Inclusion criteria for liver transplantation in patients with colorectal liver metastases: How to make the best selection?

Table 1 Inclusion criteria reported in the studies registered in ClinicalTrials.gov focused on liver transplantation for colorectal cancer liver metastases

NCT	Location	Criteria
Demographic parameters
NCT02215889	Oslo, Norway	ECOG 0-1
NCT05186116	Modena, Italy	Age ≥ 18, ECOG 0-2
NCT05750329	RenJi Hospital, Shanghai, China	Age 18-75
NCT04870879	Padua, Italy	Age ≥ 18 and < 70, ECOG 0-1
NCT05248581	Rochester, NY, United States	Age ≥ 18
NCT03803436	Milan, Italy	ECOG 0
NCT03488953	Jena, Germany	Age ≥ 18
NCT05398380	Barcelona, Spain	Age 18-70, ECOG 0-1
NCT06069960	RenJi Hospital, Shanghai, China	Age 18-75, ECOG 0-1
NCT04742621	NY, United States	Age 18-65, ECOG 0-1
NCT05185245	Bologna, Italy	ECOG 0-1
NCT03494946	Oslo, Norway	ECOG 0-1
NCT01479608	Oslo, Norway	ECOG 0-1
NCT04616495	Valencia, Spain	Age ≥ 18, ECOG 0-1
NCT02864485	Toronto, Canada	ECOG 0-1
NCT02597348	Villejuif, France	Age ≥ 18 and ≤ 65, ECOG 0-1
NCT04865471	Padua, Italy	Age ≥ 18 and < 70, ECOG 0-1
NCT04161092	Gothenburg, Sweden	Age ≥ 18, ECOG 0-1
Biochemical markers
NCT02215889	Oslo, Norway	Hb > 10 g/dL, neutrophils > 1.0, TRC > 75, bilirubin < 2 × ULN, AST/ALT < 5 × ULN, creatinine < 1.25 × ULN, albumin > LLN
NCT04870879	Padua, Italy	Hb > 10 g/dL, neutrophils > 1.0, bilirubin < 2 × ULN, AST/ALT < 5 × ULN, creatinine and albumin normal
NCT03803436	Milan, Italy	Hb > 10 g/dL, neutrophils > 1.0, TRC > 75, bilirubin < 2 × ULN, AST/ALT < 5 × ULN, creatinine < 1.25 × ULN
NCT05398380	Barcelona, Spain	Creatinine ≤ 1.25 × ULN or eGFR ≥ 60, platelets ≥ 80 × 109/L, neutrophils ≥ 2.5 × 109/L
NCT04742621	NY, United States	Hb > 10 g/dL, ANC > 1000/μL, platelets > 100000/μL, bilirubin < 2 × ULN, AST/ALT < 5 × ULN, creatinine < 1.25 × ULN, albumin > LLN
NCT05185245	Bologna, Italy	Neutrophils > 1.0
NCT03494946	Oslo, Norway	Hb > 10 g/dL, neutrophils > 1.0, TRC > 75, bilirubin < 1.5 × ULN, AST/ALT < 5 × ULN, creatinine < 1.25 × ULN, albumin > LLN
NCT01479608	Oslo, Norway	Hb > 10 g/dL, neutrophils > 1.0, TRC > 75, bilirubin < 2 × ULN, AST/ALT < 5 × ULN, creatinine < 1.25 × ULN, albumin > LLN
NCT02597348	Villejuif, France	Platelet count > 80000/mm³, WBC > 2500/mm³, normal renal function
NCT04865471	Padua, Italy	Creatinine normal, platelets > 60000/mm³, WBC > 2500/mm³
NCT04161092	Gothenburg, Sweden	Hb ≥ 90 g/L, WBC > 3.0 ×109/L, ANC ≥ 1.5 ×109/L, PLT > 75, bilirubin < 2 × ULN, AST/ALT < 5 × ULN, creatinine clearance ≥ 50 mL/minute
CEA
NCT04870879	Padua, Italy	CEA < 100 ng/mL
NCT03803436	Milan, Italy	CEA < 50 ng/mL
NCT05398380	Barcelona, Spain	CEA ≤ 80 μg/L
NCT06069960	RenJi Hospital, Shanghai, China	CEA ≤ 80 μg/L or ≥ 50% reduction after treatment
NCT04742621	NY, United States	CEA < 200 μg/L
NCT05185245	Bologna, Italy	CEA < 80 μg/L or ≥ 50% reduction
NCT01479608	Oslo, Norway	CEA < 100 ng/mL (subset)
NCT02597348	Villejuif, France	CEA < 80 μg/L or ≥ 50% decrease
NCT04865471	Padua, Italy	CEA stable or decreasing
Tumor characteristics
NCT02215889	Oslo, Norway	Unresectable CRLM, no extrahepatic disease except 1-3 resectable lung lesions < 15 mm, no local recurrence (confirmed by MR and colonoscopy)
NCT05186116	Modena, Italy	Unresectable CRLM, pT1-3, pN0/pN1 (< 4 nodes), no mucinous > 50%, R0 resection, BRAF wild-type
NCT05750329	RenJi Hospital, Shanghai, China	Unresectable HCC or CRLM, tumor shrinkage or stable after chemo, no abdominal metastases or ≤ 3 resectable lung metastases
NCT04870879	Padua, Italy	Unresectable CRLM, no extrahepatic disease, no lesion > 10 cm before chemo, < 10% chemo response accepted if 20% response after TACE/90Y
NCT03803436	Milan, Italy	Non-mucinous colon adenocarcinoma, pT1-3 pN0/1 (< 4 nodes), R0 resection, BRAF and RAS wild-type, MSS
