Adjuvant irinotecan-apatinib therapy for recurrent/metastatic gastric cancer after surgery: A real-world evaluation

Abstract

BACKGROUND

The S-1+oxaliplatin regimen shows limited efficacy in postoperative recurrent/metastatic gastric cancer (RMGC) treatment, requiring adjuvant therapy optimization to enhance effectiveness.

AIM

To clarify how adjuvant irinotecan-apatinib therapy works in postsurgical RMGC management using real-world data.

METHODS

We enrolled 124 postoperative RMGC cases (April 2021 to April 2024) and allocated them to the control (n = 60, sole irinotecan) and research (n = 64, irinotecan + apatinib) groups. All participants received intravenous S-1 infusion and oral oxaliplatin administration. Between-group comparisons were made regarding effectiveness, inflammation-associated parameters [vascular endothelial growth factor, matrix metalloproteinase (MMP)-2, MMP-9], serum tumor biomarkers [carbohydrate antigen (CA) 242, CA199, carcinoembryonic antigen], and treatment-emergent adverse events (thrombocytopenia, hemoglobin reduction, nausea/vomiting, myelosuppression). Assessments were further extended to survival and life quality outcomes Generic Quality of Life Inventory-74 (GQOLI-74).

RESULTS

The between-group comparison revealed similar effectiveness, overall complications, and survival outcomes. The research group demonstrated greater post-treatment reductions in inflammatory markers and serum tumor biomarkers and achieved higher scores across all GQOLI-74 dimensions.

CONCLUSION

In real-world postoperative RMGC management, irinotecan-apatinib therapy achieves non-inferior antitumor efficacy, tolerability, and survival relative to irinotecan and more effectively attenuates inflammation, reduces serum tumor biomarkers, and improves quality of life.

Key Words: Real-world evidence; Irinotecan; Apatinib; Postoperative recurrence; Metastatic gastric cancer

Core Tip: This study presents a real-world data analysis of clinical efficacy outcomes associated with irinotecan-apatinib adjuvant therapy among patients with postoperative recurrent/metastatic gastric cancer (RMGC). We included 124 postsurgical RMGC patients treated from April 2021 to April 2024, all of whom received the S-1 (via intravenous infusion) plus oxaliplatin (via oral administration; S-1+oxaliplatin) regimen. The irinotecan-apatinib adjuvant therapy for these patients demonstrated significant clinical advantages in inhibiting inflammation and serum tumor markers while improving quality of life, which could be a better option for these patients.

INTRODUCTION

Gastric cancer (GC), the fifth most commonly diagnosed tumor globally, is the fifth leading cause of cancer-related mortality[1]. Family history, high processed-food dietary intake, alcohol consumption, tobacco use, and Helicobacter pylori infection collectively increase GC risk among individuals[2]. Predominantly affecting individuals older than 50 years, GC shows male predominance, with an incidence nearly twofold higher than that among women[3]. Radical surgery (gastrectomy and lymph node dissection), the main GC treatment option[4], has two significant obstacles: (1) Perioperative event-induced stress may facilitate tumor spread and metastasis; and (2) Approximately four-fifths of patients experience GC recurrence within two years after surgery[5,6]. In postsurgical recurrent/metastatic GC (RMGC) management, S-1+oxaliplatin (SOX) is the preferred first-line chemotherapy regimen. However, it has limited effects, with some patients responding poorly or developing drug resistance. Hence, combination therapies (e.g., irinotecan and apatinib) for improving efficacy and prognosis are needed[7]. Among them, irinotecan is a semisynthetic, water-soluble camptothecin derivative that selectively targets DNA topoisomerase I and acts specifically on S-phase cells. To exert its tumor-fighting effects, irinotecan forms topoisomerase I-DNA cleavage complexes that break down single-stranded DNA, thus blocking DNA replication and inhibiting RNA production[8]. Meanwhile, it shows sound clinical safety, boasting negligible nephrotoxicity or cardiotoxicity, well-tolerated local tissue reactions, and a limited propensity for conferring cross-resistance[9]. Irinotecan is a valid and safe third-line therapy for metastatic GC[10]. Developed as an oral small-molecule agent, apatinib selectively inhibits vascular endothelial growth factor (VEGF) receptor-2 tyrosine kinase[11]. It extends the survival of RMGC patients through tumor growth-associated signaling suppression. Furthermore, for human epidermal growth factor receptor 2-negative advanced GC or gastroesophageal junction adenocarcinoma patients who failed first-line therapy, the irinotecan-apatinib combination proves to be a beneficial and well-tolerated option[12]. In the latest report, irinotecan-apatinib therapy demonstrated therapeutic efficacy in patients with advanced gastric adenocarcinoma or gastroesophageal junction adenocarcinoma after first-line treatment failure, with manageable clinical safety[13]. Their combination can also yield definite curative effects on patients with locally advanced gastric or gastroesophageal junction cancer, which is beneficial for improving survival outcomes on the premise of not elevating the risk of treatment-related adverse events[14].

