Liver Transplantation for Unresectable Colorectal Liver Metastases

Abstract

Colorectal cancer (CRC) is the third most common malignancy worldwide and a leading cause of cancer-related death. Nearly half of CRC patients develop metastatic disease, with the liver being the most frequent site of metastases. While curative-intent surgical resection remains the gold standard for colorectal liver metastases (CRLM), most patients are initially ineligible for surgery, and recurrence rates remain high. Systemic chemotherapy is the primary treatment for unresectable CRLM, with some patients achieving downstaging to surgical eligibility. Alternative approaches, including immune checkpoint inhibitors for MSI-H/dMMR cancers, hepatic artery infusion pumps, and locoregional therapies, have been explored to improve survival. Liver transplantation (LT) was initially abandoned for CRLM due to poor outcomes, but advancements in surgical techniques, immunosuppression, and donor availability have reignited interest in this approach. With LT becoming an established option for hepatocellular carcinoma and cholangiocarcinoma, its potential role in treating unresectable CRLM is being reconsidered. This review provides the latest evidence on LT for CRLM, including patient selection, outcomes, and future research directions.

Introduction

Colorectal cancer (CRC) is the third most common malignancy worldwide and second leading cause of cancer-related death in the United States. Nearly 50% of patients will ultimately develop metastatic disease, with the liver being the common site of metastases in approximately 70% of cases. ¹ For resectable colorectal liver metastasis (CRLM), the gold standard treatment is curative-intent surgical resection. In conjunction with modern systemic therapies, five-year overall survival for patients who undergo liver resection for CRLM approaches nearly 70%. ² Unfortunately, up to 80% of patients with CRLM are not candidates for surgical resection at initial presentation^3,4 and up to 50%-60% of patients develop disease recurrence after a curative-intent hepatic resection. ⁵

The cornerstone of the management of unresectable CRLM remains systemic chemotherapy. The primary goals of systemic therapy are to reduce disease progression, improve quality of life, and potentially, downstage patients to resectability. Historically, five-year overall survival (OS) for these patients has approximated 10%. Even with advances in chemotherapy regimens, only 20%–40% of patients respond well enough to become candidates for liver resection. ⁶ Alternative therapies have been proposed and studied. The addition of immune checkpoint blockade to chemotherapy for the small subset of patients with MSI-H/dMMR cancers (5%) has been shown to double median progression free survival (PFS). ⁷ The use of hepatic artery infusion pumps in conjunction with systemic chemotherapy may potentially improve resectability and survival at the expense of increased toxicity in non-randomized trials. The upcoming EA222 PUMP trial (NCT05863195) seeks to explore this in a randomized setting. Locoregional therapies have also been studied. Radiofrequency ablation is a good option for patients with fewer, relatively small lesions that are not located near major blood vessels. This select subset of patients are afforded improved PFS and a 5-year OS of approximately 40%. ⁸ Regarding potential surgical options, portal vein embolization followed by partial hepatectomy has also been considered for a small group of patients with primarily single-sided intrahepatic metastases. Despite advances in treatment, however, 5 -year OS remains poor.

Liver transplantation was first considered for unresectable CRLM in the 1980s. Early experiences were plagued by a prohibitively high 30 day postoperative mortality rate (11-33%), high rates of recurrence (60-70%), and dismal 5 year OS (12-18%).^9,10 Notably, in nearly 50% of early cases, graft loss was unrelated to tumor recurrence, highlighting issues with surgical technique, perioperative management, and immunosuppression. Liver transplant for CRLM was thus abandoned in the setting of graft shortages and poor outcomes. With advances in surgical technique, improvements in immunosuppression, expansion of the donor pool, and robust experience with liver transplant for hepatocellular carcinoma (HCC) and hilar cholangiocarcinoma, there has been renewed interest in transplantation as an oncologic strategy for unresectable CRLM. Further, liver transplantation has emerged as an appropriate treatment option for hepatocellular carcinoma and cholangiocarcinoma, underscoring its potential utility in oncologic treatment. The aim of this chapter is to summarize the current experience with LT for unresectable CRLM and discuss patient/allograft selection, outcomes, and future directions.

