Short-course radiotherapy plus immunochemotherapy before surgery for gastroesophageal junction cancer

Inclusion Criteria:

1. Histologically and/or cytologically confirmed diagnosis of locally advanced adenocarcinoma of the gastroesophageal junction (GEJ) (Siewert types I-III), defined as cT3-4, any N, M0 or cT2 N+, M0 according to the 8th edition of the AJCC staging system.
2. Determined as resectable locally advanced disease after multidisciplinary team (MDT) evaluation.
3. Age ≥18 years, regardless of sex.
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
5. Estimated life expectancy ≥3 months.
6. No prior anti-cancer treatment.
7. At least one measurable lesion as defined by RECIST v1.1 (lesion diameter ≥1 cm on spiral CT or ≥2 cm on standard CT or MRI), assessed within 28 days prior to enrollment.
8. Adequate organ function within 14 days prior to treatment, defined as follows (note: blood transfusions, platelet infusions, or G-CSF use not permitted within 14 days prior to hematologic assessment):

1\) Hematological: Hemoglobin ≥9 g/dL (without recent transfusion); ANC ≥1.5 × 10⁹/L; WBC ≥3.0 × 10⁹/L (no G-CSF use); Platelets ≥75 × 10⁹/L (no IL-11 or TPO use).

2\) Biochemistry: Total bilirubin ≤1.5 × ULN; AST and ALT ≤2.5 × ULN; Serum creatinine ≤1.5 × ULN or creatinine clearance ≥60 mL/min (Cockcroft-Gault formula); Serum albumin ≥25 g/L.

3\) Coagulation: INR \<1.5, APTT \<1.5 × ULN within 7 days before enrollment; PT ≤1.5 × ULN.

9.Patients with active hepatitis B or C infection must have received antiviral therapy ≥14 days prior to enrollment, with HBV DNA ≤500 IU/mL or 2500 copies/mL, HCV RNA undetectable, and agree to continue antiviral therapy during the study.

10.LVEF ≥50% on echocardiography. 11.Women of childbearing potential must have a negative pregnancy test (serum or urine) within 7 days prior to enrollment and agree to use effective contraception during the study and for at least 3 months after the last dose. Males must use effective contraception during and for at least 3 months after treatment. Female participants must not be breastfeeding or donate/retrieve ova within 60 days after the last dose.

12.Willing and able to provide written informed consent and comply with study procedures.

Exclusion Criteria:

1. Confirmed dMMR or MSI-H by immunohistochemistry or genetic testing.
2. Evidence of peritoneal or visceral metastasis (based on thoracoabdominal CT, bone scan, or MRI if bone metastasis is suspected).
3. Other malignancies within the past 5 years, except cured basal cell or squamous cell carcinoma of the skin, or carcinoma in situ of the cervix.
4. Known allergy or hypersensitivity to any study drugs or their excipients; contraindications to study drugs.
5. Clinically significant upper gastrointestinal bleeding within 30 days before enrollment or randomization.
6. Interstitial lung disease, pulmonary fibrosis, active tuberculosis, or steroid-requiring pneumonitis confirmed by CT.
7. Active autoimmune or inflammatory disease requiring immunosuppressants within 2 years (e.g., IBD, SLE, sarcoidosis, Wegener's, MG, Graves', rheumatoid arthritis, etc.); exceptions: well-controlled type 1 diabetes, hypothyroidism under hormone replacement, untreated localized skin diseases (e.g., vitiligo, psoriasis).
8. Immunodeficiency, history of HIV infection or organ transplantation.
9. Active HBV (HBsAg positive) or HCV infection. Previously treated or well-controlled HBV/HCV is allowed.
10. Systemic corticosteroids or immunosuppressants within 2 weeks prior to treatment. Exceptions: inhaled or local steroids, adrenal replacement (\<10 mg/day prednisone equivalent), or short-term corticosteroids (\<7 days) for prophylaxis or non-autoimmune indications.
11. Uncontrolled comorbidities, including:

1）Poorly controlled hypertension (SBP ≥150 mmHg or DBP ≥100 mmHg); 2）Grade II+ myocardial ischemia or MI within 6 months, arrhythmia (QT ≥480 ms, AF), uncontrolled angina, CHF (NYHA III-IV), valvular disease, cardiomyopathy, stroke or TIA history; 3）Active or uncontrolled infection; 4）Liver disease (cirrhosis, decompensation, active hepatitis); 5）Poorly controlled diabetes (FBG \>10 mmol/L); 6）Proteinuria ≥++ or 24h urine protein \>1.0 g. 12.Coagulation abnormalities (INR \>1.5 or APTT \>1.5 × ULN), known bleeding tendency, or patients receiving thrombolytic or anticoagulant therapy. Known congenital or acquired bleeding or thrombotic disorders, such as hemophilia, coagulation defects, thrombocytopenia, hypersplenism, etc.

Patients with significant hemoptysis (≥2.5 mL per day), or a history of clinically significant bleeding (e.g., gastrointestinal bleeding, hemorrhagic gastric ulcers, or fecal occult blood test ≥++) within 3 months prior to enrollment.

Patients requiring long-term anticoagulation with warfarin or heparin, or long-term antiplatelet therapy (aspirin ≥300 mg/day or clopidogrel ≥75 mg/day).

13.Major surgery (e.g., craniotomy, thoracotomy, or laparotomy) within 4 weeks prior to first dose, or expected to undergo major surgery during the study, or non-diagnostic surgery within 4 weeks prior to trial initiation.

14.History of gastrointestinal perforation and/or fistula within 6 months before enrollment; or history of arterial or venous thromboembolic events, such as stroke (except stable cerebral infarction as judged by the investigator), deep vein thrombosis, or pulmonary embolism.

15.Long-term unhealed wounds or fractures. 16.Severe gastrointestinal conditions that may interfere with oral drug absorption, such as inability to swallow, chronic diarrhea, or intestinal obstruction.

17.Severe malnutrition. 18.Pregnant or lactating women, or participants of reproductive potential (male or female not postmenopausal for at least one year) who are unwilling to use effective contraception.

19.History of substance abuse or uncontrolled psychiatric illness. 20.Unwillingness or inability to comply with study requirements. 21.Participation in another clinical trial within 30 days prior to study entry, or planning to participate in another trial during the study period.

22.Any severe or uncontrolled medical condition, judged by the investigator to potentially compromise patient safety or interfere with study completion.