This investigation examines whether adjuvant irinotecan-apatinib therapy is therapeutically beneficial for RMGC-affected individuals, utilizing real-world clinical data.

MATERIALS AND METHODS

Case selection

Eligibility criteria: A postoperative RMGC diagnosis verified through clinical manifestations and case records[15]; a survival expectancy of > 3 months or a Karnofsky Performance Status score > 70[16]; Stage II-III disease; post-radical resection progressive disease (PD), with computed tomography-confirmed lesions; treatment tolerability; no prior treatment for the condition; completion of a 1-year follow-up; clinical data completeness. Patients were excluded for other neoplasms (benign/malignant); chemotherapy contraindications; current anticoagulant/thrombolytic therapy; organic diseases; gastric disorders like gastrohelcosis and perforation; uncontrollable hypertension; allergic constitution or hypersensitivity to the drugs studied. Overall, 124 patients meeting these eligibility requirements were selected from our hospital’s records (April 2021 to April 2024). Sixty patients constituted the control group (irinotecan alone), and 64 (research group) received the combination (irinotecan-apatinib). When comparing patients’ baseline characteristics, we determined no statistical intergroup discrepancies (P > 0.05), confirming their suitability for clinical comparison.

Intervening methods

Both groups received the same standard basic treatment, the SOX scheme: Oxaliplatin was administered via intravenous drip at 130 mg/(m²·day) for 2 hours; the S-1 dosage was determined according to the body surface area (BSA); BSA < 1.25 m²: 40 mg/time; 1.25 m² ≤ BSA < 1.5 m²: 50 mg/time; BSA ≥ 1.5 m²: 60 mg/time). All patients were treated twice a day. This regimen was repeated in 3-week cycles (2 weeks on, 1 week off) for a total of 2-4 cycles. Based on the same baseline treatment described above, the two groups received different adjuvant treatments: The control group received additional irinotecan monotherapy on the first day of each cycle, with a dose of 350 mg/m², administered by intravenous drip for 30-90 minutes. The treatment was given once every 3 weeks for a total of 4 times. Based on the control group’s treatment plan (i.e., basic treatment + irinotecan), the research group took apatinib orally 30 minutes after meals every day, with a dose of 500 mg/time, once daily. Each 3-week period constituted one treatment course, with 2-4 courses conducted.

Data collection and outcome measurement

Efficacy assessment: Responses were assessed per RECIST 1.1 guidelines[17]. Complete response (CR) required all identified lesions’ complete disappearance, maintaining for a minimal of 4 weeks; partial response (PR) required at least a 30% decrease in the aggregate sum of the lesion’s longest diameters, with this reduction persisting at least 4 weeks; PD was identified by either a 20% or greater increase in the tumor’s maximum diameters or new lesions’ appearance; stable disease (SD) included all other outcomes that did not fulfill CR, PR, or PD definitions. The tumor control rate (TCR) was determined by taking the number of patients with CR, PR, or SD, dividing it by the total number of patients, and then converting the results to a percentage.

