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

This is 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. The downstaging protocol includes chemotherapy +/- immunotherapy and transarterial radioembolization (TARE) with Yttrium-90 in various combinations.

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).

Eligibility Criteria:
Inclusion Criteria:

* Histological diagnosis of iCCA (biopsy-proven tumor)
* Either first diagnosis or post-resection recurrence (occurring ≥ 6 months after resection)
* Unresectability assessment due to tumor location (leading to insufficient live remnant with/out implementation of hypertrophic parenchymal techniques) or underlying liver disease. Non-resectability assessed by an expert surgical team with experience on both resection and transplantation (centralized at INT Milan).
* Age between 18 and 70 years
* No macrovascular tumor invasion (NB: portal vein and/or hepatic vein occlusion from the external tumor compression and classified as "encasement" could be considered after expert radiology review)
* No extrahepatic spread
* Disease stability for at least 6 months
* CA 19-9 \< 200 u/ml at transplant listing in absence of jaundice
* No medical and surgical contraindications to liver transplantation
* Good performance status, Eastern Cooperative Oncology Group (ECOG) 0 or 1
* No concomitant malignancies or history of other malignancies in the previous 5 years
* Written informed consent

Exclusion Criteria:

* Hilar and distal cholangiocarcinoma
* Progression of disease under chemotherapy +/- radiation therapy, assessed with either RECIST, mRECIST or Choi criteria
* Evidence of lymph-nodal metastases
* Evidence of extrahepatic disease
* Prior extrahepatic metastatic disease
* Concomitant malignancies or history of other malignancies in the previous 5 years
* Substance abuse, medical, psychological, or social conditions that may interfere with the patient's participation in the study or evaluation of the study results
* Any reason why, in the opinion of the investigator, the patient should not participate to the study