NCT05398380	Barcelona, Spain	Bilateral, liver-limited unresectable CRLM, R0 resection of primary, stage ≤ T3N1 (or T4 if ≥ 2 years interval)
NCT06069960	RenJi Hospital, Shanghai, China	CRLM limited to liver or bilateral, unresectable, T ≤ T3N1 or T4N0/T4N2 if ≥ 2 years
NCT04742621	NY, United States	No extrahepatic disease or local recurrence, liver metastases stable/regressed for ≥ 6 months
NCT05185245	Bologna, Italy	Unresectable CRLM, p ≤ T4a, R0 resection, no extrahepatic disease
NCT03494946	Oslo, Norway	Liver metastases not resectable, No extrahepatic disease except resectable lung lesions < 15 mm
NCT01479608	Oslo, Norway	Histologically confirmed CRC, no extrahepatic disease or recurrence, ≥ 6 liver metastases (part A), pN0 (part B), metachronous liver metastases
NCT02597348	Villejuif, France	Confirmed unresectable CRLM, BRAF wild-type, no local recurrence
NCT04865471	Padua, Italy	Unresectable CRLM, no extrahepatic disease except resectable lung/hilar metastases
NCT04161092	Gothenburg, Sweden	Unresectable CRLM, R0 resection of primary, no extrahepatic disease, measurable liver metastases
Treatment history
NCT02215889	Oslo, Norway	≥ 8 weeks of chemotherapy
NCT05186116	Modena, Italy	Objective response to 1st-line (≥ 4 months) or stable disease during 2nd-line (≥ 4 months)
NCT05750329	RenJi Hospital, Shanghai, China	6-8 weeks of 1st-line chemotherapy
NCT04870879	Padua, Italy	≥ 3 months chemotherapy, RECIST response or SD, response after TACE/90Y if poor initial response
NCT03803436	Milan, Italy	1st or 2nd-line chemo response ≥ 4 months, max 2 lines
NCT03488953	Jena, Germany	≥ 8 weeks of systemic chemotherapy, SD or regression
NCT05398380	Barcelona, Spain	≥ 3 months chemotherapy, max 2 lines, response per RECIST within 3 months before screening
NCT06069960	RenJi Hospital, Shanghai, China	6-8 weeks 1st-line chemo, stable or partial regression
NCT04742621	NY, United States	≥ 6 months chemotherapy
NCT05185245	Bologna, Italy	≥ 3 months of at least 1 line, PR or SD per mRECIST
NCT03494946	Oslo, Norway	Progressive disease or intolerance to 1st-line, randomized before evaluation 8-12 weeks after 2nd-line
NCT01479608	Oslo, Norway	≥ 3 cycles chemotherapy (6 weeks), 10% response to chemo before progression (varies by subgroup)
NCT02597348	Villejuif, France	≥ 3 months tumor control on last chemo line, ≤ 3 lines total
NCT02864485	Toronto, Canada	≥ 3 months chemo with FOLFOX/FOLFIRI +/- bevacizumab, stable or regressing LM
NCT04865471	Padua, Italy	≥ 3 months chemotherapy, ≥ 8 weeks SD or PR per RECIST 11
NCT04161092	Gothenburg, Sweden	≥ 2 months chemotherapy, no progression at last RECIST evaluation
Other criteria
NCT02215889	Oslo, Norway	Imaging within 4 weeks prior to LT meeting, colonoscopy/CT colography ≤ 12 months
NCT05186116	Modena, Italy	Confirmed R0 resection, multi-modal imaging (CT + MRI + PET)
NCT04870879	Padua, Italy	≥ 10 months from CRC resection to LT listing
NCT05398380	Barcelona, Spain	≥ 12 months from primary CRC resection to transplant, TNM staging required, no contraindications from prior hepatic resection
NCT06069960	RenJi Hospital, Shanghai, China	≥ 3 months from CRC resection to transplant, MDT confirmation, imaging via PET/CT + MRI
NCT04742621	NY, United States	≥ 1 year from CRC diagnosis and ≥ 6 months from resection to LT
NCT01479608	Oslo, Norway	Signed informed consent, standard oncologic surgery with CRM ≥ 2 mm, study includes special subgroups (A-D)
NCT02597348	Villejuif, France	R0 resection, no extrahepatic localization (CT/PET), normal renal function, nephrologist evaluation
NCT02864485	Toronto, Canada	Living donor identified, ABO compatible, no major vascular invasion
NCT04865471	Padua, Italy	≥ 6 months from CRC resection to LT list, validation committee approval
NCT04161092	Gothenburg, Sweden	≥ 1 year from CRC diagnosis to inclusion, imaging within 4 weeks, colonoscopy < 12 months