Inflammation-associated markers: Morning fasting venous blood draws (5 mL) were obtained from all participants pre- and post-treatment. Serum samples were isolated by centrifugation and subsequently analyzed using enzyme-linked immunosorbent assays (ELISAs) to determine VEGF, matrix metalloproteinase (MMP)-2, and MMP-9 levels.

Serum tumor biomarkers: We performed ELISA for pre- and post-therapy serum carbohydrate antigen (CA) 242, CA199, and carcinoembryonic antigen (CEA) quantification.

Treatment-emergent adverse events: Thrombocytopenia, hemoglobin reduction, nausea/vomiting (NV), and myelosuppression were the Treatment-emergent adverse events (TEAEs) monitored, with their respective incidences and the overall incidence computed.

Survival: Survival rates were recorded at postoperative months 6, 9, and 12 for intergroup comparison.

Quality of life: We conducted pre- and post-treatment life quality assessments with the 74-item Generic Quality of Life Inventory-74 (GQOLI-74)[18] from four aspects: Material life status (12 items), psychological (20 items), physical (20 items), and social function (22 items). All items were scored on a Likert scale of 1-5. The score is directly proportional to the corresponding aspect of quality of life. To facilitate cross-dimensional comparison and statistical analysis, we followed the scale’s scoring manual to add up the items’ raw scores in the corresponding dimension for conversion into a standard score (0-100 points).

Statistical analysis

Continuous data, summarized as mean ± SD, underwent independent or paired t-testing to identify between- or within-group differences. Categorical data [n (%)] were subjected to χ² testing. Analyses were executed by SPSS 22.0, adopting a P < 0.05 significance criterion.

RESULTS

Baseline data comparison

The groups were similar in baseline characteristics (gender, age, weight, illness duration, and clinical staging, etc.; P > 0.05; Table 1).

Table 1 Baseline characteristics of the study groups, n (%).

Data	Control group (n = 60)	Research group (n = 64)	χ2/t	P value
Sex			0.719	0.396
Male	33 (55.00)	40 (62.50)
Female	27 (45.00)	24 (37.50)
Age (years)	54.62 ± 7.11	54.27 ± 7.73	0.262	0.794
Weight (kg)	61.50 ± 8.78	59.83 ± 9.38	1.022	0.309
Illness duration (months)	9.05 ± 1.66	9.17 ± 2.33	0.328	0.743
Clinical staging			0.440	0.507
II	20 (33.33)	25 (39.06)
III	40 (66.67)	39 (60.94)

Clinical outcome comparison

Table 2 summarizes the clinical responses. In the control group, we identified CR in 11 cases, PR in 27, SD in 8, and PD in 14 cases, with the corresponding cases in the research group being 17, 28, 11, and 8. Notably, 46 cases in the control group met the tumor control standards, compared to 56 cases in the research group, with a non-significant disparity in TCR (76.67% vs 87.50%; P > 0.05).

Table 2 Comparative assessment of clinical response, n (%).

Response evaluation	Control group (n = 60)	Research group (n = 64)	χ2	P value
Complete response	11 (18.33)	17 (26.56)
Partial response	27 (45.00)	28 (43.75)
Stable disease	8 (13.33)	11 (17.19)
Progressive disease	14 (23.33)	8 (12.50)
Tumor control	46 (76.67)	56 (87.50)	2.490	0.115

Evaluation of inflammation-associated markers

Figure 1 shows inflammation-related marker comparisons. No baseline differences were found in VEGF, MMP-2, or MMP-9 (P > 0.05). Post-intervention, all parameters exhibited significant decreases, with the research group achieving substantially lower levels than the controls (P < 0.05).

Figure 1 Comparative analysis of inflammation-associated markers. A: Vascular endothelial growth factor level variations in control (n = 60) vs research (n = 64) cohorts; B: Matrix metalloproteinase (MMP)-2 concentration changes across control (n = 60) and research (n = 64) groups; C: MMP-9 measurements in control (n = 60) and research (n = 64) groups. ^aP < 0.05, ^bP < 0.01 (between-group comparisons). VEGF: Vascular endothelial growth factor; MMP: Matrix metalloproteinase.

