Effects of Shenqi Xiangyi granules in advanced gastric cancer chemotherapy

Abstract

BACKGROUND

Owing to the absence of specific symptoms in early-stage gastric cancer, most patients are diagnosed at intermediate or advanced stages. As a result, treatment often shifts from surgery to other therapies, with chemotherapy and targeted therapies being the primary options for advanced gastric cancer treatment.

AIM

To investigate both treatment efficacy and immune modulation.

METHODS

A total of 116 patients with advanced gastric cancer, admitted from January 2021 to December 2023, were selected and divided into two groups of 58 each using the random number table method. The control group received FOLFOX4 chemotherapy (oxaliplatin + calcium + folinate + 5-fluorouracil) combined with intravenous sindilizumab. The observation group received the same treatment as the control group, supplemented by oral administration of Senqi Shiyiwei granules. Both groups underwent treatment cycles of 3 weeks, with a minimum of two cycles. The therapeutic efficacy, immune mechanisms, and treatment-related toxicity and side effects were compared between the groups.

RESULTS

The objective remission rate in the observation group (55.17%) was higher than that of the control group (36.21%) (P < 0.05). After two treatment cycle, CD3+, CD4+, and CD4+/CD8+ levels were higher in the observation group compared to the control group, while CD8+, regulatory T cells, and natural killer cells were lower (P < 0.05). Additionally, the incidence of leukopenia, nausea, and vomiting was lower in observed group (P < 0.05). No significant differences were observed in the incidence of other adverse reactions (P > 0.05).

CONCLUSION

Adjuvant therapy with Shenqixian granules may enhance the efficacy of simudizumab combined with FOLFOX4 chemotherapy in advanced gastric cancer and the immune function by increasing immune cell counts, making it a valuable option in clinical treatment.

Key Words: Sindilizumab; FOLFOX4 chemotherapy; Advanced gastric cancer; Ginseng Qi Xiangyi granule; Clinic treatment

Core Tip: Reasonable and effective treatment with traditional Chinese medicine is crucial for patients with advanced cancer, especially those receiving chemotherapy and targeted therapy.

INTRODUCTION

Gastric cancer is a highly prevalent malignant tumor worldwide, characterized by incidence, morbidity, and mortality rates. Statistical investigations have shown that the survival and cure rates of patients with gastric cancer are closely associated with the tumor stage, pathological type, treatment method, and the patient’s overall health status. For patients with early-stage gastric cancer, the 5-year survival rate can reach 95% or > 98% after surgery[1]. However, because of the insidious onset of gastric cancer in its early stages and the lack of significant clinical symptoms, patients are diagnosed at advanced stages, making treatment more challenging. Chemotherapy-based integrated programs are the treatment of choice for patients with advanced gastric cancer.

Chemotherapy is a cornerstone in the clinical management of advanced gastric cancer, with the FOLFOX4 regimen (oxaliplatin + calcium folinic acid + 5-fluorouracil) being a commonly used protocol. However, it is associated with adverse reactions, negatively affecting the patient's immune function, and prolonged use can lead to resistance[2]. Recently, targeted drugs have been widely utilized in cancer treatment, with sindilizumab being a commonly used agent to enhance the body's immune system and exert anti-tumor effects. It has demonstrated improved outcomes and has been clinically accepted[3]. However, immunosuppression persists in patients during the treatment. Chemotherapy, targeted therapy, and other therapies can lead to a deficiency positive qi in patients, allowing external evils to invade the body and block the meridians. This results in a deficiency of qi and blood, ultimately weakening of organs[4]. Therefore, based on the basic patho-mechanism of positive qi deficiency and blood stasis obstruction in patients with advanced gastric cancer, the treatment approach emphasizing strengthening the spleen, tonifying qi, and promoting blood circulation is proposed.

