Current perspectives and guidelines on liver transplantation for metastatic colorectal cancer

Table 1 Criteria for patients with colorectal metastatic cancer based on SECA I trial: Oslo score and Fong clinical risk score

Oslo score	Fong clinical risk score
Largest lesion diameter > 5.5 cm	Maximal lesion diameter > 5.0 cm
Pre-transplant CEA level > 80 μg/mL	Pre-resection CEA level > 200 μg/mL
Progression on chemotherapy	> 1 liver metastasis
Time from resection of the primary tumor to transplant < 24 months	Node-positive primary interval from diagnosis of primary to liver metastasis < 12 months

CEA: Carcinoembryonic antigen.

Table 2 Trials covering liver transplantation outcomes in patients with metastatic colorectal cancer

Trial	Country	Type of study	Oncological criteria/design	Primary outcomes	Secondary outcomes
Transmet	France	Multicentric phase III RCT randomized, controlled	Primary tumour resection according to oncological principles; BRAF non-mutated; CRLM definitively unresectable according to multidisciplinary panel expert; ≤ 3 chemotherapy lines for metastatic disease; Stable disease (RECIST criteria) on chemotherapy > 3 months; CEA level < 80 μg/L or at least 50% decrease of maximal level; No extrahepatic disease confirmed by CT and PET/CT	OS at 5 years	OS at 3 years, DFS, PFS, recurrence, QOL
SECA III	Norway	Randomized, controlled	LT vs other treatment options including chemotherapy, TACE, or SIRT	OS at 2 years	None listed
Soulmate	Sweden	Randomized, controlled	LT from extended criteria donors + best-established treatment (BET) vs BET alone	OS at 5 years	OS at 2 years, median OS, PFS, recurrence-free survival, QOL, QALY
Excalibur 1	Norway	Randomized, controlled	LT + chemotherapy vs HAI/FUDR + chemotherapy vs chemotherapy alone	OS at 2 years	QOL, 30-/90-day morbidity/mortality
Colt	Italy	Nonrandomized, prospective	LT vs triplet chemotherapy + anti-EGFR	OS at 5 years	PFS, complications
Melodic	Italy	Nonrandomized, prospective	LT vs chemotherapy	OS at 3 years, OS at 5 years	PFS, dropouts, complications
Livermore	Italy	Single group, open label	LDLT vs historical cohort of potentially transplantable patients who received chemotherapy only	OS at 5 years, DFS at 5 years	Graft survival, donor QOL
Litorale 2020	Italy	Single group, open label	LT	OS at 5 years	DFS
NCT04874259	Korea	Single group, open label	LDLT	OS at 1 year	DFS, OS at 3 years, recurrence
Livert(w) o heal	Germany	Single group, open label	LDLT with two-staged hepatectomy vs historic cohort of patients who received gold-standard chemotherapy	OS at 3 years	DFS, morbidity of recipient, morbidity of donor
RAPID-Padova	Italy	Single group, open label	LT with staged hepatectomy	Percent of patients receiving hepatectomy within 4 weeks of transplant	OS, PFS, dropouts, mortality, complications
Trasmetir	Spain	Cohort, prospective	LT	OS at 5 years	DFS, QOL
NCT02864485	Canada	Single group, open label	Primary CRC tumour stage ≤ T4a; BRAF non-mutated; Bilateral and non-resectable CRLM without major vascular invasion by LM; Time from primary CRC resection to transplant is ≥ 6 months; No extra hepatic disease; Preoperative systemic chemotherapy for ≥ 3 months; Stable disease on chemotherapy > 3 months; CEA values are stable or decreasing at all timepoints; LDLT vs patients who drop out prior to transplantation	OS at 5 years, DFS at 5 years	Recurrence, types of cancer recurrence treatments, dropouts, QOL, OS/DFS at 1 and 3 years
Metliver	Spain	Single group, open label	LT	OS at 5 years	OS at 1 and 3 years, recurrence-free survival, dropouts, recurrence, QOL
NCT06069960	China	Single group, open label	Hemihepatectomy with concurrent left lateral lobe LT followed by delayed residual liver resection	OS at 3 years post second liver resection	DFS
RAPID 2014	Norway	Single group, open label	Unresectable liver metastases technically; Maximal size of CRLM < 10 cm and total number < 20; CEA < 100 ng/mL at time of diagnosis; Standard surgical procedure with adequate resection; pN0 primary tumour as pN0; No extra hepatic disease confirmed by CT and PET/CT, except patients may have 1-3 resectable lung lesions all < 15 mm; At least 8 weeks of chemotherapy; Liver segmentectomy with concurrent left lateral lobe LT followed by delayed residual liver resection	Percent receiving second-stage hepatectomy within 4 weeks	OS

