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

TRANsplantation vs reSECTion After Conversion Therapy for Initially Unresectable

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Colorectal Liver Metastases
• Intervention / Treatment: Procedure: Liver Transplantation; Procedure: Liver Resection plus Ablation

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 70
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Stefano Di Sandro, MD; Phone Number: 4461 +39026444; Email: stefano.disandro@ospedaleniguarda.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Transplantation; Participants randomized to this arm will undergo liver transplantation after successful conversion to resectability following systemic therapy. In case of disease progression during the waiting period, patients may receive additional systemic therapy and be re-evaluated for transplant eligibility. In case of loss of eligibility, the patient will undergo the best standard of care (including resection). Post-transplant management will follow standard institutional protocols, including immunosuppressive therapy and oncologic follow-up.	Procedure: Liver Transplantation; Orthotopic liver transplantation performed in patients with colorectal liver metastases after successful conversion to resectability following systemic therapy. Eligibility for transplantation is confirmed through multidisciplinary evaluation and restaging. Patients continue systemic therapy after randomization until listing for transplantation or until the date of the procedure is established. Postoperative management includes standard immunosuppressive therapy and oncologic follow-up according to institutional protocols
Active Comparator: Resection; Participants randomized to this arm will undergo radical local treatment consisting of hepatic resection with or without ablative techniques after successful conversion to resectability following systemic therapy. The surgical approach will be determined based on tumor characteristics and institutional standards, with the goal of achieving complete tumor removal (R0 resection). Perioperative management and postoperative care will follow standard clinical practice	Procedure: Liver Resection plus Ablation; Liver resection with or without ablative techniques in patients with colorectal liver metastases after successful conversion to resectability following systemic therapy. Patients continue systemic therapy after randomization until the surgical procedure is performed, according to protocol. The surgical strategy is determined by a multidisciplinary team with the aim of achieving complete tumor removal (R0 resection). Perioperative and postoperative management follow standard institutional practice

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	Overall survival will be measured from the date of randomization to death from any cause and analyzed according to the intention-to-treat principle.	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease-Free Survival (DFS)	Disease-free survival is defined as the time from the date of treatment (liver transplantation or hepatic resection ± ablation) to the date of tumor recurrence or death from any cause, whichever occurs first.	Up to 3 years
Perioperative Morbidity	Assessment of postoperative complications occurring within 90 days after liver transplantation or hepatic resection + ablation, graded according to standard clinical classifications.	90 days after treatment
Perioperative Mortality	All-cause mortality occurring within 90 days after liver transplantation or hepatic resection + ablation	90 days after treatment

Collaborators and Investigators

• Sponsor: Niguarda Hospital
• Investigators: Principal Investigator: Stefano Di Sandro, MD, ASST Grande Ospedale Metropolitano Niguarda

Study record dates

Study Major Dates

• Study Start (Estimated): June 15, 2026
• Primary Completion (Estimated): June 15, 2029
• Study Completion (Estimated): June 15, 2031

Study Registration Dates

• First Submitted: May 14, 2026
• First Submitted That Met QC Criteria: May 22, 2026
• First Posted (Actual): May 26, 2026

Study Record Updates

• Last Update Posted (Actual): May 26, 2026
• Last Update Submitted That Met QC Criteria: May 22, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Randomized Controlled Trial; Colorectal Liver Metastases; Liver Transplantation; Conversion Therapy; Liver Resection
• Additional Relevant MeSH Terms: Therapeutics; Surgical Procedures, Operative; Transplantation; Digestive System Surgical Procedures; Cell- and Tissue-Based Therapy; Biological Therapy; Tissue Transplantation; Organ Transplantation; Hepatectomy; Liver Transplantation
• Other Study ID Numbers: 276671

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: After request to the PI and evaluation of the research intent.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No