Ginseng astragalus 11 flavor granules are a kind of Chinese herbal preparation with significant therapeutic effects on various cancers. They tonify the spleen and enhance qi, primarily used in clinical practice to address the symptoms of weakness, particularly limb weakness resulting from the spleen and qi deficiency[5]. Recent studies have demonstrated the effectiveness of Radix astragali decylenic granules. However, the potential of Radix astragali decylenic granules in the adjuvant treatment of advanced gastric cancer to improve patient outcomes and immune function is warrants further clinical investigation. This study analyzed the recent efficacy of adjuvant treatment with Radix Astragali Decima Granules in patients with advanced gastric cancer treated with sindilizumab combined with FOLFOX4 chemotherapy and explored its effect on the immune function. The finding aim to provide theoretical guidance for the use of Traditional Chinese medicine (TCM) in treatment of advanced gastric cancer.

MATERIALS AND METHODS

Participants

A total of 116 patients with advanced gastric cancer admitted to the hospital between January 2021 and December 2023 were selected. This study was double-blinded with medication concealment for treating physicians and patients.

The inclusion criteria were as follows: (1) Patients diagnosed with gastric cancer[6]; (2) Classified as having advanced cancer with predicted survival > 3 months; (3) At least one measurable tumor lesion detectable via imaging techniques; and (4) Awareness of the study and signed the consent form. The exclusion criteria were as follows: (1) Extensive systemic metastases; (2) Combined acute and chronic infections; (3) A history of hematopoietic stem cell transplantation and primary immunodeficiency; (4) Other types of malignant tumors; and (5) Allergies to drugs.

Treatment

The control group received FOLFOX4 chemotherapy comprising oxaliplatin (Qilu Pharmaceuticals, State Pharmaceutical Licence H20093127), IV, at a dose of 85 mg/m² for 120 minutes, day 1; Calcium folinic acid (Jiangsu Hengrui Pharmaceuticals, State Pharmaceutical Licence H20000584), IV, at a dose of 200 mg/m² for 120 minutes, day 1-2; and 5-fluorouracil (Southwest Pharmaceuticals, National Drug Licence H50020128), intravenous push at a dose of 400 mg/m² and continuous pumping at a dose of 600 mg/m² for 22 hours, day 1-2; this regimen was repeated every 3 weeks as one cycle. Sindilizumab (Xinda Bio-Pharmaceuticals, National Drug Standard S20180016) at a dose of 200 mg/dose was administered intravenously (day 1) every 3 weeks as one cycle. The observation group received the same basic treatment as the control group, with the addition of oral administration of Shenqi Xiangyiwei granules (Jiangxi Shanko Pharmaceuticals, State Pharmaceutical Approval Character Z10980002), 2 g in lukewarm water, three times a day, for 3 weeks for one cycle. Both groups underwent at least two treatment cycles.

Observation indicators

Immediate effects: Efficacy was assessed after two cycles of treatment based on the solid tumor efficacy evaluation criteria[7]: Complete remission (CR): The lesion measurable by imaging had completely disappeared and was maintained for 4 weeks or more; partial remission (PR): The lesion measurable by imaging had shrunk by > 30% compared with the pretreatment period; stable disease (SD): The lesion measurable by imaging shrunk by < 30% or increased by < 20%; progression disease: Did not meet the SD criteria; and the objective remission rate is CR rate + PR rate.

Immune function: Venous blood samples (5 mL) were collected from patients before treatment and after two cycles of treatment, centrifuged for 10 minutes at 3000 r per minute, and the plasma was kept after centrifugation and preserved for examination. Flow cytometry (Beckman Coulter, United States) was used to detect T-lymphocyte sub-populations, including CD3+, CD4+, CD8+, and CD4+/CD8+ ratio. Regulatory T-cells (Tregs) and natural killer cells (NK) were also detected.

Toxic and side effects: According to the toxicity judgment criteria[8], adverse drug reactions were assessed with grades ranging from 1 to 4, including nausea and vomiting, leukocyte reduction, platelet reduction, and liver and kidney function impairments.