LT: Liver transplantation; OS: Overall survival; DFS: Disease-free survival; PFS: Progression-free survival; QOL: Quality of life; TACE: Transarterial chemoembolization; SIRT: Selective internal radiation therapy; QALY: Quality-adjusted life years; HAI/FUDR: Hepatic arterial infusion with floxuridine; CT: Computed tomography; CRLM: Colorectal liver metastasis; CEA: Carcinoembryonic antigen; LDLT: Living donor liver transplant.

Table 3 Details on the study design, inclusion criteria, transplant type and additional therapy in the studies discussed

Study	Study design	Inclusion criteria	Transplant type	Additional therapy	Key findings
Transmet	Randomized controlled trial	Patients with resected primary tumors, stable disease post-chemotherapy	Deceased donor	Neoadjuvant chemotherapy	Study terminated due to low survival in the transplant group
SECA-III	Randomized controlled trial	Patients with limited liver metastases, controlled with chemotherapy	Deceased donor	Neoadjuvant chemotherapy	Ongoing; results pending
Soulmate	Randomized controlled multicenter	Patients with isolated colorectal liver metastases unsuitable for resection or ablation	Deceased donor (extended criteria)	Neoadjuvant and adjuvant therapy	Ongoing; aims to compare liver transplantation with best established treatment
Excalibur-1	Randomized controlled trial	Patients under 70 with inoperable colorectal liver metastases, insufficient response to current chemotherapy	Deceased donor	Hepatic Arterial infusion (HAI)/FUDR, systemic chemotherapy	Ongoing; compares liver transplantation, HAI/FUDR, and systemic chemotherapy. excaliburstudy.com
Colt	Prospective multicenter	Patients with limited liver metastases, resected primary tumors	Living donor	Neoadjuvant chemotherapy	5-year overall survival: 68%
Melodic	Randomized controlled trial	Patients with metastatic colorectal cancer meeting specific criteria	Deceased donor	Neoadjuvant and adjuvant therapy	Ongoing; results pending
Livermore	Prospective single-center	Patients with limited liver metastases	Deceased donor	Neoadjuvant chemotherapy	Ongoing; results pending
Litoral 2020	Randomized controlled trial	Patients with metastatic colorectal cancer meeting specific criteria	Deceased donor	Neoadjuvant and adjuvant therapy	Ongoing; results pending
NCT04874259	Randomized controlled trial	Patients with metastatic colorectal cancer meeting specific criteria	Deceased donor	Neoadjuvant and Adjuvant Therapy	Ongoing; results pending
Liver(t)wo heal	Prospective multicenter	Patients with limited liver metastases	Living donor	Neoadjuvant chemotherapy	Ongoing; results pending
RAPID-Padova	Prospective single-center	Patients with limited liver metastases	Deceased donor	Neoadjuvant chemotherapy	Ongoing; results pending
Transmetir	Randomized controlled trial	Patients with metastatic colorectal cancer meeting specific criteria	Deceased donor	Neoadjuvant and adjuvant therapy	Ongoing; results pending
NCT02864485	Randomized controlled trial	Patients with metastatic colorectal cancer meeting specific criteria	Deceased donor	Neoadjuvant and adjuvant therapy	Ongoing; results pending
Metliver	Randomized controlled trial	Patients with metastatic colorectal cancer meeting specific criteria	Deceased donor	Neoadjuvant and adjuvant therapy	Ongoing; results pending
NCT06069960	Randomized controlled trial	Patients with metastatic colorectal cancer meeting specific criteria	Deceased donor	Neoadjuvant and adjuvant therapy	Ongoing; results pending
RAPID 2014	Prospective single-center	Patients with limited liver metastases	Deceased donor	Neoadjuvant chemotherapy	Ongoing; results pending