive Diseases in TCM[18]; treatment with radical gastrectomy for GC; stages I–III GC without lymph node metastasis; first-time treatment; complete clinical data.

Exclusion criteria: Estimated survival of < 3 months; previous chemoradiotherapy treatment; other malignancies; severe cardiovascular, lung, brain, or kidney dysfunction; immune deficiency; infectious or metabolic disorders; psychological or mental disorders; woman during pregnancy or lactation.

Treatment methods

The control group received the FOLFOX chemotherapy scheme. On the first day, oxaliplatin (130 mg/m²) was intravenously administered. From day 1 to day 5, an intravenous infusion of 200 mg/m² of calcium folinate was administered, followed by an intravenous drip of 5-Fu at 400 mg/m². A 21-day period constitutes one treatment course, with a total of four courses administered. The research group was further administered a modified Sijunzi decoction in addition to the above treatment. The prescription consisted of Codonopsis pilosula (30 g), Poria cocos (15 g), Atractylodes macrocephala (15 g), and Radix Glycyrrhizae Preparata (15 g). Astragalus membranaceus at 30 g was added for patients with severe qi deficiency, dried tangerine peel at 12 g and Rhizoma Pinelliae Preparata at 10 g for those with nausea and vomiting, Evodia rutaecarpa at 3 g and Coptis chinensis at 6 g for patients with pantothenic acid and stomach burning sensation, and Radix Aucklandiae at 8 g and Fructus Aurantii at 9 g for patients with qi stagnation. The prescription was given 1 dose/day, which was decocted with water to obtain liquid of 300 mL for administration in the morning and evening (150 mL each time), for 12 weeks. Both groups were treated with antiemesis and vital organ function protection while receiving chemotherapy.

Analysis indexes

(1) Gastrointestinal function: The defecation time, intestinal gas discharge time, and hospitalization time of all patients were documented; (2) Serum markers: Fasting venous blood with a volume of 4 mL was sampled from both patient cohorts and centrifuged to separate the serum for low-temperature preservation and subsequent testing before and after treatment. Enzyme-linked immunosorbent assays (ELISAs) were conducted to identify carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 125, and CA199 levels; (3) Nutritional indicators. ELISA was used to detect total protein (TP) and transferrin (TRF) in patients’ serum samples; (4) TCM syndrome scores. Changes in TCM syndrome scores before and after treatment were documented, including poor appetite, gastric pain and distension, fatigue and weakness, and abdominal distension after eating. The scores ranged from 0 to 6 points according to the severity of the patient’s symptoms, with a total score of 24 points. The more severe the symptom manifestation, the higher the corresponding score; and (5) Safety: Cases with grade III–IV adverse reactions, including gastrointestinal reaction, renal/liver function impairment, and myelosuppression, were observed and recorded, with the incidence rates calculated.

Among the aforementioned indicators, those involving pre- and post-treatment measurements were all assessed before treatment and 12 weeks after treatment initiation.

Statistical analysis

The mean ± SE of the mean was used to statistically describe the quantitative data. The between-group comparisons of measurement data were conducted using independent sample t-tests, and pre- and post-treatment comparisons employed paired t-tests. Enumeration data were expressed as rates (percentages), and the between-group comparisons adopted χ² tests. The obtained experimental data were analyzed by Statistical Package for the Social Sciences version 22.0. A P value of < 0.05 indicated statistical significance.

RESULTS

Patients’ general information

We revealed no evident inter-group differences in terms of age, sex, average body mass, tumor-nodes-metastasis staging, education level, and family history when comparing patients’ general information (P > 0.05, Table 1).

Table 1 Patients’ general information.