Statistical analysis

Statistical analysis of the data within the study was performed using SPSS software (version 26.0). Measurement data were represented as mean ± SD, and independent samples t-test was used when they met the normal distribution. Measurement data that did not meet the normal distribution, were represented as median and interquartile spacing (median, interquartile range), and the rank sum test was used. Counting data were expressed as percentage rate (%), and the χ² test was performed. A P value < 0.05 was considered statistically significant.

RESULTS

Objective response rates

Both the groups exhibited no significant difference in radiographic lesions (P > 0.05; Table 1).

Table 1 Comparison of the recent effects between the two groups, n (%).

Group	CR	PR	SD	PD	Objective mitigation rate
Observation (n = 58)	5 (8.62)	27 (46.55)	23 (39.66)	3 (5.17)	32 (55.17)
Control (n = 58)	1 (1.72)	20 (34.48)	29 (50.00)	8 (13.79)	21 (36.21)
χ2					4.204
P value					0.040

CR: Complete remission; PR: Partial remission; SD: Stable disease; PD: Progression disease.

Immune responses

No difference was observed between the two groups before treatment (P = 0.05). After treatment, the two groups improved, and the improvement was greater in the observation group (P < 0.05), as presented in Table 2 and Table 3.

Table 2 Comparison of immune function indicators between the two groups before treatment (mean ± SD).

Group	CD3+ (%)	CD4+ (%)	CD8+ (%)	CD4+/CD8+	Treg cell (%)	NK cell (%)
Observation (n = 58)	42.86 ± 4.86	26.95 ± 3.10	31.04 ± 2.08	0.87 ± 0.12	5.80 ± 1.04	30.24 ± 4.85
Control (n = 58)	43.10 ± 4.96	27.05 ± 3.18	30.85 ± 2.12	0.88 ± 0.13	5.76 ± 1.08	29.82 ± 4.90
t	0.263	0.171	0.487	0.430	0.203	0.464
P value	0.793	0.864	0.627	0.668	0.839	0.644

Tregs: Regulatory T-cells; NK cell: Natural killer cells.

Table 3 Comparison of immune function indicators between the two groups after treatment (mean ± SD).

Group	CD3+ (%)	CD4+ (%)	CD8+ (%)	CD4+/CD8+	Treg cell (%)	NK cell (%)
Observation (n = 58)	61.28 ± 5.84a	38.84 ± 3.58a	21.58 ± 2.08a	1.81 ± 0.18a	2.08 ± 0.65a	21.26 ± 3.28a
Control (n = 58)	52.84 ± 5.80a	33.10 ± 3.48a	24.63 ± 2.12a	1.34 ± 0.14a	3.07 ± 0.72a	24.95 ± 3.35a
t	7.809	8.756	7.821	15.697	7.773	5.994
P value	< 0.001	< 0.001	< 0.001	< 0.001	< 0.001	< 0.001

^aP < 0.05.

Tregs: Regulatory T-cells; NK cell: Natural killer cells.

Poison side reaction

The analysis revealed that the incidence of leukocyte reduction, nausea, and vomiting was lower in the observation group than in the control group (P < 0.05). However, there were no difference in the other indicators (P < 0.05), as shown in Table 4 and Table 5.

Table 4 Comparison of the two toxic groups, n (%).

Group	White blood cell reduction		Platelet reduction		Liver and kidney function injury
	Level 1-2	Level 3-4	Level 1-2	Level 3-4	Level 1-2	Level 3-4
Observation (n = 58)	22 (37.93)	0	18 (31.03)	0	13 (22.41)	0
Control (n = 58)	31 (53.45)	3 (5.17)	20 (34.48)	2 (3.45)	23 (39.66)	0
χ2	4.971		0.611		4.028
P value	0.026		0.435		0.045

Table 5 Comparison of the two toxic groups, n (%).

