Altan Alim, Koç University Hospital, Türkiye
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Liver transplantation is increasingly being explored as a treatment option for select patients with metastatic colorectal cancer (mCRC). Historically, transplantation for mCRC was abandoned due to poor long-term outcomes and high recurrence rates. However, recent advancements in patient selection, immunosuppressive strategies, and donor organ availability have led to a renewed interest in this approach. Studies have demonstrated that highly selected patients undergoing liver transplantation can achieve significantly improved survival rates compared to those receiving standard systemic therapies. The implementation of Model for End-Stage Liver Disease (MELD) exception points, improved donor preservation techniques such as machine perfusion, and the growing role of living donor liver transplantation have further supported its feasibility. As research continues, liver transplantation may emerge as a crucial component of a multidisciplinary strategy for treating colorectal liver metastases, offering a select group of patients a chance at prolonged survival and improved quality of life.
Metastatic colorectal cancer (mCRC) is a significant health concern globally. Colorectal cancer (CRC) is the third most common cancer worldwide, with approximately 1.85 million new cases and 850,000 deaths annually. In the United States, there are nearly 150,000 new cases diagnosed and over 50,000 deaths each year due to CRC (
Examination of modern studies from Europe, Canada, and the US.
| Study | Year | Design | Inclusion criteria | Exclusion criteria | Size | Results |
|---|---|---|---|---|---|---|
| Hagness et al. (SECA-I) ( |
2013 | Prospective | Liver-only CLMs, excised primary tumors, and at least 6 weeks of chemotherapy | Extrahepatic metastases, other malignancy | OS rate at 1, 3, and 5 years were 95%, 68%, and 60%, DFS was 35% at 1-year | |
| Toso et al. ( |
2017 | Retrospective | Primary tumor resected, partial response to chemotherapy | Extrahepatic metastases, other malignancy | OS rates at 1, 3, and 5 years: 83%, 62%, 50%; DFS rates at 1, 3, and 5 years: 56%, 38%, 38% | |
| Dueland et al. (SECA-II) ( |
2020 | Prospective | Excised primary tumor <10 cm, nonresectable liver-only metastases determined by CT/MRI/PET, at least 10% response to CTX, time from diagnosis to liver transplant >1 year | Extrahepatic metastases, other malignancy | OS at 1, 3, and 5 years were 100%, 83%, and 83%; DFS at 1, 2, and 3 years were 53%, 44%, and 35%; OS from time of relapse at 1, 2, and 4 years were 100%, 73%, and 73% | |
| Smedman et al. (SECA-II D Arm) ( |
2020 | Prospective, patients who were excluded from SECA-II arms A, B or C | Same as SECA-II, allowed for patient with resectable pulmonary metastases, ECD organ donor | Extrahepatic metastasis (other than pulmonary), BMI above 30 kg/m2 and liver metastases larger than 10 cm | DFS was 4 months, OS was 18 months | |
| Hernandez-Alejandro et al. ( |
2022 | retrospective, US and Canada centers | primAry tumor resected, response to chemotherapy 6–12 months, no evidence of extrahepatic disease, CEA < 80 ng/dl, no synergistic tumor mutations | RFS was 62% and OS was 100% at 1.5 years | ||
| Sasaki et al. ( |
2023 | Retrospective | No specific inclusion criteria | 64 listed, 46 transplanted | LDLT 26 patients, DDLT 20 patients; DFS at 1-, and 3-years were 75.1%, and 53.7%, OS at 1- and 3-years were 89.0% and 60.4% | |
| Rajendran et al. ( |
2023 | Prospective, transplanted vs. resected vs. control (CTX alone) in LDLT in Canada | Primary tumor resected, time from resection to transplant ≥6 months, CTX ≥ 3 months, CEA stable or decreasing | Extrahepatic metastases, other malignancy, prior lung resection, progression of metastases, |
81 total, 7 transplant, 22 resection, 48 controls | Recurrence-free survival was superior in the LDLT group (1-year 85.7% vs. 11.4%; 3-year 68.6% vs. 11.4%; no difference in OS between transplanted and resected groups |
| Kaltenmeier et al. ( |
2023 | Retrospective; largest single center analysis of patients undergoing LDLT for mCRC | Resected primary tumor, 6–12 wks of CTX, CEA < 100 ng/dl | Extrahepatic metastases, other malignancy | Mean RFS was 2.2 years, Mean OS was 3.0 years | |
| Solheim et al. ( |
2023 | Retrospective, long term follow up of SECA-I patients | Resected primary tumor, at least 6 weeks of CTX | Extrahepatic metastases, other malignancy | 5-year and 10-year OS after LT were 43.5% and 26.1%; For patients with Oslo Score of 0 or 1, the 5-year and 10-year actual OS was 75% and 50%, respectively ( |
|
| Adam et al. (TRANSMET) ( |
2024 | Multi-center prospective RCT, randomized to CTX vs. CTX + LT | Resected primary tumor, >3 months CTX with response to CTX | Extrahepatic metastases, |
5-year overall survival was 56·6% for LT + CTX and 12·6% for CTX alone; Median PFS was 17.4 mos vs. 6.4 mos; Fifteen (40%) patients were disease-free |
The incidence of colorectal cancer has changed dramatically since the introduction of early screening techniques in the 1990s. Approximately 10%–12% of new CRC diagnoses occur in patients younger than 50 years of age (
The prognosis of mCRC remains poor, with a 5-year relative overall survival rate of approximately 15%. Advances in treatment, including systemic therapies and targeted treatments based on molecular profiling, have improved survival outcomes, but cures remain uncommon (
