Combination of apatinib mesylate and second-line chemotherapy for treating gastroesophageal junction adenocarcinoma.

OBJECTIVE: To investigate the safety and efficacy of acitinib mesylate combined with chemotherapy in the treatment of patients with gastroesophageal junction adenocarcinoma.
METHODS: A total of 119 patients with gastroesophageal junction adenocarcinoma were enrolled and randomized into an experimental group (n = 60) and a control group (n = 59). Both groups were treated with a combination of taxane, irinotecan and fluorouracil, while the experimental group also received acitinib mesylate. The clinical efficacy, survival time and adverse reactions of patients in two groups were recorded and analyzed.
RESULTS: The total remission rate in the experimental group and the control group was 15.79% and 3.23%, respectively; the disease control rate was 73.68% and 54.84%, respectively; and progression-free survival was 3.72 months (1-13.5 months) and 3.04 months (1-6 months), respectively. Overall survival was 13.66 months (5-24 months) and 10.08 months (6.5-19.5 months), in the experimental group and the control group, respectively. In addition, the incidence of adverse events in the experimental group was significantly lower than that in the control group.
CONCLUSION: Apatinib mesylate combined with chemotherapy for the treatment of patients with gastroesophageal junction adenocarcinoma was safe and effective, with improved survival benefit compared with control.

RCT Entities:   Population Interventions Outcomes

Introduction

Gastroesophageal junction (GEJ) adenocarcinoma develops between the esophagus and the stomach. Given the specificity of its anatomical location, tumor progression is rapid, lymph node metastasis is common, and complete surgical resection is challenging.[1] For unresectable or metastatic advanced GEJ adenocarcinoma, treatment is typically palliative, with the main objective of alleviating symptoms, improve quality of life, and prolonging survival time. Several clinical studies have demonstrated that perioperative chemotherapy and adjuvant chemotherapy can provide a survival benefit in patients with GEJ adenocarcinoma; however, therapeutic efficacy remains suboptimal. In recent years, the use of small-molecule targeted agents combined with chemotherapy for the treatment of stomach cancer has increased.[2] Among these agents, oral apatinib mesylate is a new antiangiogenic agent which has demonstrated efficacy in the treatment of stomach cancer.[3] Our institution adopted two regimens, taxane, and irinotecan, and fluorouracil with or without apatinib combined with second-line chemotherapy, to treat 119 patients with GEJ adenocarcinoma enrolled from January 2014 to June 2015.

Patients

From January 2014 to June 2015, 119 patients with GEJ adenocarcinoma were enrolled into the present study. The inclusion criteria were as follows: tumor center located by gastroscopy in the anocutaneous line and diagnosed pathologically as GEJ adenocarcinoma; failure on first-line chemotherapy and progressed, relapsed, or metastatic disease; expected survival time >3 months; at least one targeted focus for iconographic detection; Eastern Cooperative Oncology Group (ECOG) score of 0–2; and no contraindications for chemotherapy. Exclusion criteria included: history of preoperative or postoperative radiotherapy; postoperative pathology of T1-2, without lymphatic metastasis; non-surgical method as first course of treatment in our institution or at another hospital; palliative surgery (R1 and R2); and presence of squamous carcinoma, lymphoma, carcinoid, soft tissue mass, or stromal tumor tissue. This study was approved by the Ethics Committee of Yangzhong People’s Hospital. All patients provided written informed consent. Patients were randomized into an experimental group (n = 38) and a control group (n = 31). There were no statistically significant differences in baseline characteristics between the two groups (P > 0.05), as shown in Table 1.

Table 1.

Baseline characteristics of patients in the control and experimental groups.

Group	Patients (n)	Age	Gender	Tissue typing		Siewert typing
				Poorly differentiated adenocarcinoma	Moderately differentiated adenocarcinoma	II	III
Experimental group	38	61.5 ± 9.4	26/12	11	27	20	18
Control group	31	61.6 ± 8.3	22/9	10	21	16	15
t/χ2		0.685	0.876	0.783		0.594
P		0.290	0.201	0.332		0.402

Study treatment

Patients in both groups received baseline chemotherapy of taxane (PTX/X), irinotecan (CPT/X), and fluorouracil (FU/X), and those in the experimental group also received apatinib mesylate (APA) tablets (Jiangsu Heng Rui Medicine Co. Ltd.; batch number H20140103; product specification 0.25 g*10 s). Each cycle lasted 4 weeks, and treatment was administered for 8 weeks.

