TRANsplantation vs reSECTion After Conversion Therapy for Initially Unresectable Colorectal Liver Metastases

Liver metastases represent the leading cause of mortality in patients with colorectal cancer. Although hepatic resection combined with systemic therapy remains the standard curative-intent treatment, a substantial proportion of patients present with disease that is initially unresectable at diagnosis.

Over the last years, advances in systemic chemotherapy and targeted therapies have significantly increased conversion-to-resectability rates in patients with initially unresectable colorectal liver metastases. As systemic therapies continue to improve, the number of patients achieving conversion from initially unresectable to potentially resectable disease is expected to progressively increase, making this clinical scenario increasingly relevant in daily practice.

However, surgical treatment after conversion therapy remains associated with important oncological and surgical challenges. A complete radiological response does not necessarily correspond to a complete pathological response, with the possible persistence of microscopic residual disease and a consequent risk of intrahepatic recurrence. In addition, prolonged exposure to chemotherapy may result in liver toxicity and impairment of the residual liver parenchyma, increasing the complexity of surgical strategies required to achieve radical resection and raising the risk of post-hepatectomy liver failure.

In this context, liver transplantation may represent an alternative therapeutic strategy that could overcome some of the limitations of resective surgery by completely replacing the metastatic liver and eradicating both macroscopic and microscopic residual disease.

This is a single-center, prospective, randomized, open-label, proof-of-concept study designed to compare liver transplantation with radical local treatment in patients with colorectal liver metastases initially unresectable and subsequently converted to resectability following systemic therapy.

Patient evaluation will be performed through a centralized multidisciplinary assessment involving hepatobiliary surgeons, transplant surgeons, oncologists, and radiologists with specific expertise in the management of colorectal liver metastases. All cases will be discussed within a multidisciplinary tumor board with centralized imaging review both at diagnosis and after systemic therapy in order to define initial unresectability and subsequent potential conversion to resectability in a standardized manner.

The definition of unresectability will consider anatomical, oncological, and functional criteria, including the possibility of achieving complete radical (R0) resection, the predicted future liver remnant volume, the need for complex surgical procedures, and the presence of factors associated with increased surgical or oncological risk. Similarly, conversion to resectability will be defined according to the possibility of achieving radical local treatment with curative intent following systemic therapy.

All patients will undergo centralized radiological reassessment with contrast-enhanced CT scan and MRI; FDG-PET imaging will be performed when clinically indicated. During systemic treatment, radiological reassessments will be performed periodically to monitor oncological response, confirm the absence of extrahepatic disease, and evaluate eligibility for radical local treatment.

Eligible patients will receive induction systemic therapy according to institutional clinical practice and, in case of conversion to resectability and maintenance of eligibility criteria, will be randomized in a 1:1 ratio to one of the two treatment strategies provided by the protocol:

• liver transplantation;
• radical local treatment consisting of hepatic resection with or without ablative procedures.

In the liver transplantation arm, patients will continue systemic therapy until being listed for liver transplantation or until a transplantation date is established. If transplantation is not performed within two months after listing, patients will undergo repeat clinical, radiological, and biochemical reassessment, including imaging studies and tumor marker evaluation. In the presence of disease progression or increased tumor marker levels, patients may be temporarily suspended from the transplant waiting list and started on additional systemic therapy, followed by reassessment according to protocol-defined criteria. In the case of disease control, patients may be reconsidered for the transplant pathway. Otherwise, treatment will continue according to standard clinical practice.

In the surgical arm, radical local treatment will consist of hepatic resection with or without ablative procedures, according to multidisciplinary evaluation and the surgical strategy considered most appropriate to achieve complete disease control.

The study includes the evaluation of oncological, perioperative, and treatment adherence outcomes, in addition to exploratory translational analyses including radiomic characteristics, quality of life, and circulating biomarkers.

Patients will undergo clinical, laboratory, and radiological follow-up according to the study protocol and institutional clinical practice in order to monitor disease recurrence, oncological outcomes, and treatment safety.