Serum tumor biomarkers in the control versus research groups

Figure 2 displays the comparative data for serum tumor biomarkers. At baseline, CA242, CA199, and CEA were comparable between control and research cohorts (P > 0.05). All biomarkers exhibited significant post-intervention reductions in both groups, with even lower concentrations in the research group vs controls (P < 0.05).

Figure 2 Comparative evaluation of serum tumor biomarkers. A: Carbohydrate antigen (CA) 242 measurements in control (n = 60) and research (n = 64) groups; B: Comparative analysis of CA199 levels (control n = 60, research n = 64); C: Carcinoembryonic antigen concentrations across control and research groups (n = 60 vs n = 64). ^aP < 0.05, ^bP < 0.01 (between-group comparisons). CA: Carbohydrate antigen; CEA: Carcinoembryonic antigen.

TEAE analysis

Table 3 lists the TEAE results. The control and research groups showed no significant intergroup variation in the number of cases developing thrombocytopenia [17 (28.33%) vs 10 (15.63%)], hemoglobin reduction [11 (18.33%) vs 13 (20.31%)], NV [15 (25.00%) vs 14 (21.88%)], and myelosuppression [12 (20.00%) vs 15 (23.44%)]; overall incidence: 20.00% vs 23.44%; P > 0.05.

Table 3 Comparative evaluation of treatment-emergent adverse events, n (%).

Adverse reactions	Control group (n = 60)	Research group (n = 64)	χ2	P value
Thrombocytopenia	17 (28.33)	10 (15.63)	2.936	0.087
Hemoglobin reduction	11 (18.33)	13 (20.31)	0.078	0.780
Nausea/vomiting	15 (25.00)	14 (21.88)	0.169	0.681
Myelosuppression	12 (20.00)	15 (23.44)	0.215	0.643

Comparative assessment of survival rates

Table 4 provides a comparative evaluation of survival outcomes between the control and research groups. As indicated by the data, the survival rates were comparable at all measured postoperative time points (6, 9, and 12 months) (P > 0.05).

Table 4 Comparison of survival outcomes, n (%).

Survival rate	Control group (n = 60)	Research group (n = 64)	χ2	P value
6 months post operation	55 (91.67)	61 (95.31)	0.682	0.409
9 months post operation	47 (78.33)	56 (87.50)	1.850	0.174
12 months post operation	42 (70.00)	50 (78.13)	1.068	0.302

Comparative quality of life evaluation

Table 5 provides a comparative overview of the quality of life between the groups. Before treatment initiation, the two groups did not differ significantly in their GQOLI-74 scores across various domains: Material conditions, mental well-being, bodily function, and societal role (P > 0.05). Post-intervention, each dimension score rose across groups (P < 0.05), particularly in the research group (P < 0.05).

Table 5 Comparative life quality evaluation.

Quality of life	Control group (n = 60)	Research group (n = 64)	t	P value
Material conditions (points)
Pre-treatment	64.05 ± 6.02	64.19 ± 7.51	0.114	0.909
Post-treatment	82.72 ± 7.06c	86.03 ± 6.32c	2.754	0.007
Mental well-being (points)
Pre-treatment	60.98 ± 5.91	62.80 ± 7.29	1.521	0.131
Post-treatment	82.87 ± 6.53c	88.66 ± 6.54c	4.930	< 0.001
Bodily function (points)
Pre-treatment	63.23 ± 5.00	64.27 ± 6.03	1.042	0.300
Post-treatment	84.57 ± 5.32c	89.33 ± 6.27c	4.544	< 0.001
Societal role (points)
Pre-treatment	66.25 ± 6.63	64.52 ± 6.38	1.481	0.141
Post-treatment	83.13 ± 6.77c	88.25 ± 5.66c	4.580	< 0.001

^cP < 0.001 vs pre-treatment within the same group.