Surgical resection remains the only potentially curative treatment for liver-limited metastatic colorectal cancer. Approximately 20%–30% of patients with colorectal cancer with liver metastasis are candidates for surgical resection, which can significantly improve survival outcomes. The American Society of Clinical Oncology (ASCO) recommends neoadjuvant chemotherapy followed by surgery vs. surgery alone for patients who are candidates for potentially curative resection of liver metastases (
Systemic therapy is essential for patients with unresectable liver metastases or those with extrahepatic disease. The National Comprehensive Cancer Network (NCCN) guidelines recommend systemic chemotherapy regimens such as FOLFOX (fluorouracil, leucovorin, and oxaliplatin), FOLFIRI (fluorouracil, leucovorin, and irinotecan), or FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan), often combined with biologic agents like bevacizumab or cetuximab, depending on the molecular profile of the tumor. Pembrolizumab is recommended for patients with microsatellite instability-high or deficient mismatch repair tumors (
Liver-directed therapies include ablation techniques (radiofrequency ablation, microwave ablation), transarterial chemoembolization (TACE), selective internal radiation therapy (SIRT), and hepatic arterial infusion (HAI) chemotherapy. These therapies are particularly useful for patients with unresectable liver-confined disease or those who are not candidates for surgery due to comorbidities. The American College of Radiology (ACR) also supports the use of these interventional radiological techniques to address limitations of curative resection (
Limitations of these treatments include the risk of postoperative liver failure due to insufficient future liver remnant volume, the potential for disease relapse after liver surgery, and the adverse effects associated with systemic and liver-directed therapies. Additionally, the role of stereotactic body radiation therapy (SBRT) and liver transplantation in the management of colorectal cancer with liver metastasis are still being evaluated, with ongoing studies needed to establish definitive recommendations (
The rationale for exploring liver transplantation as a treatment option for metastatic colorectal cancer, specifically in the context of colorectal cancer with metastasis to the liver, is based on several key factors: improved survival outcomes, patient selection, and management of recurrence.
Liver transplantation has demonstrated significantly improved overall survival rates in highly selected patients with nonresectable liver-only metastases. Prospective studies have shown 5-year survival rates of up to 80% in selected patients, which is markedly higher than the approximately 10% 5-year survival seen with palliative chemotherapy alone (
Advances in patient selection criteria have been crucial. Factors such as carcinoembryonic antigen (CEA) levels, response to chemotherapy, size of liver lesions, and time from primary tumor resection to transplantation have been identified as important prognostic indicators. These criteria help identify patients who are more likely to benefit from liver transplantation (
Although recurrence is common, it often occurs as slow-growing metastases, particularly in the lungs, which can be amenable to further curative interventions. This contrasts with the rapid progression typically seen in patients treated with chemotherapy alone (
Liver transplantation for colorectal cancer metastasized to the liver has undergone significant evolution, marked by key historical outcomes and advancements in patient selection and perioperative management. Initially, liver transplantation for colorectal cancer with liver metastasis was abandoned in the 1990s due to poor outcomes and high rates of recurrence, with 5-year overall survival rates as low as 18% (
Subsequently, the SECA-II study further refined these criteria and reported even better outcomes. In this study, patients with CRC and unresectable liver metastases on imaging with favorable prognostic factors, such as low carcinoembryonic antigen (CEA) levels and significant response to chemotherapy, had a 5-year overall survival rate of 83% in patients (
A prospective cohort study at Oslo University Hospital evaluated multiple clinical trials on liver transplant for colorectal liver metastases to determine disease recurrence, overall survival and survival after relapse in the modern age. This led to the development of the Oslo scoring system which identified negative predictive factors for overall survival including tumor size greater than 5.5 cm, disease progression on chemotherapy, plasma CEA > 80 μg/L, and time interval between primary tumor resection and liver transplant of less than 2 years (
A systematic review and meta-analysis by Varley et al. reported pooled 5-year overall survival rates ranging from 50% to 80%, with disease-free survival (DFS) rates between 35% and 56% (
Overall, the historical outcomes of liver transplantation for colorectal cancer with liver metastasis have improved significantly due to better patient selection and perioperative management, making it a viable treatment option for selected patients with nonresectable liver-only metastases.