General data	Control group (n = 45)	Research group (n = 54)	χ2/t	P value
Age (years old)	51.47 ± 6.98	52.59 ± 5.88	0.867	0.388
Sex	29/16	30/24	0.805	0.370
Average body mass (kg)	70.91 ± 5.88	68.67 ± 8.25	1.526	0.130
Tumor-nodes-metastasis staging (I/II/III)	9/24/12	11/25/18	0.607	0.738
Histological classification (poorly differentiated adenocarcinoma/tubular adenocarcinoma/signet-ring cell carcinoma)	22/18/5	25/22/7	0.108	0.948
Education level (below senior high school/senior high school or above)	21/24	18/36	1.828	0.176
Family medical history (none/yes)	37/8	40/14	0.943	0.332

Gastrointestinal function

The defecation time was 29.87 ± 3.53 hours, the exhaustion time was 31.93 ± 3.46 hours, and the hospitalization time was 15.20 ± 4.62 days in the control group. Conversely, the defecation time was 28.94 ± 2.38 hours, the intestinal gas discharge time was 22.11 ± 3.50 hours, and the length of hospital stay was 12.67 ± 3.36 days in the research group. Comparative analyses revealed comparable defecation time in the control and research groups (P > 0.05) but shortened intestinal gas discharge time and hospitalization duration in the research group (P < 0.05, Figure 1).

Figure 1 Defecation time, intestinal gas discharge time, and hospitalization time of the two groups. A: Inter-group comparison of defecation time; B: Inter-group comparison of intestinal gas discharge time; C: Inter-group comparison of hospitalization time. ^aP < 0.05, ^bP < 0.01.

Serum markers

In the control and research groups, the CEA levels were 31.84 ± 3.74 ng/mL and 32.37 ± 3.519 ng/mL before treatment and 17.36 ± 2.89 ng/mL and 11.50 ± 2.73 ng/mL after treatment, the CA125 levels were 59.71 ± 8.52 IU/mL and 62.13 ± 8.49 IU/mL before treatment and 35.02 ± 7.26 IU/mL and 21.61 ± 4.06 IU/mL after treatment, and the CA199 levels were 85.47 ± 6.34 IU/mL and 85.96 ± 6.81 IU/mL before treatment and 27.69 ± 3.18 IU/mL and 17.33 ± 2.77 IU/mL after treatment, respectively. The detection of serum markers, such as CEA, CA125, and CA199, revealed no statistical difference in all these indicators before treatment (P > 0.05). Further, all the indexes were significantly inhibited after treatment in the research group (P < 0.05), with lower levels than the control group (P < 0.05, Figure 2).

Figure 2 Serum markers of two groups. A: Inter-group comparison of carcinoembryonic antigen levels; B: Inter-group comparison of carbohydrate antigen 125 (CA125) levels; C: Inter-group comparison of CA199 levels. ^bP < 0.01, ^cP < 0.001. CEA: Carcinoembryonic antigen; CA: Carbohydrate antigen.

Nutritional indicators

The TP levels were 57.62 ± 4.24 g/L and 57.78 ± 4.31 g/L before treatment, which increased to 61.64 ± 4.32 g/L and 66.50 ± 4.73 g/L after treatment in the control and research groups, respectively. The TRF levels were 2.12 ± 0.20 g/L and 2.15 ± 0.23 g/L before treatment, which increased to 2.34 ± 0.39 g/L and 2.87 ± 0.35 g/L after treatment in the control and research groups, respectively. The detection of nutritional indicators, such as TP and TRF, in the two groups revealed similar levels before treatment (P > 0.05) and significantly increased levels after treatment (P < 0.05). Moreover, the research group demonstrated higher TP and TRF levels than the control group after treatment (P < 0.05, Figure 3).

Figure 3 Nutritional indicators. A: Inter-group comparison of total protein levels; B: Inter-group comparison of transferrin levels. ^aP < 0.05, ^bP < 0.01. TP: Total protein; TRF: Transferrin.