Observation indices

The endpoints of the study included the evaluation of efficacy after 4 weeks of treatment, and repeated every 8 weeks thereafter. Clinical effectiveness was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST), and was classified as complete remission (CR), partial remission (PR), stable disease (SD), or disease progression (PD); disease control rate (DCR) was calculated as CR+PR+SD, while overall remission rate (RR) was CR+PR. Progression-free survival (PFS) was measured from the start of treatment to tumor progression, loss to follow-up, or death. Overall survival (OS) was measured from the start of treatment until death or loss to follow-up. Adverse reactions were evaluated according to the common terminology criteria for toxic and side effects (WHO), and classified as grade 0–IV. The cut-off date for follow-up was June 2017.

Statistical analysis

All data were analyzed using SPSS version 18.0 (SPSS Inc., Chicago, IL, USA). Categorical variables were compared using the χ2-test, and measurement data were displayed as ( ± s) and analyzed using a t-test. Survival rates were analyzed by the Kaplan–Meier method. Comparisons of effectiveness between the groups were assessed using Fisher’s method. Values of P < 0.05 were accepted as statistically significant.

Results

Clinical therapeutic effect

The treatment and demographics of patients in the control and experimental groups is shown in Table 2. The RR in the experimental group and the control group was 15.78% and 3.23%, respectively. The DCR was 73.98% and 54.84%, respectively. A statistically significant difference in RR and DCR was shown between the two groups, as shown in Table 3.

Table 2.

Treatment and demographics of patients in the control and experimental groups.

Group	Patients (n)	Males/females	Age range	Median age
Control group	31	20/11	43–77	56.9
PTX/X	8	5/3	61–75	63.5
CPT/X	14	10/4	43–73	56.5
FU/X	9	5/4	45–77	62.1
Experimental group	38	24/14	43–77	56.9
APA+PTX/X	10	7/3	58–77	63.9
APA+CPT/X	16	10/6	47–77	61.5
APA+FU/X	12	7/5	42–74	58.6

Table 3.

Comparison of effectiveness for the control and experimental groups.

Group	ORR (%)	Fisher precise testing P value	DCR (%)	Fisher precise testing P value
PTX/X	3.23	0.015	16.13	0.025
APA+PTX/X	7.89		23.68
CPT/X	0	0.022	25.81	0.045
APA+CPT/X	2.63		26.32
FU/X	0	0.010	12.90	0.012
APA+FU/X	5.26		23.98
Control group	3.23	0.000	54.84	0.015
Experimental group	15.78		73.98

Note: ORR, overall remission rate; DCR, disease control rate.

PFS and OS

The follow-up period for the two groups was 18 months. PFS in the experimental group and the control group was 3.72 months (1–13.5 months) and 3.04 months (range: 1–6 months), respectively, and the difference between the groups was statistically significant (P = 0.013) (Figure 1a). OS in the experimental group and the control group was 13.66 months (5–24 months) and 10.08 months (6.5–19.5 months), respectively, and the difference between the groups was statistically significant (P = 0.031) (Figure 1b).

Figure 1.

Comparison of clinical effect between the control and experimental groups. (a) Kaplan–Meier analysis of progression-free survival (PFS) from randomization. Median PFS was 3.04 months (1–6 months) for the control group and 3.72 months (1–13.5 months) in the experimental group (p < 0.05). (b) Kaplan–Meier analysis of overall survival (OS) from randomization. Median OS was 10.08 months (6.5–19.5 months) in the control group and 13.66 months (5–24 months in the experimental group (p < 0.05).

Adverse events

Adverse events including diarrhea, nausea, vomiting, fatigue, hand-foot syndrome, granulocytopenia, and thrombocytopenia were observed in both groups, but the incidence of adverse events was significantly lower in the experimental group compared with the control group (P=0.020), as shown in Tables 3, 4, and 5.

Discussion

Stomach cancer is a common malignancy of the digestive system, and is associated with the highest mortality rate among malignant tumors. Changes or irregularities in diet, foods that are spicy or have been barbecued, and modern lifestyles, can contribute to the development of stomach cancer.[4] GEJ adenocarcinoma transverses the boundary between the ichthyogram of the gastroesophagus, regardless of where the center of the tumor is located, and includes distal esophageal adenocarcinoma, cardia adenocarcinoma, and proximal gastric adenocarcinoma. Adenocarcinoma is the most important histological type of gastric cancer, and accounts for 95% of all malignant gastric tumors. In most developed countries, the incidence of gastric cancer in the distal stomach is decreasing, while the incidence of GEJ adenocarcinoma is on the rise.[5] GEJ adenocarcinoma can invade the gastric wall downwards and the distal esophagus upwards, leading to obstruction and hemorrhage and resulting in a poor prognosis.[6]

