Liver Transplantation for Non-Resectable Colorectal Liver Metastases Without Local Treatment Options

German Transplant Oncology Study 001: Liver Transplantation for Patients With Colorectal Liver Metastases Without Local Treatment Options:

Patients whose colorectal cancer has spread to the liver, and whose liver metastases cannot be removed by surgery or destroyed by ablation, currently receive palliative chemotherapy in Germany. Fewer than one in ten of these patients survive five years. International studies have shown that replacing the whole liver by transplantation can achieve much longer survival in carefully selected patients, because removing the entire liver removes all of the tumour when the disease is confined to it. The TransMet trial reported five-year survival of 57% with transplantation plus chemotherapy, compared with 13% for chemotherapy alone. This approach is not yet available in German routine care, where liver transplantation for this indication is permitted only within a clinical study.

GTO-001 will enrol approximately 260 adults aged 18 to 65 years with colorectal liver metastases that are confined to the liver, that cannot be removed or ablated, and that have remained stable or improved for at least six months on chemotherapy. Every participant is assessed by a newly established National Tumor Board for Transplant Oncology, which meets monthly, reviews the imaging and case independently of the local centre, and decides whether the patient may be listed for transplantation. Patients who are approved are listed with a study-specific priority status, continue their chemotherapy while they wait, and undergo a surgical inspection of the abdomen at the start of the transplant operation to confirm that the cancer has not spread outside the liver. Participants who are not listed, or in whom transplantation is not performed, remain in the study and are followed in the same way.

The main question is how many patients are alive five years after transplantation. The study also measures how many of the patients assessed are eventually listed and transplanted, how many leave the waiting list because their disease progresses or becomes operable, survival after each of the treatments patients actually receive, how well the transplanted livers function, and complications after surgery. Because the study follows everyone who is assessed, it will also establish for the first time how many patients in Germany genuinely qualify for this treatment. Participants are followed for five years after transplantation; the study runs until 2036.

Rationale. Colorectal liver metastases (CRLM) are resectable in only 20-40% of patients. For the remainder, palliative systemic therapy is the only option recommended by the German S3 and ESMO guidelines, with 5-year overall survival of approximately 10%. The premise of transplant oncology is that total hepatectomy constitutes an R0 resection provided disease is liver-confined. The Oslo experience (61 transplanted patients, median overall survival 60.3 months, 5-year survival 50.4%) and the randomised TransMet trial (5-year overall survival 57% vs 13% intention-to-treat; 73% vs 9% per protocol) support the approach, but neither has been reproduced under Eurotransplant allocation. In Germany, patients with non-resectable CRLM are not eligible for a ReMELD-Na Standard Exception, and under Section 16(1)(1) nos. 2 and 5 of the German Transplantation Act, liver transplantation for oncological indications beyond established ones is permissible only within clinical studies.

Design and selection. GTO-001 is a prospective, multicentre, non-randomised, non-blinded interventional study at up to 19 German transplant centres, coordinated by Charité - Universitätsmedizin Berlin. Randomisation to a non-transplant arm was judged neither ethically justifiable nor feasible given the magnitude of the survival difference already demonstrated. Bias is instead addressed by strict eligibility criteria, binding central adjudication of resectability and listing, centralised imaging assessment on pseudonymised data transferred through the RACOON network, uniform standard operating procedures across sites, structured investigator training, and independent DSMB oversight.

Two selection features distinguish GTO-001 from TransMet: a mandatory period of at least six months of disease control under active chemotherapy before listing (TransMet required three), and prospective application of a PET-derived metabolic tumour volume threshold of 70 cm³, a cut-off associated with recurrence-free and overall survival in the Norwegian SECA experience and subsequently validated in a two-centre transplanted cohort. BRAF V600E mutation and MSI-H/dMMR status of the colorectal primary are exclusion criteria.