ECOG: Eastern Cooperative Oncology Group; Hb: Hemoglobin; TRC: Tanned red cell; ULN: Upper limit of normal; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; LLN: Lower limit of normal; ANC: Absolute neutrophil count; WBC: White blood cell; CEA: Carcinoembryonic antigen; CRLM: Colorectal cancer liver metastases; MR: Magnetic resonance; HCC: Hepatocellular carcinoma; TACE: Transcatheter arterial chemoembolization; MSS: Micro satellite stability; CRC: Colorectal cancer; PR: Partial response; SD: Stable disease; LT: Liver transplantation; CT: Computed tomography; MRI: Magnetic resonance imaging; PET: positron emission tomography; TNM: Tumor node metastasis; MDT: Multi-disciplinary treatment; CRM: Circumferential resection margin; eGFR: Estimated glomerular filtration rate.

Table 2 Exclusion criteria reported in the studies registered in ClinicalTrials.gov focused on liver transplantation for colorectal cancer liver metastases

NCT	Location	Criteria
Demographic parameters
NCT02215889	Oslo, Norway	Weight loss > 10% in the last 6 months; BMI > 30
NCT04870879	Padua, Italy	Weight loss > 10% in the last 6 months; BMI > 30
NCT03494946	Oslo, Norway	Weight loss > 10% in the last 6 months; BMI > 30
NCT01479608	Oslo, Norway	Weight loss > 10% in the last 6 months; BMI > 30
NCT04616495	Valencia, Spain	BMI ≥ 30; pregnancy at time of inclusion; 10% weight loss
NCT04865471	Padua, Italy	Weight loss > 10% in the last 6 months; BMI > 30; pregnancy or breastfeeding
NCT04161092	Gothenburg, Sweden	Weight loss > 10% in the last 6 months; pregnancy or breastfeeding
Biochemical markers
NCT04616495	Valencia, Spain	Creatinine clearance < 50 mL/minute
NCT02864485	Toronto, Canada	Renal dysfunction with creatinine clearance < 50 mL/minute
CEA
NCT03494946	Oslo, Norway	CEA > 80 ng/mL with 2 other negative prognostic factors
NCT04616495	Valencia, Spain	CEA > 80 ng/mL at time of enrolment
Tumor characteristics
NCT02215889	Oslo, Norway	Bone or CNS metastases; prior breast cancer or malignant melanoma
NCT05186116	Modena, Italy	Prior extrahepatic disease or primary tumor relapse
NCT05750329	RenJi Hospital, Shanghai, China	Extrahepatic tumor burden (except resectable lung metastases); macrovascular infiltration
NCT04870879	Padua, Italy	Prior extrahepatic metastases or local relapse
NCT03803436	Milan, Italy	Prior extrahepatic metastases or primary tumor relapse; extraperitoneal tumors
NCT05398380	Barcelona, Spain	Lesion > 5.5 cm; primary tumor recurrence; Lynch syndrome; BRAF/MSI tumors
NCT06069960	RenJi Hospital, Shanghai, China	Extrahepatic burden or large vessel invasion; lesion > 5.5 cm; BRAF/MSI
NCT04742621	NY, United States	Extrahepatic disease; MSI-H/dMMR or BRAF mutation; prior lung metastasectomy
NCT05185245	Bologna, Italy	Extrahepatic metastases; local recurrence
NCT03494946	Oslo, Norway	Local relapse; non-hepatic metastasis; thoracic/abdominal lymph nodes; lesion > 10 cm; > 5.5 cm with other risks
NCT01479608	Oslo, Norway	Extrahepatic metastases or local relapse
NCT04616495	Valencia, Spain	Extrahepatic metastases; lesion > 5 cm; BRAF mutation
