Efficacy and Safety of Apatinib Combined With S-1 in the Treatment of Advanced Gastric Cancer: a Meta-analysis

doi:10.21203/rs.3.rs-481813/v1

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Efficacy and Safety of Apatinib Combined With S-1 in the Treatment of Advanced Gastric Cancer: a Meta-analysis

https://doi.org/10.21203/rs.3.rs-481813/v1

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Objective: To study the efficacy and safety of apatinib combined with S – 1 in the treatment of advanced gastric cancer, in order to provide more evidence based medical evidence for the clinic.

Methods: Randomized controlled trials of apatinib combined with S – 1 (experimental group) versus S - 1 (controlg roup) in the treatment of advanced gastric cancer were collected by computer literature search in Chinese and English databases, for the deadlines of March 21, 2021. Two investigators independently screened the literature, extracted the data, and evaluated the quality of the literature using the Cochrane risk bias assessment tool. And the Meta – analysis was performed using Review Manager 5. 3 software almost.

Results: A total of 20 articles were included, totaling 1,150 patients. Meta – analysis showed that the objective response rate [OR = 2.02, 95% CI (1.56, 2.63), P < 0.00001], disease control rate [OR = 3.10, 95% CI (2.30, 4.17), P < 0.00001], median overall survival [MD = 3.99, 95% CI (3.56, 4.43), P < 0.00001] of patients with apatinib combined with S – 1 group were higher than the S – 1 group, then the median progression – free survival had not significant differences [MD = 1.24, 95% CI (-1.19, 3.67), P = 0.32]. In the adverse reactions, only the incidence of hypertension [OR = 6.19, 95% CI (1.89, 20.23), P = 0.003] and the incidence of proteinuria [OR = 4.02, 95% CI (1.11, 14.62), P = 0.03] in the apatinib combined with S – 1 group were higher than the S – 1 group, and there was no significant difference in the other adverse reactions. In addition, the levels of IFN – γ and TNF – α in the apatinib combined with S – 1 group were higher than those in the S – 1 group, and the levels of IL - 10, IL – 4, TSGF, CA199 and CEA were lower than those of the S – 1 group.

Conclusion: Current evidence suggests that apatinib combined with S - 1 can achieve higher objective response rate, disease control rate, median overall survival, less adverse reactions, and improve immune function, effectively reduce the level of tumor markers.

Oncology

apatinib

S – 1

gastric cancer

efficacy

safety

Meta – analysis

Gastric cancer is one of the common malignant tumors in China with a high incidence rate and is mostly advanced at the time of diagnosis^[1]. Phase I, II, and III registration clinical trials of apatinib have shown clear objective efficacy and significant survival benefit for the treatment of patients with advanced gastric cancer after failure of standard chemotherapy, and therefore apatinib has been approved for more than second-line treatment of advanced gastric cancer in China^[2]. Considering that most patients with advanced gastric cancer are elderly, in poor general condition, or combined with multiple underlying diseases, combination chemotherapy (especially three-drug combination) is mostly intolerable. Therefore, this article intends to include several studies to systematically evaluate the effect of apatinib in combination with tegeo in the treatment of advanced gastric cancer and the effect on related cytokines, in order to provide more evidence-based medical evidence for clinical practice.

Inclusion and Exclusion Criteria

Inclusion Criteria

(1) Type of study: domestic and foreign published randomized controlled trials (RCTs). Languages were limited to Chinese and English. (2) Study subjects: patients with advanced gastric cancer diagnosed by pathology. (3) Intervention: Apatinib combined with Tegeo in the trial group and single agent Tegeo treatment in the control group with unlimited duration of treatment. (4) Outcome indicators: objective remission rate (ORR), disease control rate (DCR), median progression-free survival (median PFS), median overall survival (median OS), adverse events, Th1, Th2, and relevant tumor markers.

Exclusion Criteria

(1) Literature such as reviews, systematic evaluations, or case reports. (2) Literature on intervention protocols. (3) Outcome indicators that do not match. (4) Non-RCTs.