Conduct. Approved patients are listed through their local transplant conference and receive a study-specific ReMELD-Na Standard Exception on application to Eurotransplant. Systemic chemotherapy continues until transplantation, without anti-EGFR antibodies, anti-VEGF antibodies or checkpoint inhibitors. Surveillance during waiting comprises CT of chest, abdomen and pelvis and CEA every three months. Patients are removed from the list if progression is suspected, and relisted once disease control is re-established. Grafts are allocated by Eurotransplant; living donation is an equally acceptable option to be evaluated per patient; full and split grafts are both permitted, but staged hepatectomy techniques are not. All patients undergo a mandatory staging exploration - as the first step of deceased-donor transplantation, or within seven days before living-donor transplantation - performed by a surgeon with more than 50 liver resections or transplants, comprising systematic four-quadrant inspection of the peritoneal cavity with frozen-section examination of suspicious findings before hepatectomy begins. Transplantation is abandoned and the graft reallocated without delay if CEA exceeds 80 ng/mL preoperatively, or if peritoneal or extrahepatic disease is found. Follow-up after transplantation is every 4 weeks to month 3, every 3 months to year 3, then every 6 months to year 5, each visit comprising clinical examination, laboratory testing with tumour markers, and CT of chest, abdomen and pelvis.

Sample size. Approximately 260 patients will be screened and enrolled. Based on the Toronto experience, about 50% of patients proposed by local boards are expected to pass central review and about 80% of listed patients to drop out before transplantation, so approximately 26 patients (10% of those enrolled) are expected to undergo transplantation. The primary statistical objective is to demonstrate that 5-year survival after transplantation exceeds 50%, equivalent to median survival beyond 5 years. Assuming 65% 5-year survival and constant hazards, median survival is 8.041 years; with 9 expected deaths the one-sided 95% confidence interval for median survival is (5.014, ∞), which supports the conclusion, whereas 8 expected deaths would give (4.893, ∞) and would not. Nine expected events therefore require 26 transplanted patients. Alpha is 5% and no interim analysis is planned.

Analysis populations. The transplant cohort (patients transplanted after board approval and without contraindications at transplantation) is used for the primary analysis. The screened cohort comprises all patients screened, retaining those who withdraw or become ineligible through progression. The as-treated cohort comprises screened patients who received one of the three definitive treatments - transplantation, local treatment, or systemic treatment alone. The primary endpoint is estimated by Kaplan-Meier with a two-sided 95% confidence interval. As-treated comparisons use log-rank tests and Cox proportional hazards models adjusted for age and sex. Missing data are handled by multiple imputation using chained equations under a missing-at-random assumption, with 20 imputed datasets combined by Rubin's rules. A statistical analysis plan will be finalised before database lock.

Governance. The study is conducted in accordance with ICH E6 (R3), the Declaration of Helsinki, and the Professional Code for Physicians of the competent State Chamber of Physicians. Data are captured pseudonymously in a server-based eCRF (secuTrial); Charité is the controller under Art. 4 no. 7 GDPR, with consent as the legal basis under Art. 6(1)(a) and Art. 9(2)(a) GDPR. Monitoring is performed by the Charité Clinical Trial Office on a risk-adapted basis. An optional translational sub-study biobanks blood from all enrolled participants and a liver wedge biopsy from transplanted participants at the Charité central biobank (ZeBanC).

Inclusion Criteria:

• Age 18 to 65 years at enrolment
• ECOG performance status 0 or 1
• Written informed consent before any study-related procedure
• Colorectal liver metastases stable for at least 6 months under active chemotherapy of no more than 2 lines
• Colorectal liver metastases not amenable to curative local treatment by resection or ablation because of insufficient liver capacity or future liver remnant, as judged by the local interdisciplinary tumour board
• For metachronous colorectal liver metastases: a colorectal primary resected in the past with T4a or lower and local R0 status
• For synchronous colorectal liver metastases: a potentially curatively resectable primary
• No evidence of peritoneal disease, as documented by a surgical report within the preceding 36 months
• Suitability for liver transplantation according to local centre criteria
• Participants of childbearing potential: negative highly sensitive pregnancy test before inclusion, and use of a contraceptive method with a failure rate below 1%, or confirmed post-menopausal status

Exclusion Criteria:

• Inability to give informed consent
• General contraindications to liver transplantation
• Large-vessel infiltration
• Extrahepatic disease, including lymph node involvement
• Listing for multi-organ transplantation
• Prior solid organ or bone marrow transplantation
• BRAF V600E mutation in the molecular pathology of the colorectal primary
• MSI-H/dMMR status in the molecular pathology of the colorectal primary
• Breastfeeding
• Institutionalisation by order of a court or public authority
• Dependence on the overall study lead, the investigator or the study site
• Participation in another clinical study with an investigational medicinal product or medical device