Group	Nausea and vomiting		Hand-foot syndrome		Senses the abnormalities in peripheral nerves
	Level 1-2	Level 3-4	Level 1-2	Level 3-4	Level 1-2	Level 3-4
Control (n = 58)	21 (36.21)	1 (1.72)	3 (5.17)	0	6 (10.34)	0
Observation (n = 58)	33 (56.90)	3 (5.17)	5 (8.62)	0	9 (15.52)	0
χ2	6.759		0.134		0.689
P value	0.009		0.714		0.406

DISCUSSION

Chemotherapy is the preferred treatment for advanced gastric cancer, with the FOLFOX4 regimen, in which fluorouracil disrupts the synthesis pathway of tumor cell DNA, blocks mitosis, inhibits the growth of tumor cells, and promotes apoptosis. Oxaliplatin is a non-specific cell cycle drug that impedes tumor cell progression, while leucovoror calcium can improve the anti-tumor effect of fluorouracil, further promoting tumor apoptotic effect[9]. However, chemotherapy alone has toxic effects, and its efficacy cannot meet clinical needs. Sindilizumab is a targeted drug commonly used in clinical practice. It improves the immune system of patients with cancer and enhances the T-cell-mediated killing of tumor cells in the body, promoting tumor cell apoptosis[10]. However, cindilizumab has some adverse effects, and its ability to mitigate chemotherapy-induced side effects is limited. According to TCM, patients with advanced gastric cancer develop heat poisoning and blood stasis due to the decline of visceral function and the deficiency of vital qi, and after a long time, qi, blood, and yang are unbalanced. Consequently, the toxic effects of chemotherapy further weakens body’s vital qi, exacerbating cancer-induced obstruction of the meridians. Therefore, based on the etiology and pathogenesis, TCM advocates invigorating the spleen and replenishing qi. Shenqi, known for nourishing blood and replenishing marrow-filling essence, has demonstrated significant adjuvant therapeutic effects in cancer treatment.

This study revealed that the recent objective response rate in the observation group was 55.17% higher than in the control group (36.21%; P < 0.05). This indicates that the efficacy of cindilizumab combined with FOLFOX4 chemotherapy can be further improved. The FOLFOX4 chemotherapy regimen inhibits the proliferation of tumor cells, promotes apoptosis, and, when combined with cinalimmab, alleviates the state of immune suppression by activating T cells in the body and then exerting the killing ability of immune cells to tumor cells, improving antitumor effect[11]. Simultaneously, combined with Shenqi granules, Chinese ginseng can replenish qi, invigorate qi, astragalus, nourish yang yi wei, nourish the kidney, nourish blood, angelica, nourish qi and blood, nourish water dampness, heat release, remove turbidity and reduce fat, relieve cold, remove wind, and relieve pain; cassia, barbary wolfberry and kidney, warm antler and kidney yang eliminate blood and swelling; silk, nourish the liver and kidney, solid essence, and reduce urine. Therefore, the prescription emphasizes strengthening the body’s constitution and eliminating harmful elements, which helps restore the function of the spleen and stomach and modulate the tumor microenvironment. This synergistic approach can enhance the treatment of advanced gastric cancer and improve short-term therapeutic outcomes.

Tumors arise from dysplasia of normal cell, which invades surrounding tissues and impairs the immune function of patients. In advanced stages, patients often suffer from chronic illness, with reduced spleen and stomach functions, leading to weakened immunity and decreased tolerance to treatment[12]. T lymphocyte subsets are important factors that reflect the human immune system and participate in human immune regulation. Treg cells have the role of maintaining immune tolerance and immune homeostasis, inhibiting the activity of other immune cells, and avoiding excessive reaction of the immune system, as well as antiviral infection and immune regulation, which can identify target cells and kill mediators[13]. Owing to the widespread immunosuppressive state in patients with tumors, immune function is impaired, and the immune regulation system is destroyed, resulting in reduced levels of CD3+ and CD4 and increased CD8+, Treg, and NK cells. Meng et al[14] confirmed that Peiyuan Yiqi soup can alleviate the symptoms of gastric cancer and enhance immune function. This indicates that TCM prescriptions are important for improving the immune function of patients with malignant tumors. However, compared with Shenqi Shiyi granules, Chinese medicine decoction is not convenient enough, and some patients cannot bear the taste of the Chinese medicine decoction; therefore, the feasibility of its application in clinical practice was confirmed again.