Retrieval Strategy

Computer searches of PubMed, EMBASE, CochraneLibrary, China Knowledge Network, and Wanfang databases were conducted (until March 21, 2021). A combination of subject terms and keywords was used for the search, and the Chinese search terms included apatinib, apatinib mesylate, tegeo, and gastric cancer, and the English search terms included apatinib, S − 1, gastric cancer, gastric carcinoma.

Literature Screening, Data Extraction and Quality Evaluation

Two investigators independently screened the literature and extracted data according to inclusion and exclusion criteria, and a third investigator assisted in adjudication in case of disagreement. The indicators for data extraction included: (1) General information: authors and year of publication, trial population, age, etc.; (2) Experimental design: sample size, intervention group protocol; (3) Outcome indicators: DCR, ORR, median PFS, median OS, adverse events, Th1, Th2, and relevant tumor markers. The Cochrane risk bias assessment tool in ReviewManager 5.3 was used for quality assessment.

Statistical Analysis

Meta-analysis was performed using RevMan 5.3 software. Dichotomous variables and continuous variables in the outcome index were used to calculate OR, MD to estimate the effect of the trial using the Mantel-Haenszel method. Heterogeneity was defined as statistical significance when P < 0.1 or I² > 50%, using a random-effects model; conversely, a fixed-effects model was used. Potential sources of heterogeneity were explored by sensitivity analysis. Publication bias was additionally assessed by Egger's test, p < 0.05 was considered statistically different.

Literature Screening Results and Basic Information of Included Studies

A total of 178 papers were retrieved after the above search strategy, and 88 were left after removing duplicates. 39 papers were screened out after reading the titles and abstracts and excluding related papers such as reviews, among which 5 papers were not eligible for the trial / control group, 10 papers were not RCTs, and 4 papers were not eligible for the outcome index, and 20 papers were finally included. The screening process is shown in Fig. 1, and the basic characteristics of the final 20 included papers^[3–22] are shown in Table 1. 1,150 patients were included in this analysis, 576 in the trial group and 574 in the control group.

Table 1

Basic characteristics of the included studies
Author (years)	Age (years)	Object of study	Experimental / control group (n)	Interventing measure of experimental group	Outcome indicator
Bao Yu 2019^[3]	>30	AGC	49 / 48	Apatinib 500–850 mg + S − 1	ABCDEHIJ
Chen Zhaojun 2019^[4]	45–79	AGC	40 / 40	Apatinib 500 mg + S − 1	ABCIJ
Lv Xiaoyan 2019^[5]	49–78	AGC	23 / 23	Apatinib 250–500 mg + S − 1	ABC
Ji Huaqing 2019^[6]	38–78	AGC	20 / 20	Apatinib 500 mg + S − 1	ABC
Wang Fang 2019^[7]	60–83	First line and above AGC	29 / 29	Apatinib 500 mg + S − 1	ABC
Yang Ningjuan 2019^[8]	61–85	AGC	24 / 24	Apatinib 250–500 mg + S − 1	ABCDF
Cai Hongxu 2018^[9]	65–76	Second line AGC	40 / 40	Apatinib 250–500 mg + S − 1	ABC
Ai Liang 2018^[10]	47–78	Second line AGC	30 / 30	Apatinib 850 mg + S − 1	ABCH
Xiong Yi 2018^[11]	27–70	AGC	32 / 32	Apatinib 850 mg + S − 1	ABC
Huang Yichao2018^[12]	44–78	AGC	15 / 15	Apatinib 500–850 mg + S − 1	ABCDGHIJ
Zhou Lei 2018^[13]	N	Second line above AGC	20 / 20	Apatinib 850 mg + S − 1	ABCH
Wu Zhiwei 2017^[14]	25–74	Second line AGC	14 / 14	Apatinib 500 mg + S − 1	ABC
Fan Xinxin 2017^[15]	26–73	First line and above AGC	15 / 15	Apatinib 500 mg + S − 1	ABC
Gao Jingping 2017^[16]	47–83	First line and above AGC	16 / 15	Apatinib 500–850 mg + S − 1	ABC
Li Dehua 2019^[17]	50–78	First line AGC	26 / 26	Apatinib 500 mg + S − 1	ABC
Gou Lanqiong 2019^[18]	62–73	First line and above AGC	75 / 75	Apatinib 250–500 mg + S − 1	ABC
Bai Xue 2018^[19]	24–73	AGC	30 / 30	Apatinib 250 mg + S − 1	ABC
Hu Shanshan 2016^[20]	49–78	AGC	23 / 23	Apatinib 800–850 mg + S − 1	ABC
Ou Zhangsong 2019^[21]	46–79	AGC	34 / 34	Apatinib 500 mg + S − 1	ABC
Jing Xiaohui 2016^[22]	N	AGC	21 / 21	Apatinib 500 mg + S − 1	ABC
Note: A: DCR; B: ORR; C: Related adverse reactions; D: Th1 (IFN-γ, TNF-α); E: Th2 (IL-6, IL-10); F: Th2 (IL-4, IL-19); G: Th2 (IL-4, IL-10); H: Related tumor markers; I: Median PFS; J: Median OS; N: Not mentioned.