TCM syndrome scores

Poor appetite scores were 4.49 ± 0.59 points and 4.31 ± 0.58 points before treatment, which decreased to 3.02 ± 0.94 points and 2.11 ± 0.57 points after treatment in the control and research groups, respectively. Epigastric distension and pain scores were 4.42 ± 0.66 points and 4.31 ± 0.67 points before treatment, which decreased to 2.93 ± 0.65 points and, significantly, 1.93 ± 0.64 points after treatment in the control and research groups, respectively. Fatigue and weakness scores were 4.27 ± 0.54 points and 4.07 ± 0.70 before treatment, which decreased to 2.36 ± 0.68 points and 1.70 ± 0.54 points after treatment in the control and research groups, respectively. Abdominal distension after eating scores were 4.69 ± 0.51 points and 4.48 ± 0.69 points before treatment, which decreased to 2.89 ± 0.80 points and 2.09 ± 0.81 points after treatment in the control and research groups, respectively. The comparative analysis of pre- and post-treatment TCM syndrome scores in terms of poor appetite, epigastric distension and pain, fatigue and weakness, and abdominal distension after eating revealed no significant difference in each TCM syndrome score between groups before treatment (P > 0.05). Further, each TCM syndrome score of both groups was decreased after treatment (P < 0.05), particularly in the research group (P < 0.05, Figure 4).

Figure 4 Traditional Chinese medicine syndrome scores. A: Poor appetite scores before and after treatment in the two groups; B: Epigastric distension and pain scores before and after treatment in the two groups; C: Fatigue and weakness scores of the two groups before and after treatment; D: Abdominal distension after eating scores before and after treatment in the two groups. ^bP < 0.01, ^cP < 0.001.

Incidence of grade III–IV adverse events in the control and research groups

The incidence rates of grade III-IV adverse events, such as gastrointestinal reactions, renal/liver function impairment, and myelosuppression, indicated comparable incidence rates in the control and research groups (P > 0.05, Table 2).

Table 2 Incidence of grade III-IV adverse events, n (%).

General data	Control group (n = 45)	Research group (n = 54)	χ2	P value
Gastrointestinal reaction	4 (8.89)	3 (5.56)
Renal function impairment	2 (4.44)	2 (3.70)
Liver function impairment	2 (4.44)	1 (1.85)
Myelosuppression	1 (2.22)	1 (1.85)
Total	9 (20.00)	7 (12.96)	0.897	0.344

DISCUSSION

Surgical resection is the primary treatment method for patients with GC. However, it may cause postoperative gastrointestinal dysfunction, mainly manifested as weakened gastrointestinal peristalsis and consequently the gradual gastrointestinal secretion accumulation[19]. This does not only induce nutritional deficiency in patients with GC but may also cause systemic dysfunction, affecting normal postoperative recovery[20,21]. Thus, exploring an effective treatment method that is beneficial for the recovery of gastrointestinal function in patients after GC surgery is extremely important.