This study found that after treatment, the improvement of all immune cells in the observation group was higher than that in the control group. Han et al[15] reported that the combined chemotherapy regimen of Shenqi can significantly improve the immune function of patients with advanced colorectal cancer. These results indicate that it can improve the immune function of patients with advanced gastric cancer. Sindilimumab can increase the number of immune cells in patients, relieve immunosuppression, and restore immune responses in the human body, thereby improving immune function. However, Chen et al[16] revealed that there is no considerable difference between the tumor immune microenvironment and chemotherapy after neoadjuvant cisplatin treatment, which may be attributed to variations in the treatment cycle and individual patient differences. Therefore, the efficacy of cisplatin-based immunotherapy remains debatable.

Modern pharmacological research has shown that ginseng can increase the number of white blood cells, improve immune function, inhibit the proliferation of tumor cells, and promote the apoptosis of tumor cells in the human body. Ratan et al[17] revealed that ginseng has the regulation of human immune function and plays antiviral, antibacterial, and other roles. Astragalus has a significant effect on immune disorders, cancer, and other diseases, which can promote the proliferation of hematopoietic stem cells, repair the damage of bone marrow cells, and improve the body's immune function. Sheik et al[18] found that astragalus can regulate the immune system during drug treatment; its polysaccharide, methanoside, and other components have significant potential anticancer activity[18,19]. Therefore, treatment with Shenqi Shiyiwei granules can activate the immune response in the human body and inhibit the immune escape of tumor cells, thus improving immune function. Moreover, the study demonstrated that the incidence of leukocyte reduction, nausea, and vomiting was lower in the treatment group than in the control group (P < 0.05). Treatment is helpful to further improve the immune response of patients, reduce the tumor load, and regulate the blood system to reduce the toxicity and side effects of drug treatment to a certain extent. Previous studies have demonstrated the therapeutic effects of TCM on gastric cancer. Previous studies demonstrated that the treatment of Yianpi Huayu in patients with gastric cancer effectively improved their quality of life, increased the number of immune cells, and improved their immunotherapy. Treatment with Shenqi Xiangyi granules in this study also exhibited its effects on improving immune function.

This study had some limitations. First, the sample size of 116 patients was relatively small, which may limit the generalizability of the results. Additionally, the follow-up duration was restricted to two treatment cycles. Thus, the study mainly focused on the immediate effects after these two cycles and lacked an assessment of long-term outcomes, such as progression-free survival, overall survival, or long-term immune recovery. Future studies should include longer follow-up periods to capture data on long-term survival and quality of life. Second, although the study reported some toxicity outcomes, such as leukopenia and nausea, it failed to provide a comprehensive toxicity profile. There is a lack of data on other potential side effects, including the impairment of liver and kidney function, fatigue, and gastrointestinal disturbances. A more comprehensive analysis of toxicity would provide a more accurate understanding of the treatment safety profiles. However, it is hoped that these limitations can be compensated for in future studies. Larger sample sizes and longer follow-up periods can help obtain more accurate and generalizable results. A comprehensive assessment of toxicity can provide a more complete understanding of treatment safety and guide clinical decision-making.

CONCLUSION

When patients with advanced gastric cancer are treated with cintilizumab combined with FOLFOX4 chemotherapy, it can modulate the immune system, improve immune function, enhance recent treatment outcomes, and reduce the toxic side effects of chemotherapy. This has significant implications for promoting the use of TCM in cancer treatment. However, the study had small sample size and only focused on short-term effects through immune mechanism, which may introduce bias results. Therefore, future studies should aim to expand the sample size, extend the observation period, and explore the treatment efficacy from multiple perspectives to provide more comprehensive evidence for the use of Shenqixian granules in advanced gastric cancer.