Literature Quality Evaluation

The 20 included papers^[3–22] were evaluated for quality using the Cochrane Risk Bias Assessment Tool in ReviewManager 5.3 (Fig. 2).

Results of Meta-Analysis

ORR

Twenty studies^[3–22] (n = 1,150) reported ORRs with a test of heterogeneity across studies of P = 0.71, I² = 0%, using a fixed-effects model. meta-analysis showed that the objective remission rate was higher in the apatinib combined with tegeo group than in the tegeo group, with a statistically significant difference [OR = 2.02, 95% CI (1.56, 2.63), P < 0.00001] (Fig. 3).

DCR

Twenty studies^[3–22] (n = 1,150) reported DCR, with a test of heterogeneity across studies of P = 0.90, I² = 0%, using a fixed-effects model. meta-analysis showed that the disease control rate was higher in the apatinib combined with tegeo group than in the tegeo group, with a statistically significant difference [OR = 3.10, 95% CI (2.30, 4.17), P < 0.00001] (Fig. 4).

Median PFS

Only three studies^{[3, 4, 12]} (n = 207) reported median PFS with a heterogeneity test of P < 0.0001 across studies, I² = 98%, using a random-effects model. Meta-analysis showed that median progression-free survival in the apatinib combined with tegeo group was not significantly different from that in the tegeo group [MD = 1.24, 95% CI ( -1.19, 3.67), P = 0.32] (Fig. 5).

Median OS

Only three studies^{[3, 4, 12]} (n = 207) reported median OS, with a test of heterogeneity across studies of P = 0.66, I² = 0%, using a fixed-effects model. meta-analysis showed that the median overall survival was higher in the apatinib combined with tegeo group than in the tegeo group, with a statistically significant difference [MD = 3. 99, 95% CI (3. 56, 4. 43), P < 0.00001] (Fig. 6).

Adverse Reactions

Meta-analysis of the incidence of adverse reactions in the two groups showed that the incidence of hypertension was higher in the apatinib combined with tegeo group than in the tegeo group, with a statistically significant difference [OR = 6.19, 95% CI (1.89, 20.23), P = 0.003]; The incidence of proteinuria was also higher in the apatinib combined with tegeo group than in the tegeo group, with a statistically significant difference [OR = 4.02, 95% CI (1.11, 14.62), P = 0.03]. The difference was statistically significant [OR = 4.02, 95% CI (1.11, 14.62), P = 0.03]; There was no significant difference between the two groups in the remaining adverse effects such as diarrhea, hand-foot syndrome, and bone marrow suppression (Table 2).

