Liver Transplantation Versus Conventional Medical Therapy for Low-Grade GEP-NET With Liver Metastases (TRANET-GEP)

Liver Transplantation Compared With Conventional Medical Therapy for Well-Differentiated (G1/G2) Gastroenteropancreatic Neuroendocrine Tumors With Unresectable Liver Metastases: A Two-Center, Non-Randomized, Patient-Preference-Based Prospective Cohort Study

Liver Transplantation Versus Conventional Medical Therapy for Low-Grade GEP-NET With Liver Metastases

Study Overview

• Status: Enrolling by invitation
• Conditions: Neuroendocrine Tumors
• Intervention / Treatment: Procedure: Liver Transplantation

Detailed Description

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a heterogeneous group of neoplasms; when liver metastases occur, prognosis deteriorates substantially. For patients with low-grade (well-differentiated G1/G2, low Ki-67 proliferation index), liver-dominant, unresectable metastases, conventional medical therapy-including somatostatin analogues, molecular targeted agents, peptide receptor radionuclide therapy (PRRT), and locoregional transarterial treatments-offers disease control but limited survival benefit, with an estimated 5-year overall survival below 30%.

Liver transplantation has emerged as a potentially curative option for highly selected patients with unresectable NET liver metastases. Non-randomized data from specialized centers suggest that patients meeting strict selection criteria (well-differentiated histology, low proliferative index, no uncontrolled extrahepatic disease) may achieve a 5-year overall survival of approximately 70% after transplantation. However, the absence of a concurrently enrolled non-transplant comparator group has limited the evidence.

This study establishes a two-center, prospective, non-randomized cohort in which treatment selection (liver transplantation versus conventional medical therapy) is based on patient/family preference following multidisciplinary evaluation at each center, with both groups intended to be broadly comparable at baseline. Liver transplantation is performed at the Department of Liver Transplantation, Tianjin First Central Hospital; conventional medical therapy is delivered at Fudan University Shanghai Cancer Center.

The primary objective is to compare 5-year overall survival between the two groups. Secondary objectives include 1- and 3-year overall survival, progression-free survival, post-transplant disease-free survival and recurrence patterns, safety and treatment-related morbidity, quality of life, and health economic outcomes.

Because assignment is not randomized, baseline comparability will be assessed and adjusted using propensity score matching or inverse probability of treatment weighting, complemented by multivariable Cox proportional hazards regression. Exploratory subgroup analyses will be performed by tumor grade, Ki-67 index, primary tumor site, and hepatic tumor burden.

• Study Type: Observational
• Enrollment (Estimated): 100

Contacts and Locations

Study Locations

• China
  • Tianjin Municipality
    • Tianjin, Tianjin Municipality, China, 300192
      • Tianjin Firsr Central Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Adult patients (aged 18-70 years) with histologically confirmed, well-differentiated (G1/G2) gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and unresectable, liver-dominant metastases, with Ki-67 proliferation index ≤ 10% and ECOG performance status 0-1. The population includes two cohorts: (1) patients who undergo liver transplantation at Tianjin First Central Hospital and (2) patients with comparable baseline characteristics who receive conventional medical therapy at Fudan University Shanghai Cancer Center, with cohort assignment based on patient/family preference following balanced multidisciplinary counseling. Both cohorts are drawn from consecutive patients meeting the eligibility criteria at the two participating centers between January 2019 and December 2028.

Description

Inclusion Criteria:

1. Age 18-70 years at enrollment.
2. Histologically confirmed, well-differentiated (G1 or G2) gastroenteropancreatic neuroendocrine tumor (pancreatic or midgut/hindgut primary).
3. Unresectable, liver-dominant metastatic disease (multifocal/bilobar involvement not amenable to curative resection or ablation).
4. Ki-67 proliferation index ≤ 10% at the most recent biopsy, with stable disease for at least 6 months on standard therapy.
5. Primary tumor resected, or resectable/planned for resection as part of the treatment strategy.
6. No uncontrolled extrahepatic metastatic disease.
7. ECOG performance status 0-1.
8. Treatment group assigned by patient/family preference after balanced multidisciplinary counseling; both options (transplantation vs conventional therapy) medically feasible and discussed.
9. Written informed consent.

Exclusion Criteria:

1. Poorly differentiated neuroendocrine carcinoma (G3, Ki-67 above threshold) or mixed neuroendocrine/non-neuroendocrine neoplasm (MiNEN).
2. Uncontrolled extrahepatic metastases or progressive disease despite adequate systemic therapy at enrollment.
3. For candidates considering transplantation: serious comorbidities precluding major surgery, including uncontrolled cardiopulmonary disease, active infection, decompensated cirrhosis with severe portal hypertension, or other contraindications to transplantation and immunosuppression.
4. Pregnancy or lactation.
5. Other active malignancy within the past 5 years (except adequately treated non-melanoma skin cancer or cervical carcinoma in situ).
6. Inability or unwillingness to comply with protocol follow-up.
7. Participation in another interventional clinical trial with potential interference with endpoints.

Study Plan

How is the study designed?

