HCCANANO-HOPE1: IRE After Chemotherapy for Locally Advanced Unresectable Perihilar Cholangiocarcinoma

A Prospective, Randomized Controlled Phase II Clinical Study of Sequential or Non-sequential Irreversible Electroporation After Chemotherapy Induction in Patients With Locally Advanced Unresectable Perihilar Cholangiocarcinoma

Irreversible electroporation is a non-thermal ablative technology that uses high-voltage electric pulses to create permanent nanopores in tumor cell membranes, leading to apoptosis or other forms of cell death. Because the mechanism is primarily non-thermal, IRE may better preserve extracellular matrix, bile ducts, vessels, and other critical structures than thermal ablation, which is relevant for tumors adjacent to major vascular or biliary anatomy.

The main anticipated clinical value of IRE in these protocols is local disease control and potential survival benefit when used after induction therapy in patients with non-progressive disease. The procedure may be performed by open or percutaneous access according to tumor location, safety considerations, and institutional expertise. Perioperative management, imaging guidance, and post-procedure monitoring will follow institutional standards.

Post-IRE gastrointestinal dysfunction may occur. Symptom-directed supportive care, including electroacupuncture where appropriate and approved by the investigator, may be used as supportive management. Such care is not intended to replace oncologic treatment and will be recorded as concomitant treatment when administered.

Inclusion Criteria:

- Age 18-75 years, both sexes

Histologically or cytologically confirmed locally advanced perihilar cholangiocarcinoma (Bismuth-Corlette type III/IV or equivalent)

Non-progressive disease (PR or SD) after 3 cycles of standard induction chemotherapy

MDT-confirmed unresectable disease after induction therapy

No prior palliative systemic therapy

At least one measurable lesion per RECIST 1.1

ECOG Performance Status 0-1

Adequate organ and marrow function: Hb ≥9.0 g/dL, ANC ≥1.5×10⁹/L, platelets ≥100×10⁹/L, TBIL ≤3×ULN, AST/ALT ≤5×ULN, serum creatinine ≤1.5×ULN or CrCl >60 mL/min

Life expectancy ≥3 months

Willing to use contraception if of childbearing potential

Written informed consent

Exclusion Criteria:

- Refusal to receive systemic chemotherapy or possible surgery

Metastasis to liver, peritoneum, lung, bone, brain, or other distant sites

History of other malignancies (except cured basal cell carcinoma or cervical carcinoma in situ)

Severe uncontrolled comorbidities (e.g., NYHA III/IV heart failure, unstable angina, uncontrolled arrhythmia, uncontrolled hypertension, active infection, uncontrolled diabetes, significant effusions, severe portal hypertension, gastric outlet obstruction, respiratory insufficiency)

Major surgery within 30 days before screening

EGFR monoclonal antibody or EGFR-TKI within 30 days before screening

Allergy to any protocol-related drug or component

Known HIV infection or chronic hepatitis B/C (active)

Unresolved toxicity ≥CTCAE grade 2 from prior treatment (except anaemia, alopecia, skin pigmentation, or chemotherapy-induced neuropathy)

Any condition judged by the investigator to make participation inappropriate