Table 2

Meta-analysis results of the incidence of adverse reactions in the two groups
Adverse reactions	Number of studies	Sample size (n)	OR	95% CI	P
Nausea or vomit	16	911	0.85	[0.61, 1.16]	0.30
Hepertension	11	565	6.19	[1.89, 20.23]	0.003
Diarrhea	15	823	0.93	[0.62, 1.40]	0.72
Hand-foot syndrome	14	798	1.35	[0.92, 1.98]	0.13
Proteinuria	11	735	4.02	[1.11, 14.62]	0.03
Myelosuppression	15	878	1.08	[0.72, 1.61]	0.72
Liver injury	4	338	0.87	[0.31, 2.47]	0.79
Mucositis	6	246	1.29	[0.69, 2.44]	0.42
Weakness	13	701	1.08	[0.75, 1.54]	0.69
Neurotoxicity	6	396	1.15	[0.72, 1.84]	0.55
Hemorrhage	3	276	1.52	[0.61, 3.76]	0.37
Rash	2	230	1.75	[0.52, 5.90]	0.37

Related Cytokines

Comparing the levels of relevant cytokines in the two groups after treatment, Meta-analysis showed that the levels of IFN-γ and TNF-α in the apatinib combined with tegeo group were higher than those in the tegeo group, and the difference was statistically significant (P < 0.0001); The levels of IL-10, I L-4, TSGF, CA199, and CEA levels in the apatinib combined with tegeo group were lower than those in the tegeo group, and the differences were statistically significant (P < 0.05) (Table 3).

Table 3

Meta-analysis of the cytokines of the two groups after treatment
Cytokines	Number of studies	Sample size (n)	OR	95% CI	P
IFN-γ	3	175	3.22	[1.91, 4.53]	<0.00001
TNF-α	3	175	1.60	[1.45, 1.75]	<0.00001
IL-10	2	127	-2.79	[-4.06, -1.52]	<0.001
IL-4	2	78	-2.08	[-2.71, -1.45]	<0.00001
TSGF	2	157	-12.27	[-21.67, -2.86]	0.01
CA199	4	227	-3.89	[-4.60, -3.19]	<0.00001
CEA	4	227	-0.06	[-0.82, -0.51]	<0.00001

Sensitivity Analysis

The results of meta - analysis of some outcome indicators suggest that the heterogeneity is large, and the random effects model has been used for analysis. In the Meta analysis of median PFS and CEA factors, the results of analysis using the article-by-article exclusion method did not change significantly, suggesting that the results are relatively stable. However, in the Meta analysis of IFN-γ, the sensitivity analysis was carried out by excluding each study one by one. The study by Bao Yu et al^[3] significantly reduced the heterogeneity (P = 0.91, I² = 0%). Consider the possible source of heterogeneity. In the Meta analysis of CA199, the heterogeneity decreased significantly (P = 0.6, I² = 0%) after excluding the study of Huang Yichao et al^[12], which may also be considered as a source of heterogeneity. The heterogeneity considerations of the two studies are highly correlated with factors such as sample size, testing reagents, and treatment population.

Publication Bias Analysis

A publication bias study was conducted on the included studies. In the objective remission rate study, the Egger test results indicated that P = 0.550 and P > 0.05, indicating that there was no publication bias (Fig. 7A). In the disease control rate study, the Egger test results indicated that P = 0.112 and P > 0.05, indicating that there was no publication bias (Fig. 7B). Due to the limited number of included studies, other survival analysis indicators were not analyzed for publication bias.

Angiogenesis is one of the important steps in the pathological process of tumor progression^[23]. A variety of growth factors and their receptors are involved in tumor angiogenesis-related processes, of which vascular endothelial growth factor (VEGF) and its receptor VEGFR play a major role. VEGFR-2 plays a leading role in VEGF signal transduction and vascular endothelial formation. This signaling pathway can promote the formation of new blood vessels, and it can also mediate the DNA synthesis and proliferation of tumor vascular endothelial cells and changes in vascular permeability. VEGFR is often highly expressed in gastric cancer tissues^[24].