Norwegian Studies - SECA I, SECA II, and Follow Up

The first trial that demonstrated positive outcomes and suggested a potential role for LT as therapy for CLRM was the Norwegian Secondary Cancer (SECA) I study, completed in 2013. This was a prospective single arm study of 21 patients. Inclusion criteria mandated liver-only metastases, excision of primary colorectal tumors, and at least 6 weeks of chemotherapy prior to transplantation. Response to chemotherapy was not used as a selection criteria. This study showed 95%, 68%, and 60% 1-, 3-, and 5-year survival, respectively. However, there was a significant recurrence rate, with 1-year disease-free survival 35%. Regardless, the study was notable as proof-of-concept, and can be credited with spurring a renewed interest towards LT as a viable option for unresectable CRLM. ¹¹ The Oslo score risk-stratified patients with unresectable CRLM enrolled in the SECA-I trial with the goal of prognosticating posttransplant survival. The score assigns 1 point to each of the following risk factors associated with poor posttransplant outcome: maximum tumor size >5.5 cm, pre-transplant CEA >80, disease progression on chemotherapy, and LT within 24 months of primary tumor resection. ¹²

The same Norwegian group conducted a follow-up, the SECA II trial, with stricter inclusion criteria. This was a prospective study of 15 patients and included those with liver-limited disease on pretransplant PET-CT, at least a 10% response rate from chemotherapy, at least 1 year between colorectal cancer diagnosis and listing for transplantation, and ECOG functional status of 0 or 1. With stricter inclusion criteria, SECA II showed improved survival – overall 5-year survival was 83% and 5-year disease-free survival was 35%. This study further solidified LT as a viable treatment option for unresectable CLRM and demonstrated that for a select group of patients, excellent overall survival and improved disease-free survival was achievable. ¹³

The Oslo group subsequently published their experience of 61 patients undergoing liver transplantation for CRLM. Subjects achieved a 50% 5-year overall survival and 18.3% 5- year disease free survival. Notably, the 5 year survival of patients with an Oslo Score 0–2 was 63.5% versus 8.3% for patients with an Oslo score 3–4. As such, these results further solidified LT as a viable option for CRLM, with overall survival not too dissimilar from transplantation for other malignant indications in the low risk subgroup. ¹⁴

Smaller Trials

After the success of the SECA trials, several smaller series were published which corroborated favorable outcomes with LT for unresectable CRLM. In 2017 Toso et al published a prospective study of 12 patients. Overall, 1-, 3- and 5-year survival was 83%, 62% and 50%, respectively. ¹⁵ Hernandez-Alejandro et al reported the first results from North America. This was a prospective study of 10 patients who underwent living donor liver transplantation (LDLT). At the time of publication, 100% overall and 62% disease-free survival was reported at median 1.5 years follow up. ¹⁶ Rajendran et al further highlighted a potential role for LDLT in unresectable CRLM demonstrating in a small cohort of transplanted patients (n = 7) 1-year and 3- year disease-free survivals of 85.7% and 68.6% respectively, versus 11.4% at 3 years in the group treated non-surgically. ¹⁷ This study was particularly remarkable for the large number of potential candidates screened for eligibility (81) for the relatively small number able to receive LDLT (7).

IABHA Consensus Statement

In 2021, the International Hepato-Pancreato-Biliary Association published consensus guidelines for patient selection for liver transplantation. ¹⁸ Inclusion criteria put forth by these guidelines include resection of primary tumor with R0 margins, at least one year from diagnosis of nonresectable liver-only metastases, and treatment with at least six months of bridging chemotherapy with no radiologic progression or rise in CEA (checked every 2–3 months). Exclusion criteria include a signet ring cell or undifferentiated primary tumor, metabolic tumor volume of >70 cm3 and total lesion glycolysis of >260 g on 18F-FDG PET-CT scan, BRAF V600E mutation. High microsatellite instability (MSI-h) or mismatch repair deficient (dMMR) cancers are recommended to be excluded because these tumor tend to be responsive to immune checkpoint inhibitors, which cannot be easily used after organ transplantation. Relative exclusion criteria include CEA downtrending but >80, and for synchronous liver metastasis, N2 of primary tumor. These inclusion criteria are significantly stricter than those used in the initial SECA I trial. Notably, prior liver resection was not considered a contraindication for liver transplant.