GEJ adenocarcinoma can be classified into three types. Type I is adenocarcinoma of the distal esophagus, where the tumor center is located 1–5 cm into the gastric cardia. Type II is adenocarcinoma of the cardia, with the tumor center 1–2 cm above or below the gastric cardia. Type III is adenocarcinoma of the subcardial stomach, with the tumor located 2–5 cm below the gastric cardia.[7] Radical resection is the only curative treatment for GEJ adenocarcinoma, and the high recurrence rate means that a multi-disciplinary comprehensive treatment strategy is required.[8] A number of studies have shown that postoperative adjuvant therapy is an important factor in reducing local recurrence rate and improving survival.[9-11]

In the present study, apatinib mesylate was combined with second-line chemotherapy for the treatment of patients with GEJ adenocarcinoma. The RR and DCR were significantly improved in the experimental group compared with the control group, indicating the effectiveness of apatinib mesylate in combination with second-line chemotherapy. A key characteristic of malignant tumors is abnormal angiogenesis, in which vascular endothelial growth factor (VEGF) plays an important role and is secreted by tumor stromal cells or tumor cells. With increasing tumor volume, abnormal blood vasculature may increase VEGF levels, thus inducing dyregulated neo-angiogenesis.[12] A previous study showed the over-expression of VEGF in GEJ adenocarcinoma, and VEGF-targeted treatment represents a new treatment strategy for stomach cancer.[13] Apatinib is a novel tyrosine kinase inhibitor that can specifically bind the tyrosine ATP binding site in recipient cells and block the phosphorylation pathway to inhibit the transduction of downstream signaling and prevent tumor angiogenesis.[14]

The use of apatinib in third-line chemotherapy is increasing.[15] As targeted therapy, apatinib is the first orally administered anti-angiogenic drug, and has been shown to be highly effective.[16-18] A large number of clinical studies have reported that apatinib is effective and safe for the treatment of advanced stomach cancer. Wang Yuanpeng et al. evaluated apatinib and tegafur gimeracil oteracil potassium as second-line treatment for advanced stomach cancer, and found that the effectiveness of these two regimens was similar but that apatinib has fewer toxicities and adverse reactions.[19] In another study in patients with advanced GEJ adenocarcinoma, second-line chemotherapy combined with apatinib or tegafur gimeracil oteracil potassium showed similar effectiveness, but that apatinib again had fewer adverse reactions.[20] With the clinical effectiveness of apatinib for the treatment of stomach cancer established, apatinib for the treatment of GEJ adenocarcinoma appears to be effective, with a significant survival benefit.[21-23] The results of the present study indicate that PFS and OS in the experimental group were higher than in the control group, with PFS prolonged by 0.72 months and OS by 3.58 months. Therefore, oral apatinib mesylate combined with second-line chemotherapy was associated with an increased survival benefit compared with control. Adverse reactions in the experimental group were lower than those in the control group (P < 0.05), indicating the safety of oral apatinib mesylate combined with second-line chemotherapy.

In summary, oral apatinib mesylate combined with second-line chemotherapy was associated with improved efficacy and safety in patients with GEJ adenocarcinoma, with a clear survival benefit, further establishing its clinical value.

Table 4.

Comparison of clinical therapeutic effect between the control and experimental groups (number of patients and %).

Group	Patients (n)	CR	PR	SD	PD	RR	DCR
Experimental group	38	0 (0.00)	6 (15.79)	22 (57.89)	10 (26.32)	6 (15.79)	28 (73.68)*
Control group	31	0 (0.00)	1 (3.23)	16 (51.61)	14 (45.16)	1 (3.23)	17 (54.84)

Note: CR: complete remission; PR: partial remission; SD: stable disease; PD: disease progression; RR: overall remission rate; DCR: disease control rate; comparison with the control group, *P<0.05.

Table 5.

Adverse reactions in the control and experimental groups (number of patients and %).

Group	Patients (n)	Nausea	Vomiting	Diarrhea	Fatigue	Hand-foot syndrome	Granulocytopenia	Thrombocytopenia
Experimental group	38	6 (15.79)	4 (10.53)	2 (5.26)	6 (15.79)	1 (2.63)	2 (5.26)	2 (5.26)
Control group	31	14 (45.16)	12 (38.71)	5 (16.13)	10 (32.26)	4 (12.90)	7 (22.58)	8 (25.81)