The anti-PD-1 agents were proved effective by several clinical trials and recommended to treat gastric cancer. In order to protect the interest of patients, this trial was withdrawn after carefully discussion with all investigators.

Gastric cancer is a highly heterogeneous tumor. The most commonly used clinical classifications of gastric cancer are Lauren classification (intestinal, diffuse, mixed) and World Health Organization(WHO) classification (papillary adenocarcinoma, tubular adenocarcinoma, mucinous glands cancer and low-adhesion cancer). Hepatoid adenocarcinoma of the stomach (HAS) is a special and rare type of gastric cancer.

Compared with ordinary gastric cancer, HAS has unique clinicopathological characteristics, prone to liver metastasis and lymph node metastasis, has a highly aggressive and malignant biological behavior, a worse prognosis than alpha fetoprotein(AFP) normal gastric cancer, and is easily confused with hepatocellular carcinoma(HCC). There is the possibility of misdiagnosis and mistreatment, so it has gradually attracted people's attention. Most of the domestic and foreign literature on HAS in the past 30 years are retrospective cases or small sample reports, and there are few prospective studies. There is no standard treatment plan for HAS. The main treatment is based on gastric adenocarcinoma. The clinical treatment principle is a comprehensive treatment plan with surgical resection as the mainstay, supplemented by systemic chemotherapy and local interventional therapy. This type of gastric cancer has a relatively high degree of malignancy, rapid progress of the disease, and easy recurrence after surgery. There is no standard treatment plan in China and other foreign countries.

The aim of this study was to evaluate the efficacy and safety of apatinib with oxaliplatin and S-1 treatment advanced hepatoid adenocarcinoma of the stomach.

Inclusion Criteria:

1. Age: 18 to 70 years old, no gender limitation;

2. Histopathological diagnosis of locally advanced, recurrent or metastatic HAS (pathological histomorphology and immunohistochemical diagnosis of AFP, sal-like 4(SALL4), Hep, glypican-3(GPC3), etc.);

3. Immunohistochemical(IHC) human epidermal growth factor receptor-2 (HER2) negative persons; HER2 positive is defined as IHC 3+ or IHC 2+ and fluorescence in situ hybridization(FISH)+, and FISH positive is defined as the ratio of HER2 gene copy number to chromosome 17 centromere(CEP17) signal number ≥2.0;

4. According to the RECIST 1.1 standard, at least one measurable lesion (spiral CT scan ≥10mm);

5. ECOG performance status(PS): 0-2 points;

6. The expected survival time is ≥3 months;

7. The main organs are functionally normal, without serious blood, heart, lung, liver, kidney dysfunction and immune deficiency disease. The blood test meets the following requirements; (1) Routine blood examination, which must be met (no blood transfusion within 14 days);

   1. HGB≥100g/L;
   2. WBC≥4.0×10^9/L; absolute neutrophil count(ANC) ≥2.0×10^9/L;
   3. PLT≥2.0×10^9/L; (2) The biochemical inspection must meet the following standards:
   1. BIL≤1.5 times the upper limit of normal (ULN);
   2. Alanine aminotransferase(ALT) and aspartate aminotransferase(AST)≤2.5×ULN; if there is liver metastasis, ALT and AST≤5×ULN;
   3. serum Cr≤1.5×ULN, endogenous creatinine clearance≥50ml/min (Cockcroft-Gault formula); (3) Occult blood in stool (-); (4) Urine routine is normal, or urine protein <(++), or 24-hour urine protein <1.0g;

8. The coagulation function is normal, without active bleeding and thrombosis disease;

   1. International standardized ratio INR≤1.5×ULN;
   2. Partial thromboplastin time APTT≤1.5×ULN;
   3. Prothrombin time PT≤1.5×ULN;

9. Female subjects with fertility and male subjects whose partner is a female of childbearing age who need to take effective contraceptive measures during the study treatment period and at least 6 months after the last use of the study drug;

10. Subjects voluntarily participate in this study and sign an informed consent form (ICF);

11. Those who have good compliance and can follow up as required by the plan.

Exclusion Criteria:

1. Various types of liver inflammatory diseases (especially hepatitis A, B, and C viral hepatitis active period) and other diseases that may produce AFP such as liver cirrhosis;
2. Germ cell tumors;
3. Have previously received any regimen of palliative chemotherapy for gastric cancer;
4. Have previously received apatinib treatment;
5. S-1 and/or oxaliplatin have been used in the past 6 months;
6. Those who have hypertension and cannot be reduced to the normal range after treatment with antihypertensive drugs (shrinking Pressure>140mmHg or diastolic pressure>90mmHg);
7. Suffering from coronary heart disease ≥2 grade, arrhythmia corrected QT interval(QTc) interval prolonged male> 450ms, female;>470ms) and cardiac insufficiency;
8. There are many factors that affect the absorption of oral drugs (such as inability to swallow, nausea and vomiting, chronic abdominal Diarrhea and intestinal obstruction, etc.);
9. Patients at risk of gastrointestinal bleeding or those with a history of gastrointestinal bleeding within 1 month;
10. Abnormal blood coagulation function (INR>1.5×ULN, activated partial thromboplastin time(APTT)>1.5×ULN), those with bleeding tendency;
11. Those with thrombotic diseases or receiving anticoagulant treatment;
12. Those with peripheral sensitive neuropathy with dysfunction;
13. Central nervous system metastasis;
14. Pregnant or lactating women;
15. Those who have participated in other clinical research in the past 30 days;
16. Other patients considered by the treating physician to be unsuitable for inclusion