Surgical Total Clearance Versus Extrahepatic Bile Duct Preservation for Biliary Tract Malignancies: A Single-Center, Randomized, Two-Arm, Prospective Phase II Clinical Trial

Inclusion Criteria:

• Age 18 years or older, regardless of gender.

Voluntary participation with full informed consent; signed written informed consent form; good compliance.

Histologically or cytologically confirmed cholangiocarcinoma (CCA).

Gallbladder cancer or intrahepatic cholangiocarcinoma with preoperative lymph node metastasis.

No prior systemic chemotherapy, immunotherapy, targeted therapy, or local treatment for CCA (including but not limited to transarterial chemoembolization, arterial embolization, arterial infusion chemotherapy, and radioactive particle embolization).

At least one measurable lesion according to RECIST v1.1.

Child-Pugh class A liver function, and no history of hepatic encephalopathy.

Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0-1.

Life expectancy ≥ 12 weeks.

Adequate organ function meeting the following requirements (no blood transfusion, blood products, hematopoietic growth factors, or other medications to correct blood counts within 14 days prior to randomization):

White blood cell count ≥ 4.0 × 10⁹/L;

Absolute neutrophil count ≥ 1.5 × 10⁹/L;

Platelet count ≥ 90 × 10⁹/L;

Hemoglobin ≥ 90 g/L;

Serum albumin ≥ 30 g/L;

Serum total bilirubin ≤ 2 × upper limit of normal (ULN); any biliary obstruction must be resolved before randomization;

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN;

Creatinine clearance (CrCl) ≥ 50 mL/min (calculated using the Cockcroft-Gault formula);

International normalized ratio (INR) ≤ 2 and prothrombin time (PT) prolonged ≤ 3 seconds above the ULN.

For active hepatitis B, effective antiviral therapy (per local standard of care, e.g., entecavir or tenofovir) is required, with HBV DNA < 2000 IU/mL or a ≥ 10-fold decrease in HBV DNA after antiviral treatment; patients must agree to continue effective anti-HBV therapy throughout the study period.

Within 7 days prior to randomization, women of childbearing potential must have a negative serum pregnancy test and agree to use effective contraception during the study treatment period and for 6 months after the last dose. In this protocol, a woman of childbearing potential is defined as a sexually mature woman who: 1) has not undergone hysterectomy or bilateral oophorectomy; 2) has not been naturally postmenopausal for at least 24 consecutive months (amenorrhea following cancer therapy does not rule out fertility) (i.e., has had menses at any time in the preceding 24 consecutive months). Male patients with female partners of childbearing potential must agree to use effective contraception during the study treatment period and for 5 months after the last dose.

Exclusion Criteria:

• Histopathologically or cytologically confirmed hepatocellular carcinoma, mixed hepatocellular-cholangiocarcinoma, sarcomatoid hepatocellular carcinoma, or fibrolamellar hepatocellular carcinoma.

Other malignancy within 5 years, except for cured localized tumors, including non-melanoma skin basal cell carcinoma, cervical carcinoma in situ, and papillary thyroid carcinoma.

Radiotherapy for CCA within 4 weeks prior to randomization; major surgery (excluding diagnostic biopsy) within 4 weeks prior to randomization.

History of severe cardiovascular or cerebrovascular disease:

New York Heart Association (NYHA) class II or greater congestive heart failure, unstable angina, myocardial infarction, poorly controlled arrhythmia, or cerebrovascular accident within 12 months prior to randomization;

Left ventricular ejection fraction (LVEF) < 50% on echocardiography;

Corrected QT interval (QTc) > 480 ms (calculated using the Fridericia method; if QTc is abnormal, it may be measured three times consecutively at 2-minute intervals, and the average taken);

Poorly controlled hypertension (systolic blood pressure ≥ 150 mmHg and/or diastolic blood pressure ≥ 100 mmHg, based on the average of ≥ 2 readings);

Prior hypertensive crisis or hypertensive encephalopathy.

Evidence of significant bleeding/coagulation disorder or bleeding tendency:

Clinically significant hemoptysis or tumor bleeding of any cause within 4 weeks prior to randomization;

Prior tumor rupture (unless surgically treated);

Thrombotic or embolic event within 6 months prior to randomization;

Therapeutic anticoagulation within 2 weeks prior to randomization (except for low-molecular-weight heparin);

Need for antiplatelet therapy;

Use of aspirin (> 325 mg/day), clopidogrel (> 75 mg/day), dipyridamole, ticlopidine, or cilostazol within 10 days prior to randomization.

Known central nervous system metastasis and/or meningeal metastasis (including dural and leptomeningeal metastasis).

Any other condition that, in the investigator's opinion, renders the patient unsuitable for enrollment.