Recent studies from Europe, Canada, and the United States have provided compelling evidence supporting the use of liver transplantation as a treatment for metastatic colorectal cancer in highly selected patients (
A multicenter, randomized controlled trial from Europe, the TransMet study, demonstrated that liver transplantation plus chemotherapy significantly improved 5-year overall survival to 56.6% compared to 12.6% with chemotherapy alone in patients with permanently unresectable colorectal cancer with liver metastasis (
In Canada, the Toronto Living Donor Liver Transplant Program reported promising outcomes with living donor liver transplantation (LDLT) for unresectable colorectal cancer with liver metastasis. This prospective study recruited patients with unresectable CRLM (defined as bilobar disease) receiving systemic chemotherapy. The participants were then divided into three groups: patients who underwent LDLT, patients who underwent chemotherapy alone, and patients who underwent chemotherapy, converted to resectable disease, and underwent liver resection only. The study found that LDLT provided superior recurrence-free survival compared to resection, with a 3-year recurrence-free survival of 68.6% vs. 11.4% (
In the United States, a systematic review and meta-analysis by Dawood et al. reported pooled 5-year overall survival rates of 53% for liver transplantation in patients with nonresectable colorectal cancer with liver metastasis, with the lungs being the most common site of recurrence (
Sasaki et al. identified 46 patients with mCRC who underwent liver transplant in the US. 21% of patients experienced disease recurrence. 1- and 3-year disease free survival rates were 75% and 53%, and 1- and 3-year overall survival rates were 89% and 60%, respectively (
CRC primary tumors in the left colon have better outcomes than primary right colon tumors. This is because
Mismatch repair deficiency in mCRC occurs in about 5% of patients and results in high mutation burden and microsatellite instability (MSI-H). The KEYNOTE-177 study demonstrated that Pembrolizumab, a PD-1 blockade immunotherapy, had superior progression free survival and no difference in overall survival in patients with MSI-H mCRC (
The follow up study for patients with extended criteria, the SECA-II arm D study, included patients with poorly differentiated or signet ring cell primary tumors as well as patients with primary tumors in the ascending colon and patients with extensive liver tumor burden. Median disease-free survival was 4 months, with the most common recurrence being pulmonary metastasis, and median OS was 18 months which was significantly lower compared to patients in the SECA-I and SECA-II trials (
Overall, recent and current studies in mCRC and liver metastases aim to refine strict patient selection criteria for candidates of liver transplant to improve outcomes.
Model for End-Stage Liver Disease (MELD) exception points are used to prioritize patients with metastatic colorectal cancer for liver transplantation by assigning them a higher allocation MELD (aMELD) score. This is done to reflect the patient's increased risk of waitlist dropout and to ensure equitable access to transplantation.
Patients with colorectal cancer with liver metastasis often have a lower laboratory MELD (lMELD) score, which may not accurately represent their urgency for transplantation. MELD exception points are granted to these patients to adjust their priority on the transplant waitlist, thereby increasing their chances of receiving a liver transplant. This approach is supported by studies showing that patients with non-HCC MELD exceptions, including those with colorectal cancer with liver metastasis, have a higher likelihood of undergoing liver transplantation and a reduced risk of waitlist dropout when adjusted for aMELD (
The allocation of MELD exception points are all adjudicated via the National Liver Transplant Oncology Review Board and United Network for Organ Sharing (UNOS). These boards evaluate the medical urgency and potential benefit of transplantation for each patient, ensuring that those with colorectal cancer with liver metastasis who meet specific criteria receive appropriate prioritization (
In June 2024, the OPTN and UNOS approved updates to the transplant oncology allocation policy to include MELD exception points for patients with mCRC with unresectable liver metastases. Criteria for MELD exception points include resection of primary tumor with negative margins, no extrahepatic metastatic disease or local recurrence and stable disease on systemic chemotherapy. Exclusion criteria include extrahepatic disease after primary tumor resection, local relapse of primary disease, or CEA > 80 μg/L. A table summarizing these inclusion and exclusion criteria is included as
MELD exception points: colorectal liver metastases.
