Liver Transplantation for Unresectable Intrahepatic Colangiocarcinoma After Sustained Response to Neoadjuvant Treatments

This is a single-arm, observational, academic, investigator-driven study investigating the efficacy of liver transplantation after successful and sustained downstaging/tumor control of liver-limited unresectable intrahepatic cholangiocarcinoma.

Patients with biopsy-proven unresectable ICC who fit within inclusion criteria will be enrolled in the study. Patients with unresectable ICC who enter the protocol with an intention-to-treat strategy will first undergo CT scan +/- MRI, FDG-PET and staging laparoscopy with nodal sampling at the hepatic hilum (at least stations 8 and 12). In case of negative staging (no peritoneal carcinomatosis, no tumor spread in lymph nodes, negative tumor citology in the peritoneal washing), they will receive downstaging with state-of-the-art chemotherapy +/- immune checkpoint inhibitors (ICIs) (at the time of writing: gemcitabine-cisplatin +/- durvalumab) for 2 cycles, followed by transarterial radioembolization with Y90 (Y90-TARE), followed by at least 4 other cycles of gemcitabine-cisplatin +/- durvalumab. If actionable mutations are present at gene sequencing of tumoral tissue are present, molecular-targeted treatments with FGFR-inhibitors, IDH-1 inhibitors and PARP-inhibitors are allowed after multidisciplinary evaluations. Patients who cannot undergo Y90-TARE due to absolute contraindications (e.g., evidence of pulmonary shunts at angioscintigraphy) may be considered for stereotactic body radiation therapy (SBRT).

After downstaging, patients will undergo disease restaging with CT scan +/- MRI, FDG-PET and CA19-9 and, if at least tumor stability is confirmed with CA19-9 \< 200 u/ml, they will undergo transplant screening and listing.

Both naive patients and patients already receiving systemic and/or locoregional therapies for their unresectable ICC are eligible as long as sustained response is demonstrated. In all instances, they will undergo staging laparoscopy and, if negative (see above) with at least 6 months of tumor stability from diagnosis, they will go directly to transplant screening and listing.

During listing, restaging will be performed every two months with CT scan and/or MRI, molecular markers and FDG-PET. Maintenance therapy is allowed at the discretion of the patient's oncology team. The target interval between listing and transplant should be less than 90 days.

Tumor response will be determined according to RECIST, mRECIST and Choi criteria.

In case of disease progression during listing, the patient will be suspended from the transplant waiting list. Re-listing is allowed after second-line therapy if disease stability for at least four months if achieved, at the discretion of the multidisciplinary tumor and transplant board of INT Milan.

Any kind of donor will be considered as suitable for the recruited patients, including marginal marginal organ donation (DCD, split-liver, age \>75, severe steatosis, etcetera).

• 3-year recurrence-free survival vs unresectable patients [Time frame: 3 years]
• 90-day morbidity [Time frame: 90 days and long-term]
• Quality of life [Time frame: 3 years]
• 3-year OS vs resectable patients [Time frame: 3 years]
• 3-year DFS vs resectable patients [Time frame: 3 years]