United Kingdom Criteria

In 2022, the United Kingdom Liver Advisory Group of NHS Blood and Transplant established an independent fixed-term working unit (FTWU) to outline criteria used to initiate a national liver transplant program for unresectable CRLM. ¹⁹ Inclusion criteria included an R0 primary resection of histologically confirmed adenocarcinoma >3 months prior to transplant assessment, liver metastasis assessed with MRI and documented as unresectable by local multidisciplinary tumor board, and >30% response by RECIST 1.1 criteria at either 3 or 6 months with induction chemotherapy and no evidence of progression for 2 years on maintenance chemotherapy. Exclusion criteria included a nonepithelial primary tumor, second primary tumor, unresected primary tumor, prior liver resection for liver metastasis, evidence of extra-hepatic disease, and sequential increase in CEA (even in the absence of radiologic progression). Notably the group did not consider further histopathologic/molecular markers from the primary tumor considering the 2-year period requirement for stability to be a sufficient biologic test of time.

Recent Trials

With growing evidence to suggest improved oncologic outcomes with LT, two recent multicenter prospective trials have sought to directly compare transplantation with the current clinical standard for unresectable CRLM – systemic chemotherapy. The COLT (Improving Outcome of Selected Patients with Non-resectable Hepatic Metastases from Colo-rectal Cancer with Liver Transplantation) trial was published in 2023. This trial compared patients who underwent liver transplantation after chemotherapy with patients with similar tumor characteristics receiving three-agent chemotherapy plus anti-EGFR therapy enrolled in a different trial. The study continues to recruit, however projections of 5-year survival in the transplantation group approximate 70% compared with 30% in the chemotherapy/targeted therapy group. ²⁰

The only RCT directly comparing transplant with chemotherapy to chemotherapy alone so far is the Liver Transplantation in Patients With Unresectable Colorectal Liver Metastases Treated by Chemotherapy (TRANSMET) trial. The TRANSMET trial was published in 2024 and randomized patients (n = 94) to LT followed by chemotherapy versus chemotherapy alone. Inclusion criteria were notable for unresectable CRLM with no evidence of extrahepatic disease in patients who had already undergone resection of primary BRAF negative colorectal cancer with positive response to adjuvant chemotherapy. Notably, 9 patients (19%) of the LT arm progressed while on the waiting list and were thus ineligible for transplantation. In the intent-to-treat analysis, 5-year OS was 57% in CT + LT arm and 13% in CT alone arm. Per-protocol analysis demonstrated 73% 5-year survival with LT and chemotherapy compared to 9% of chemotherapy alone. Median PFS was 17.4 months versus 6.4 months and 40% of patients in the LT arm were ultimately disease-free at 5 years. Perhaps somewhat different than other studies, transplanted patients were treated with adjuvant chemotherapy when deemed feasible, and all patients in the transplant arm underwent a staging operation ahead of transplantation – in fact 3 of the 9 exclusions due to tumor progression were detected at the time of operative staging. The TRANSMET trial constitutes the largest randomized trial to date demonstrating positive outcomes with LT, and the only one with a systemic therapy-only control arm concomitantly enrolled, thus providing the highest level of evidence for the benefit of liver transplantation in select patients with CRLM. ²¹

Actively Recruiting Trials

With a growing body of literature supporting acceptable outcomes following liver transplant in highly selected patients with unresectable CRLM, further validation in larger, heterogenous populations is imperative. There are currently several active trials that seek to compare deceased donor liver transplant for unresectable CLRM to the best alternative therapy, including a Norwegian RCT (NCT03494946) and the Swedish SOULMATE RCT (NCT04161092) which additionally evaluates outcomes of extended criteria donors as a strategy to reduce waitlist time. Another trial, the Italian MELODIC trial (NCT04870879), is a nonrandomized propensity-matched cohort study comparing patients who undergo chemotherapy followed by deceased donor liver transplant and patients with similar tumor characteristics treated only with chemotherapy.

