Table 3.

Ongoing clinical trials on LT for CRLMs.

	Toronto NCT 02864485	TRANSMET NCT02597348	RAPID NCT02215889	LIVER-T(W)O-HEAL NCT03488953	SOULMATE NCT04161092	SECA III NCT03494946	COLT NCT03803436	RAPID-PADOVA NCT04865471	MELODIC NCT04870879
Type of study	Prospective cohort	Prospective, multicenter randomized parallel	Prospective	Prospective bi-institutional, one-arm trial.	Randomized controlled, open-label, multicenter study	Randomized study standard	Multicenter, non-randomized	Prospective, multicenter, non-randomized	Prospective multicenter, non-randomized
Design	LDLT + CT vs. CT	CT + LT vs. CT	Liver resection and partial section S2/3 transplanted with two-stage hepatectomy	LDLT with two-stage hepatectomy	LT with ECD + CT vs. CT	LT vs. CT, TACE, SIRT or other available treatment options	LT + CT vs. CT	Liver resection and partial section S2/3 transplanted	LT + CT vs. CT
Country	Canada	France	Norway	Germany	Swedish	Norway	Italy	Italy	Italy
Start	8/2016	9/2015	6/2014	5/2018	2/2020	12/2016	1/2019	To be determined	To be determined
State	Recruiting	Recruiting	Recruiting	Recruiting	Not yet recruiting	Recruiting	Recruiting	Not yet recruiting	Not yet recruiting
Definition of non resectability	Bilateral and non-resectable CRLMs	Independent Steering Committee including hepatobiliary surgeons, oncologists, radiologists, and hepatologists	Liver metastases, not amenable to liver resection	Unresectability is evaluated by experienced, independent hepatobiliary surgeons	Patients with non-resectable, non-ablatable liver metastases	Liver metastases, not amenable to liver resection	Liver metastases not eligible for curative liver resection	Liver metastases, not amenable to liver resection	Liver metastases, not amenable to liver resection
Type of graft and donor	Living donor liver transplantation	Whole liver from deceased donor.	Living donor segment 2/3 Stage 1: S2–S3 removed and liver donor implanted. Stage 2: After growth of donor segments, the remaining liver segments of the recipient were removed	Living donor segment 2/3 with two-stage hepatectomy	Liver grafts from extended criteria donors not utilized for approved indications	Whole liver from deceased donor	LT from cadaveric donors	Living donors or cadaveric donors	LT from cadaveric donors
Main inclusion criteria	- ECOG 0-1 - Proven colorectal liver metastases - Primary tumor stage ≤ T4a - Time from primary to LT ≥6 months - No major vascular invasion - Metastases isolated to liver - Previous CT for ≥3 months with stability or regression of CRLMs - CEA values are stable or decreasing - BRAF wild-type	- ECOG 0 or 1 - ≥ 18 and ≤ 65 years - Histologically proved adenocarcinoma in colon or rectum - BRAF wild-type - High-standard oncological surgical resection of the primary* - No local recurrence on colonoscopy - ≥ 3 months of tumor control during the last CT line: stable or partial response on RECIST criteria - ≤ 2 lines of CT for metastatic disease - CEA <80 microg/L or a decrease ≥ 50% - No extrahepatic tumor	- ECOG 0 or 1 - Histologically proved adenocarcinoma in the colon or rectum - No extrahepatic or local recurrence (except 1–3 resectable lung lesions all <15 mm) - At least 8 weeks of CT	- Stable disease after 8 weeks of CT - Primary tumor < pT3, N1 - No extrahepatic tumor burden (except resectable lung metastases)	- ECOG 0 or 1 - ≥ 18 years - Histologically proved adenocarcinoma in the colon or rectum - Primary tumor removed with an R0 resection - No extrahepatic or local recurrence - At least 2 months of CT with no signs of progression - >1 year from initial diagnosis - BRAF wild-type	- ECOG 0 or 1 - Histologically proved adenocarcinoma in the colon or rectum - No extrahepatic or local recurrence (except resectable lung lesions all <15 mm). - All patients should have progressive disease according to RECIST criteria, or intolerance to 1. line CT. - Patients must be randomized before evaluation 8–12 weeks after starting the second-line chemotherapy	- ECOG 0 - Histologically confirmed non-mucinous colon adenocarcinoma - pT1-3, pN0 or pN1 (metastases in <4 regional lymph nodes), confirmed R0 resection. - RAS and BRAF wild-type - Objective response according to RECIST 1.1 to first-line treatment, with sustained response for at least 4 months, OR disease control (CR + PR + SD) during the second-line treatment for at least 4 months. - A maximum of two prior CT treatment lines. - CEA <50 ng/ml	- ECOG 0 or 1 - ≥ 18 and <70 years - BRAF wild-type - High standard oncological surgical resection of the primary* - Histologically proved adenocarcinoma in the colon or rectum - Time from primary surgery to WL ≥6 months - At least 2 months of stable disease or partial response according to RECIST 1.1 - At least 1 CT line treatment (3 months) - CEA stability or reduction - No extrahepatic disease, expect for lung metastases (up to three resectable nodules or liable to radiotherapy with no progression after 3 months) - Resected hilar hepatic adenopathy with no progression after 3 months	- ECOG 0 or 1 - ≥ 18 and <70 years - High-standard oncological surgical resection of the primary* - BRAF wild-type - At least 1 CT line treatment (3 months) - No extrahepatic or local recurrence - No hepatic lesions > 10 cm before CT treatment - Tumor response according to RECIST 1.1 on two stadiation with no CEA elevation - If tumor response after CT <10%, only in 20% tumor reduction after TACE (DEB-IRI) o 90Y-spheres - Time from primary surgery to WL ≥10 months - CEA <100 ng/ml
Main exclusion criteria	- General contraindication to LT - Prior lung resection - Progression of CRLMs at any timepoint prior to LT - History of HIV or chronic HBV/HCV.	- General contraindication to LT - Patients not having received standard treatment for the primary CRC - Extrahepatic metastatic disease or local relapse	- General contraindication to LT - Weight loss >10% the last 6 months - BMI > 30 - Palliative resection of primary CRC tumor.	- General contraindication to LT - Macroscopic vascular tumor infiltration - Tumor progression during CT	- General contraindication to LT - Extrahepatic disease - Weight loss >10% the last 6 months - Liver metastases larger than 10 cm. - Pathological lymphatic nodes in the abdomen. - Microsatellite instability—previous transplantation	- General contraindication to LT - Weight loss >10% the last 6 months - BMI > 30 - Resection of local relapse or non-hepatic metastasis within 2 years or resection of pulmonary/liver hilus lymph node metastases <1 year - Liver lesion>10cm - 3 negative prognostic factors (CEA>80, less than 2 years from diagnosis, diameter of largest liver lesion > 5.5 cm).	- General contraindication to LT - Hereditary CRC syndromes - Extrahepatic metastatic disease or primary tumor local relapse. - Active intravenous or alcohol abusers - HIV infection	- General contraindication to LT - Patients not having received standard treatment for the primary CRC - BMI > 30 - Weight loss >10% the last 6 months	- General contraindication to LT - Patients not having received standard treatment for the primary CRC - BMI > 30 - Weight loss >10% the last 6 months

^*defined by : Safe margin of resection, curative resection of primary tumor according to oncological principles and TNM adequate staging.

BMI, Body Mass Index; CT, Chemotherapy; ECD, Extended Criteria Donor; ECOG, Eastern Cooperative Oncology Group; LDLT, Living Donor Liver Transplantation; LT, Liver Transplant.