DISCUSSION

Although individualized therapies can help most patients with GC achieve good disease remission, many postsurgical RMGC cases have poor clinical outcomes, and their overall postoperative survival rate is often relatively lower[19]. To facilitate improved clinical outcomes among patients, the exploration and validation of more optimal therapeutic strategies remain necessary.

This study found that irinotecan-apatinib, as an adjuvant therapy for patients with RMGC, had TCRs comparable to irinotecan alone. Irinotecan, as a semisynthetic camptothecin derivative, belongs to an S-phase cell cycle-specific antitumor agent, helping inhibit excessive GC cell proliferation[20]. One study revealed that apatinib’s anti-GC mechanism may also be related to its induction of ferroptosis through lipid peroxidation[21]. Another animal study indicated that apatinib can further enhance antitumor actions by maintaining tumor vascular normalization, alleviating intratumoral hypoxia, and ameliorating the immunosuppressive microenvironment[22]. Hence, the two play their anti-GC role via distinct pathways, with their combined use possibly working synergistically to achieve efficacy enhancement. However, we found no significant efficacy improvement, which may be related to the insufficient sample size. Irinotecan-apatinib can also be used for recurrent high-grade glioma treatment. In a preliminary clinical study, irinotecan-apatinib demonstrated a high disease control rate (78%) and manageable medication-related adverse effects[23].

The high activity of VEGF in various cancers correlates strongly with aberrant endothelial cell proliferation and abnormal microvascular formation, which may aggravate vascular overgrowth and immune system suppression in the tumor microenvironment[24]. MMP-2 may promote the growth of residual metastatic tumors, while MMP-9 is closely linked to GC cell epithelial-mesenchymal transition and metastasis[25,26]. Notably, CA242, CA199, and CEA are all prognostic indicators of post-radical gastrectomy RMGC[27]. Therefore, we also analyzed the clinical effects of the two therapies on the above indicators. Irinotecan-apatinib in adjuvant treatment of postoperative RMGC patients better suppressed inflammation-related indicators (VEGF, MMP-2, MMP-9) and serum tumor markers (CA242, CA199, CEA) than irinotecan alone. This effect may reflect the highly selective competitive inhibition of VEGF receptor-2 by apatinib, a novel antiangiogenic agent involved in tumor metastasis, thereby suppressing metastatic progression and limiting tumor advancement[28]. Chen et al[29] applied apatinib in advanced GC cases and identified significant clinical advantages in tumor marker suppression and immune factor regulation, findings complementary to the present data.

The two therapies showed equivalent clinical safety, with the combined therapy not significantly increasing the risk of TEAEs (thrombocytopenia, hemoglobin reduction, NV, and myelosuppression), similar to Han et al’s findings[30]. When assessing survival outcomes, we found no marked between-group differences at postoperative months 6, 9, and 12. Finally, analysis of the GQOLI-74 scale results revealed that the quality of life of RMGC patients receiving irinotecan-apatinib had a more significant improvement effect on material life and psychological-physical-social functioning. Yuan et al[31] reported that apatinib markedly improved the quality of life in patients with advanced GC while markedly downregulating MMP-9, findings consistent with the present results.

This study presents several limitations that warrant further refinement. First, the sample size derives from a single geographic region; multicenter, cross-regional recruitment remains necessary to enhance sample representativeness and result generalizability. Second, mechanistic basic research addressing the therapeutic actions of the combined regimen remains absent. Supplementation with in vitro and in vivo analyses would facilitate a clearer elucidation of the underlying molecular mechanisms. Finally, long-term follow-up remains unavailable; future studies should incorporate 3-5-year follow-up to clarify the long-term prognostic impact of the combined regimen.

CONCLUSION

Based on the standard SOX protocol, irinotecan-apatinib adjuvant therapy for RMGC did not further improve oncological outcomes compared with irinotecan alone but conferred distinct clinical benefits: Stronger anti-inflammatory effects, better responses in serum tumor markers, and significant improvement in quality of life. This provides new evidence for optimizing the adjuvant treatment model for RMGC.