Apatinib is a new type of oral small molecule VEGFR-2 tyrosine kinase inhibitor, which can effectively inhibit the growth of tumor blood vessels to achieve the purpose of anti-cancer. In a phase II randomized, double-blind trial, apatinib was used for advanced, metastatic gastric cancer and gastroesophageal junction cancer that failed second-line and above chemotherapy. The results showed that the apatinib group was more effective than the placebo group in improving patients The median survival time (6.5 months vs 4.7 months) and the median progression-free survival (2.6 months vs 1.8 months)^[25]. Therefore, apatinib was approved by China in 2014 for the treatment of advanced gastric cancer and gastroesophageal junction cancer in the third line and above. And it can be concluded from the phase I-III trial that common adverse reactions of apatinib include bone marrow suppression, hypertension, proteinuria, hand-foot syndrome, fatigue, gastrointestinal reactions, etc.

This article intends to systematically evaluate the efficacy and safety of apatinib combined with tigio. Some studies use immune-related factors and tumor markers as outcome indicators. Th cells are of great significance to the body’s immune system. They are mainly divided into two subgroups: Th1 and Th2. Th1 cells participate in cellular immunity and delayed-type hypersensitivity reactions, and can secrete cytokines such as IFN-γ and TNF-α; Th2 cells Participating in humoral immunity can assist the secretion of B cells into antibody-secreting cells, which can secrete cytokines such as IL-4 and IL-10^[26]. In normal organisms, Th1 and Th2 cells secrete multiple cytokines to maintain a dynamic balance. In tumor patients, Th1 cytokines can indirectly kill tumor cells, and Th2 secretes relatively more cytokines. This phenomenon It is called Th1 / Th2 offset^[27]. This phenomenon is closely related to the degree of malignancy and prognosis of tumors, and the degree of Th1 / Th2 deviation is positively correlated with the body's immunosuppression^[28].

The results of this Meta analysis showed that the ORR, DCR, and median OS of apatinib combined with ticgio are higher than that of single-agent ticgio, and there is no significant difference between the median PFS. In terms of adverse reactions, only in the incidence of hypertension and proteinuria, apatinib combined with ticgio is higher than ticgio. The other adverse reactions (including hand-foot syndrome, bone marrow suppression, etc.) are not significantly different between the two. The levels of cytokines (IFN-γ, TNF-α) secreted by Th1 of apatinib combined with Tiggio were higher than those of the Tiggio group. Cytokines (IL- 10, IL-4) and related tumor markers (TSGF, CA199, CEA) levels were lower than the Tiggio group. After removing each study one by one, sensitivity analysis was performed, and the results did not change in direction, indicating that the results of this study were relatively stable.

The limitations of the research are: (1) Although the included studies are all mentioned as randomized controlled trials, some of them did not explicitly mention the random allocation method. Most of the studies did not carry out allocation concealment and blinding, and most of them were small-sample studies, and the risk of bias was high, may affect the reliability and stability of the results; (2) Although the study population is mostly elderly, the age span of some studies is large, and the dosage, course of treatment, and previous treatment of apatinib are not uniform, which may affect reliability of results.

In summary, current evidence shows that apatinib combined with tigio can obtain higher ORR, DCR, and median OS than single-agent tigio, with fewer adverse reactions, improved immune function, and can effectively reduce Tumor marker level.

Acknowledgements:

We are grateful to Mr. He Xiaodong and Mr. Zhang Youcheng of the Second Hospital of Lanzhou University for their support in data management, and to Mr. Yang Kehu, Mr. Tian Jinhui and Mr. Chen Yaolong of the Evidence-based Centre of the School of Basic Medicine of Lanzhou University for their support in statistical data.

Author Contributions:

All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; gave final approval of the version to be published; and agree to be accountable for all aspects of the work.

Compliance with ethical standards

Conflict of interest:

The authors declare that they have no conflict of interest. The present study was conducted following the Helsinki Declaration of the World Medical Association. All participants have given consent for publication.

Funding:

This research received no specific funding/grant from any funding agency in the public, commercial, or not-for-profit sectors.

Ethics approval and consent:

Not applicable.

Consent for publication:

Not applicable.

An availability of data and materials:

All data generated or analysed during this study are included in this published article.

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Efficacy and Safety of Apatinib Combined With S-1 in the Treatment of Advanced Gastric Cancer: a Meta-analysis

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