The TRANSECT trial is a prospective randomized study designed to evaluate the role of liver transplantation (LT) versus radical local treatment (hepatic resection and/or ablation) in patients with initially unresectable colorectal liver metastases (CRLM) converted to resectability after conversion therapy.

Liver metastases are the leading cause of mortality in colorectal cancer patients. Although hepatic resection combined with chemotherapy remains the standard curative-intent treatment, only a minority of patients are eligible for upfront surgery. Advances in modern conversion chemotherapy have substantially increased the proportion of patients who can subsequently undergo curative local treatment. However, liver resection after intensive chemotherapy is still associated with high rates of intrahepatic recurrence, risk of R1 resections, chemotherapy-induced liver injury, and the need for complex surgical procedures carrying considerable morbidity and mortality. In parallel, recent studies investigating LT for unresectable CRLM, including the TRANSMET trial, demonstrated highly promising oncological outcomes, with 5-year overall survival rates exceeding 50% in selected patients.

Based on these findings, the TRANSECT trial hypothesizes that LT may represent a more effective therapeutic strategy also in patients initially deemed unresectable but subsequently converted to resectability, by completely removing the hepatic metastatic niche.

TRANSECT is a single-center, randomized, open-label, proof-of-concept trial. Patients with liver-only CRLM initially assessed as unresectable by a dedicated multidisciplinary tumor board and subsequently converted to resectability after systemic therapy will be randomized to either LT or hepatic resection and/or ablation. The primary endpoint is 3-year intention-to-treat overall survival (OS). Secondary endpoints include perioperative morbidity and mortality, disease-free survival, treatment adherence, quality of life, and exploratory translational analyses including radiomics and circulating tumor DNA assessment.

A total of 70 patients (35 per arm) will be enrolled, with an estimated overall study duration of 5 years. TRANSECT represents the first randomized trial directly comparing LT and liver-directed surgery in patients with initially unresectable CRLM converted to resectability after systemic therapy, with the aim of redefining curative treatment strategies in this selected patient population.

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.

Inclusion Criteria screening phase (before randomization):

• Signed screening phase informed consent.
• Age >18.
• Performance status score of Eastern Cooperative Oncology Group (PS-ECOG) 0-1
• Adequate organ functions.
• Liver-limited Metastatic Disease Confirmed as Unresectable by Colorectal Oncology Multidisciplinary Tumor Board (MTB).
• Histologically documented adenocarcinoma of the colon or intra-peritoneal rectum
• Absence of extra-hepatic disease demonstrated by contrast-enhanced CT + MRI and, in clinically indicated (clinical suspicion or elevated biomarkers), FDG-PET.
• No previous systemic treatment for unresectable disease.
• No previous systemic treatment for primary tumor resection
• Recurrence occurring beyond six months after completion of adjuvant treatment.
• MMR proficient cancer (MSS) regardless of RAS mutational status, BRAF-WT except for BRAF V600E-mut treated and responding to anti-BRAF + cytotoxic therapy.

Exclusion criteria:

• Absolute contraindication to liver transplant.
• Other malignancies in the previous 5 years excluding non melanoma skin-cancers or in situ disease.
• Hereditary CRC syndromes including FAP and Lynch syndrome.
• Previous extrahepatic metastatic localization or locoregional tumor recurrence.
• Extra-peritoneal cancers.
• BRAFV600E-mut patients non-responder to 1st line anti-BRAF + cytotoxic therapy (Elez et al NEJM 2025, ref. 8)

Randomization inclusion criteria:

• Signed randomization phase informed consent.
• CEA < 80 ng/ml or decrease in CEA level at least 50% from baseline (TRANSMET criteria (5)).
• Conversion to resectability according to MTB discussion during first 6 months of induction chemotherapy.
• Sustained objective response defined as stable disease (SD), partial response (PR) or complete response (CR) according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria (19), under chemotherapy, for at least 3 months.
• Surgical resection of the primary tumor with a high oncological standard, as outlined in The American Society of Colon and Rectal Surgeons Clinical Practice Guidelines for the Management of Colon Cancer (20), ensuring safe margins of resection and adequate TNM staging.
• Histologically confirmed primary tumor staged as pT4a and/or pN2, with achievement of R0 resection. In patients with pT4a and/or pN2 disease, only metachronous metastases are eligible. For pT4a tumors, a minimum disease-free interval of 6 months from primary tumor resection is required before randomization.
• Time from primary resection to liver transplantation or radical local treatment >6 months
• Absence of local recurrence and extra-hepatic disease demonstrated by contrast-enhanced CT + MRI and, in clinically indicated (clinical suspicion or elevated biomarkers), FDG-PET.
• PS-ECOG 0-1. Adequate organ functions.

After request to the PI and evaluation of the research intent.