The theory of TCM indicates that patients after GC surgery present manifestations, such as blood and qi deficiency and spleen and stomach weakness, which may further result in insufficiency of the body’s vital qi[22]. Sijunzi decoction is composed of Radix Codonopsis, Poria cocos, Rhizoma Atractylodis Macrocephalae, Radix Glycyrrhizae Preparata, etc. Codonopsis pilosula benefits qi, harmonizes the stomach, strengthens the spleen, and dries dampness. Poria cocos and Rhizoma Atractylodis Macrocephalae are conducive to restoring the function of transporting spleen-qi and oozing dampness and turbidity out of the body. Radix Glycyrrhizae Preparata exerts effects of invigorating qi, tonifying the spleen, and harmonizing various medicines. The above medicines work together to exhibit the role of reinforcing the spleen and invigorating the stomach. The dosage of Astragalus membranaceus is increased in patients with severe qi deficiency to maximize therapeutic effectiveness[23-26]. Previously, several studies have conducted in-depth analyses of the therapeutic mechanism of Sijunzi decoction. Ding et al[27] emphasized that the therapeutic mechanism of Sijunzi decoction in GC may be associated with its effects of vascular proliferation inhibition and phosphoinositol-3-kinase/protein kinase B pathway regulation to induce apoptosis. Li et al[28] revealed that the anti-GC therapeutic effect of Sijunzi decoction is associated with its suppression effects on β-catenin nuclear accumulation and DNA binding activity. In this study, the research group demonstrated shorter defecation time than the control group, but the difference was not significant. However, the intestinal gas discharge time and hospitalization time were significantly shorter in the research group than in the control group, indicating that the combination of Sijunzi decoction and chemotherapy is somewhat beneficial for gastrointestinal function and postoperative recovery improvement in patients after GC surgery. This could be because the herbal components of Sijunzi decoction can ameliorate the spleen-deficiency syndrome in patients. They achieve this by alleviating diarrhea, rectifying gastrointestinal hormone and neurotransmitter secretion disorders, and mending ileal morphology and intestinal barrier damage[29]. The measurement of nutritional indicators revealed statistically increased TP and TRF after treatment in the research group, which was notably higher than in the control group, indicating that Sijunzi decoction plus chemotherapy in patients after GC surgery could significantly improve the nutritional status. The above-mentioned effects may be attributed to various components utilized in the Sijunzi decoction. Once harmonized, they synergistically perform functions such as strengthening the spleen, benefiting the stomach, replenishing qi, and nourishing blood. Additionally, they improve the gastrointestinal function of patients with GC and enhance the body’s nutritional status by regulating the composition and proportion of the gut microbiota[30]. Serum tumor markers, including CEA, CA125, and CA199, were markedly decreased after treatment in the research group, which were statistically lower than the control group, indicating that the combination of Sijunzi decoction and chemotherapy intervention actively regulates abnormal CEA, CA125, and CA199 levels in patients after GC surgery. Moreover, the down-regulation of the aforementioned serum tumor markers in patients with GC caused by Sijunzi decoction may be attributed to its potential regulatory effect on exosomal microRNA-151-3p in saliva[31]. The investigation of TCM syndrome scores revealed greatly reduced scores of the research group in terms of poor appetite, gastric pain and distension, fatigue and weakness, and abdominal distension after eating after treatment, which were significantly lower than those of the control group. This indicates that receiving the combination of Sijunzi decoction and chemotherapy treatment for patients after GC surgery significantly alleviates typical clinical symptoms. As far as safety is concerned, the total incidence rates of grade III–IV adverse events, such as gastrointestinal reactions, renal/liver function impairment, and myelosuppression, in the research group was comparable to that in the control group (12.96% vs 20.00%). This indicates that the combination of Sijunzi decoction and chemotherapy does not remarkably augment the risk of adverse events in patients after GC surgery. A meta-analysis reveals that Sijunzi decoction significantly shortens flatulence and hospitalization duration, reduces postoperative complication incidences, and increases albumin, prealbumin, and TRF levels in patients with GC, similar to our research results[32]. A prospective observational cohort study demonstrated that Sijunzi decoction for patients postoperatively with non-small cell lung cancer significantly alleviated specific symptoms, such as dyspnea, cough, hemoptysis, pain, and peripheral neuropathy, thereby supporting our research results[33].

This research has several limitations. First, considering its retrospective design, the implementation of a prospective study in the future would, to a certain extent, be instrumental in circumventing issues related to information collection bias. Second, the sample size needs to be increased. Conducting a multi-center, large-scale sample analysis in the future will be conducive to improving the accuracy of the research results. Third, the inclusion of additional sampling time points would make the dynamic alteration analysis in diverse data of patients throughout the entire treatment course possible. In the future, a thorough analysis aimed at the improvement of this research project will be executed from the aspects expounded above.

CONCLUSION

Altogether, the combination of the Sijunzi decoction and chemotherapy exerts a positive effect on improving the gastrointestinal function and nutritional status of patients after GC surgery. It significantly downregulates serum tumor marker levels, such as CEA, CA125, and CA199, and alleviates symptoms, including poor appetite, gastric pain and distension, fatigue and weakness, and postprandial abdominal distension, while ensuring a favorable clinical safety profile. The aforementioned results provide effective intervention options for the perioperative intervention of patients after GC surgery and offer more references and evidence for the clinical management of such patients.