NCT04161092	Gothenburg, Sweden	Extrahepatic disease; lesion > 10 cm; abdominal lymphadenopathy; BRAF mutation
Treatment history
NCT05186116	Modena, Italy	Disease progression
NCT05750329	RenJi Hospital, Shanghai, China	Tumor progression during chemotherapy
NCT03488953	Jena, Germany	Progression during chemotherapy
NCT05398380	Barcelona, Spain	Tumor recurrence in the last 12 months
NCT06069960	RenJi Hospital, Shanghai, China	Tumor progression during chemotherapy
NCT04874259	Seoul, Korea	Progression of liver metastases at any time point
NCT04616495	Valencia, Spain	No neoadjuvant chemotherapy
NCT01479608	Oslo, Norway	Not received standard CRC treatment
NCT02597348	Villejuif, France	Not received standard CRC treatment
Other criteria
NCT05186116	Modena, Italy	HIV, psychiatric disorders, active substance abuse, low compliance
NCT05750329	RenJi Hospital, Shanghai, China	AIDS, uncorrectable cardiopulmonary disease, anatomical abnormalities
NCT03803436	Milan, Italy	HIV, substance abuse
NCT05398380	Barcelona, Spain	Substance abuse, psychological/social issues, cardiac/pulmonary disease, infection
NCT06069960	RenJi Hospital, Shanghai, China	Cardiopulmonary disease, anatomical abnormalities, substance abuse, AIDS
NCT04874259	Seoul, Korea	Hemodynamic instability, peptic ulcer, HIV, pregnancy
NCT04616495	Valencia, Spain	HIV or HCV, pregnancy, general contraindication to LT, insurance issues
NCT02864485	Toronto, Canada	HIV, HBV/HCV, cardiac or pulmonary insufficiency, debilitating neuropathy
NCT02597348	Villejuif, France	Severe comorbidities, active infection, alcohol abuse, lack of compliance/support
NCT04865471	Padua, Italy	General contraindication to LT, refusal, pregnancy/breastfeeding
NCT04161092	Gothenburg, Sweden	Pregnancy, previous organ transplant

LT: Liver transplantation; BMI: Body mass index; CEA: Carcinoembryonic antigen; CNS: Central nervous system; MSI: Microsatellite instability; MSI-H: Microsatellite instability-high; dMMR: Mismatch repair-deficient; CRC: Colorectal cancer; HIV: Human immunodeficiency virus; AIDS: Acquired immune deficiency syndrome; HBV: Hepatitis B virus; HCV: Hepatitis C virus.

Table 3 Characteristics of the Oslo, Fong, and Eastern Cooperative Oncology Group scoring systems

Score	Component	Scoring/criteria	Cutoff	Clinical interpretation
Oslo	Tumor size	> 5.5 cm = 1 point	≥ 2 points	Higher recurrence risk post-LT
	CEA level	> 80 ng/mL = 1 point
	Time from primary to LT	< 2 years = 1 point
	Response to chemotherapy	< 10% shrinkage = 1 point
Fong	Nodal status of primary	Positive = 1 point	≥ 3 points	Worse prognosis post-resection
	Disease-free interval	< 12 months = 1 point
	Number of liver metastases	> 1 = 1 point
	CEA level	> 200 ng/mL = 1 point
	Largest tumor	> 5 cm = 1 point
ECOG	Performance status	0 = fully active; 1 = symptomatic but completely ambulatory; 2 = symptomatic, < 50% in bed during the day; 3 = symptomatic, > 50% in bed, but not bedbound; 4 = bedridden	≥ 2 = ineligible	Stratifies fitness for treatment or surgery

ECOG: Eastern Cooperative Oncology Group; LT: Liver transplantation; CEA: Carcinoembryonic antigen.