| Criteria type | Inclusion criteria | Exclusion criteria |
|---|---|---|
| Primary tumor |
Resected colorectal primary tumor (R0 resection) |
Unresected primary tumor Rectal tumors with pelvic spread |
| Metastatic disease |
Liver-only metastases <10 lesions (some protocols allow >10 if <10 cm cumulative) No extrahepatic disease on PET/CT/MRI Stable disease ≥6 months with chemotherapy |
Extrahepatic metastases (e.g., lung, bone) Progressive disease on chemotherapy Peritoneal carcinomatosis |
| Response to chemotherapy |
Partial or complete response to at least 6 months of systemic chemotherapy (e.g., FOLFOX, FOLFIRI) CEA trend downward and preferably <80 ng/ml |
No response or progression on chemotherapy CEA >100–200 ng/ml and rising |
| Time from diagnosis |
≥12–24 months since diagnosis of metastatic disease Sustained disease control |
<12 months since metastasis Rapid progression within short time |
| Surgical feasibility |
Complete hepatectomy technically feasible Performance status ECOG 0–1 |
Incomplete resectability Poor performance status (ECOG ≥2) |
| Other requirements |
Multidisciplinary tumor board approval Enrolled in research protocol or trial Informed consent for experimental nature |
Not eligible or willing to participate in trial Transplant center does not offer protocol |
In summary, MELD exception points are used to prioritize patients with metastatic colorectal cancer for liver transplantation by assigning them a higher MELD score, reflecting their increased risk and ensuring equitable access to transplantation.
The study by Sjule et al. utilized a discrete event simulation model to explore the effects of expanding liver transplantation eligibility to include CRLM patients in Norway (
Additionally, the study by Adam et al. in the TransMet trial demonstrated that liver transplantation plus chemotherapy significantly improved 5-year overall survival compared to chemotherapy alone, supporting the validation of liver transplantation as a new standard option for patients with permanently unresectable liver-only metastases (
Marginal or historically discarded livers can be utilized for liver transplantation in patients with metastatic colorectal cancer through the application of machine perfusion technology, specifically normothermic machine perfusion (NMP). NMP allows for the ex vivo preservation and functional assessment of livers that would otherwise be discarded due to concerns about their viability. This technology maintains the liver at physiological temperatures, providing oxygen and nutrients, which helps to reduce ischemia-reperfusion injury and allows for real-time evaluation of liver function.
Studies have demonstrated that NMP can successfully rescue a considerable proportion of marginal livers. For instance, the RESTORE trial reported that 72.7% of declined livers treated with NMP were successfully transplanted, with no graft-related deaths or primary nonfunction (
NMP has expanded the donor pool, increased the utilization of marginal allografts, and has been increasingly adopted in transplant centers across the US. UNOS reported the use of NMP rose to over 11% in 2022 compared to 3.5% in 2021 (
Liver transplantation is emerging as a viable treatment option for select patients with metastatic colorectal cancer. Studies from Europe, Canada, and the United States demonstrate that liver transplantation can achieve 5-year survival rates exceeding those of standard systemic therapies, particularly when strict eligibility criteria are applied. The implementation of MELD exception points, advances in donor organ preservation through machine perfusion technology, and the growing acceptance of living donor liver transplantation further support the feasibility of expanding liver transplantation for colorectal liver metastases. However, ongoing research is needed to refine patient selection criteria, optimize immunosuppressive strategies, and address long-term outcomes, including disease recurrence. As the field continues to evolve, liver transplantation is likely to become an integral component of the multidisciplinary approach to managing metastatic colorectal cancer, offering select patients a potential for long-term survival and improved quality of life.
VB: Writing – review & editing, Writing – original draft. DO: Writing – original draft, Writing – review & editing. GS: Conceptualization, Writing – review & editing, Writing – original draft.
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mCRC, Metastatic colorectal cancer; CRC, colorectal cancer; ASCO, American Society of Clinical Oncology; NCCN, National Comprehensive Cancer Network; FOLFOX, fluorouracil, leucovorin, and oxaliplatin; FOLFIRI, fluorouracil, leucovorin, and irinotecan; FOLFOXIRI, fluorouracil, leucovorin, oxaliplatin, and irinotecan; TACE, transarterial chemoembolization; SIRT, selective internal radiation therapy; HAI, hepatic arterial infusion; ACR, American College of Radiology; SBRT, stereotactic body radiation therapy; CTX, chemotherapy; CEA, carcinoembryonic antigen; DFS, disease-free survival; OS, overall survival; RFS, recurrence free survival; LT, liver transplantation; LDLT, living donor liver transplantation; DDLT, deceased donor liver transplantation; EGFR, epidermal growth factor receptor; MSI-H, microsatellite instability; MELD, Model for End-Stage Liver Disease; UNOS, United Network for Organ Sharing; OPTN, organ procurement and transplantation network; CRLM, colorectal liver metastases; NMP, normothermic machine perfusion.