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
Studieoversigt
Status
Betingelser
Intervention / Behandling
Detaljeret beskrivelse
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.
Undersøgelsestype
Tilmelding (Anslået)
Kontakter og lokationer
Studiesteder
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Tianjin Municipality
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Tianjin, Tianjin Municipality, Kina, 300192
- Tianjin Firsr Central Hospital
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Deltagelseskriterier
Berettigelseskriterier
Aldre berettiget til at studere
Tager imod sunde frivillige
Køn, der er berettiget til at studere
Prøveudtagningsmetode
Studiebefolkning
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.
Beskrivelse
Inclusion Criteria:
- Age 18-70 years at enrollment.
- Histologically confirmed, well-differentiated (G1 or G2) gastroenteropancreatic neuroendocrine tumor (pancreatic or midgut/hindgut primary).
- Unresectable, liver-dominant metastatic disease (multifocal/bilobar involvement not amenable to curative resection or ablation).
- Ki-67 proliferation index ≤ 10% at the most recent biopsy, with stable disease for at least 6 months on standard therapy.
- Primary tumor resected, or resectable/planned for resection as part of the treatment strategy.
- No uncontrolled extrahepatic metastatic disease.
- ECOG performance status 0-1.
- Treatment group assigned by patient/family preference after balanced multidisciplinary counseling; both options (transplantation vs conventional therapy) medically feasible and discussed.
- Written informed consent.
Exclusion Criteria:
- Poorly differentiated neuroendocrine carcinoma (G3, Ki-67 above threshold) or mixed neuroendocrine/non-neuroendocrine neoplasm (MiNEN).
- Uncontrolled extrahepatic metastases or progressive disease despite adequate systemic therapy at enrollment.
- 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.
- Pregnancy or lactation.
- Other active malignancy within the past 5 years (except adequately treated non-melanoma skin cancer or cervical carcinoma in situ).
- Inability or unwillingness to comply with protocol follow-up.
- Participation in another interventional clinical trial with potential interference with endpoints.
Studieplan
Hvordan er undersøgelsen tilrettelagt?
Design detaljer
- Observationsmodeller: COHORT
- Tidsperspektiver: PROSPECTIVE
Kohorter og interventioner
Gruppe / kohorte |
Intervention / Behandling |
|---|---|
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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. |
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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. |
Deceased-donor or living-donor liver transplantation performed at Tianjin First Central Hospital on the basis of conventional medical therapy. |
Hvad måler undersøgelsen?
Primære resultatmål
Resultatmål |
Foranstaltningsbeskrivelse |
Tidsramme |
|---|---|---|
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5-Year Overall Survival
Tidsramme: Up to 5 years after enrollment
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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
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Sekundære resultatmål
Resultatmål |
Foranstaltningsbeskrivelse |
Tidsramme |
|---|---|---|
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Overall Survival Rate at 1 Year
Tidsramme: 1 year after enrollment
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Percentage of participants alive at 1 year after enrollment, estimated by the Kaplan-Meier method. |
1 year after enrollment
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Overall Survival Rate at 3 Years
Tidsramme: 3 years after enrollment
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Percentage of participants alive at 3 years after enrollment, estimated by the Kaplan-Meier method. |
3 years after enrollment
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Progression-Free Survival
Tidsramme: Up to 5 years after enrollment
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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
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Post-transplant Disease-Free Survival
Tidsramme: Up to 5 years after liver transplantation
|
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
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Recurrence Pattern After Liver Transplantation
Tidsramme: Up to 5 years after liver transplantation
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Anatomic pattern of first recurrence, categorized as intrahepatic (graft) recurrence or extrahepatic recurrence. |
Up to 5 years after liver transplantation
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Treatment-Related Adverse Events
Tidsramme: Up to 5 years after enrollment
|
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
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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
Tidsramme: Baseline, 6 months, 1 year, and annually thereafter up to 5 years
|
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
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Total Direct Medical Costs
Tidsramme: Up to 5 years after enrollment
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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
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Exploratory Prognostic Value of Ki-67 Proliferation Index
Tidsramme: Baseline
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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
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Exploratory Prognostic Value of Serum Chromogranin A
Tidsramme: Baseline, every 3 months up to 5 years
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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
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Exploratory Prognostic Value of NETest Multigene Blood-Based Biomarker Score
Tidsramme: Baseline, every 6 months up to 5 years
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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
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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
Tidsramme: Baseline, 6 months, 1 year, and annually thereafter up to 5 years
|
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
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Samarbejdspartnere og efterforskere
Sponsor
Datoer for undersøgelser
Studer store datoer
Studiestart (Faktiske)
Primær færdiggørelse (Anslået)
Studieafslutning (Anslået)
Datoer for studieregistrering
Først indsendt
Først indsendt, der opfyldte QC-kriterier
Først opslået (Faktiske)
Opdateringer af undersøgelsesjournaler
Sidste opdatering sendt (Faktiske)
Sidste opdatering indsendt, der opfyldte kvalitetskontrolkriterier
Sidst verificeret
Mere information
Begreber relateret til denne undersøgelse
Nøgleord
Yderligere relevante MeSH-vilkår
- Neoplasmer
- Neoplasmer efter histologisk type
- Neuroektodermale tumorer
- Neoplasmer, kimceller og embryonale
- Neoplasmer, nervevæv
- Neuroendokrine tumorer
- Terapeutik
- Kirurgiske procedurer, operative
- Transplantation
- Kirurgiske procedurer for fordøjelsessystem
- Celle- og vævsbaseret terapi
- Biologisk terapi
- Vævstransplantation
- Organtransplantation
- Levertransplantation
Andre undersøgelses-id-numre
- TRANET-GEP-2026-01
Plan for individuelle deltagerdata (IPD)
Planlægger du at dele individuelle deltagerdata (IPD)?
IPD-planbeskrivelse
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-deling Understøttende informationstype
- STUDY_PROTOCOL
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