Design Details

• Observational Models: COHORT
• Time Perspectives: PROSPECTIVE

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Conventional Medical Therapy; Conventional medical therapy as clinically indicated, including somatostatin analogues (octreotide or lanreotide), molecular targeted therapy (everolimus, sunitinib), peptide receptor radionuclide therapy (177Lu-DOTATATE, when available), and/or transarterial locoregional therapy (TACE/TAE). This therapy constitutes the background treatment for both cohorts.
Other; Conventional medical therapy as clinically indicated, including somatostatin analogues (octreotide or lanreotide), molecular targeted therapy (everolimus, sunitinib), peptide receptor radionuclide therapy (177Lu-DOTATATE, when available), and/or transarterial locoregional therapy (TACE/TAE). This therapy constitutes the background treatment for both cohorts. This group of patients is willing to undergo a liver transplant.	Procedure: Liver Transplantation; Deceased-donor or living-donor liver transplantation performed at Tianjin First Central Hospital on the basis of conventional medical therapy.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
5-Year Overall Survival	Time from enrollment to death from any cause, assessed up to 5 years after enrollment. OS will be estimated by the Kaplan-Meier method and compared between groups using the log-rank test.	Up to 5 years after enrollment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival Rate at 1 Year	Percentage of participants alive at 1 year after enrollment, estimated by the Kaplan-Meier method.	1 year after enrollment
Overall Survival Rate at 3 Years	Percentage of participants alive at 3 years after enrollment, estimated by the Kaplan-Meier method.	3 years after enrollment
Progression-Free Survival	Time from enrollment to radiological progression (per RECIST 1.1) or death from any cause, whichever occurs first, assessed in the conventional medical therapy group.	Up to 5 years after enrollment
Post-transplant Disease-Free Survival	Time from liver transplantation to first radiological recurrence or death from any cause, whichever occurs first, assessed in the liver transplantation group.	Up to 5 years after liver transplantation
Recurrence Pattern After Liver Transplantation	Anatomic pattern of first recurrence, categorized as intrahepatic (graft) recurrence or extrahepatic recurrence.	Up to 5 years after liver transplantation
Treatment-Related Adverse Events	Percentage of participants experiencing treatment-emergent adverse events, graded by severity according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, including post-transplant surgical complications, graft-related events, and systemic drug toxicities.	Up to 5 years after enrollment
Quality of Life Assessed by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Global Health Status/Quality of Life Score	The EORTC QLQ-C30 global health status/quality of life subscale score ranges from 0 to 100, with higher scores indicating better quality of life.	Baseline, 6 months, 1 year, and annually thereafter up to 5 years
Total Direct Medical Costs	Total direct medical costs attributable to the treatment course, including surgery, hospitalization, systemic therapy, and management of adverse events, reported in Chinese Yuan (CNY).	Up to 5 years after enrollment
Exploratory Prognostic Value of Ki-67 Proliferation Index	Ki-67 proliferation index (percentage of positively stained tumor cell nuclei) assessed by immunohistochemistry on tumor tissue; ranges from 0% to 100%, with higher values indicating higher proliferative activity.	Baseline
Exploratory Prognostic Value of Serum Chromogranin A	Serum chromogranin A concentration measured by immunoassay, reported in ng/mL; higher values may indicate greater tumor burden.	Baseline, every 3 months up to 5 years
Exploratory Prognostic Value of NETest Multigene Blood-Based Biomarker Score	NETest multigene assay score based on circulating neuroendocrine tumor transcripts, reported as a normalized score from 0 to 100, with higher scores indicating more active disease.	Baseline, every 6 months up to 5 years
Neuroendocrine Tumor-Specific Symptoms Assessed by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for Neuroendocrine and Gastrointestinal Tumors (EORTC QLQ-GINET21) Score	The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for Neuroendocrine and Gastrointestinal Tumors (EORTC QLQ-GINET21) score ranges from a minimum of 0 to a maximum of 100, with higher scores indicating a greater burden of disease-specific symptoms, i.e., a worse outcome.	Baseline, 6 months, 1 year, and annually thereafter up to 5 years

Collaborators and Investigators

• Sponsor: Chiyi Chen

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2019
• Primary Completion (Estimated): December 31, 2028
• Study Completion (Estimated): December 31, 2028

Study Registration Dates

• First Submitted: October 22, 2026
• First Submitted That Met QC Criteria: October 28, 2026
• First Posted (Actual): November 3, 2026

Study Record Updates

• Last Update Posted (Actual): November 3, 2026
• Last Update Submitted That Met QC Criteria: October 28, 2026
• Last Verified: October 1, 2026

More Information

Terms related to this study

• Keywords: liver transplantation; liver metastasis; overall survival; somatostatin analogue; neuroendocrine tumor; peptide receptor radionuclide therapy
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Therapeutics; Surgical Procedures, Operative; Transplantation; Digestive System Surgical Procedures; Cell- and Tissue-Based Therapy; Biological Therapy; Tissue Transplantation; Organ Transplantation; Liver Transplantation
• Other Study ID Numbers: TRANET-GEP-2026-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Individual de-identified participant data that underlie the results of this study (baseline characteristics, survival outcomes, and adverse event data) will be shared. The study protocol and statistical analysis plan will also be available. Data will be shared with qualified researchers upon reasonable request, after approval of a data use proposal by the study steering committee and the ethics committees of both participating institutions, and after publication of the primary results. Proposals should be directed to the corresponding principal investigator; requests will be reviewed within 3 months. Data will be available for 5 years following article publication.

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

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