Patient Selection

In accordance with the first international consensus conference for transplant oncology, the most essential clinical question regarding LT for CLRM remains patient selection. ²² To be considered for transplant, patients must 1) not be a candidate for other curative intent locoregional therapies and 2) stand to significantly benefit from liver transplant. In our discussion of “unresectable” CRLM, it is important to recognize both a lack of standardization with this definition and that the distinction of “resectability” is an artificial criterion applied in the setting of allograft scarcity. For example, there is no internationally standardized process to determine “resectability,” and advances in portal vein embolization, two stage hepatectomy, resection with vascular reconstruction, and radiofrequency ablation continue to expand what can be achieved without liver transplantation. The flip side of this coin is that in an ideal world with unlimited access to high quality allografts, LT may be superior to liver resection, even in patients whose lesions are considered resectable. Explant pathology from patients with CRLM who undergo LT for either unresectable disease or liver failure secondary to systemic therapy has demonstrated alarming rates of tumor viability on final pathological assessment among patients thought to have complete radiologic response preoperatively. ²³ From an oncologic standpoint, LT may ensure R0 resections in patients with unresectable CRLM and indolent micrometastatic intrahepatic disease. This point becomes particularly important to consider in context of a donor pool supported by living donors. While recipients of both living and deceased donor allografts should stand to benefit more from LT than alternative therapies, it may be reasonable to accept a lower threshold for transplant in recipients of living donor allografts who do not need to achieve posttransplant outcomes equivalent to recipients undergoing LT for other indications in order to justify organ allocation. So far, the majority of early international experience with LT for CRLM has primarily involved deceased donor liver transplant. LDLT for CRLM is discussed further under graft selection.

It is well known that certain factors are predictive of oncologic outcomes in patients undergoing liver resection for CRLM. The Fong clinical risk score (FCRS) is one of the oldest scores evaluating OS in patients who undergo liver resections for CRLM. ²⁴ It allocates one point for each of the following prognostic factors: synchronous disease (metastases detected less than 1 year from the diagnosis of the primary), more than one liver lesion, size of the largest tumor more than 5 cm, CEA levels above 200 μg/L, and a node positive primary tumor. The Oslo group was the first to study factors predictive of oncologic outcomes following liver transplant. Compared to the SECA I trial, the SECA II trial excluded patients who did not respond to chemotherapy with a significant increase in survival and disease-free progression, underscoring the importance of patient selection. The Oslo score specifically evaluates the OS of LT patients, giving one point for each present prognostic factor: tumors larger than 5.5 cm, CEA over 80 μg/L, surgery of the primary less than 2 years before the LT, and progression of metastases at the time of LT. ¹¹

The Oslo group compared the FCRS, Oslo score, and metabolic tumor volume (MTV) of patients in the SECA I and SECA II studies with their outcomes at seven years posttransplant. Factors predictive of the highest posttransplant survival included a FCRS of 0–2 and Oslo score of 0–2. Although not significant, KRAS wild type tumors and left sided primary tumors also correlated with better posttransplant survival. Interestingly, MTV <70 cm3 appeared to correlate with lower FCRS and Oslo scores regardless of primary tumor T/N stage, KRAS mutation status, sidedness of primary tumor, and time from primary resection to LT. The best survival occurred in patients with FCRS 0–2, which accounted for fewer than half of all transplanted patients.

This data guided selection criteria for the COLT and TRANSMET trials. Although recipients were not assigned an Oslo score, the majority of patients in the TRANSMET trial who underwent LT had an Oslo score of 1 - lesions <5.5 cm, CEA <80, but median time from diagnosis of synchronous metastastic liver disease to LT was just 16 months. Patients who progressed on chemotherapy were excluded from transplantation. Additionally, patients with high CEA levels (>80 without >50% decrease with chemotherapy) and BRAF mutation were excluded. Thus, despite a promising 5-year OS estimated at 70–80% achieving survival similar to LT for other indications, it is unclear whether LT for CRLM can achieve similar outcomes in a more diverse population. Early selection criteria and outcomes for LT for CRLM are summarized in Table 1.

Table 1.

Selection Criteria for Liver Transplantation in Patients with Unresectable Colorectal Liver Metastasis.

Selection Criteria for LT	Primary Tumor	Burden of Disease	Systemic Therapy	3 Year OS	3 Year DFS
IABHA	Non signet ring cell colorectal adenocarcinoma Primary tumor resected with negative margins <N2 disease BRAF V600E mutation and MSI-h/MMR-d excluded RAS mutation relative contraindication	Unresectable liver disease No evidence of extrahepatic disease Metabolic tumor volume <70 cm3 Total lesion glycolysis <260 g	Minimum 6 months chemotherapy Minimum 1 year from diagnosis to LT CEA <80 or downtrending (checked q2–3 months) No evidence of progressive disease using RECIST criteria	-	-
UK	Colorectal adenocarcinoma Primary tumor resected with negative margins Complete clinical response prior to radical resection of primary tumor >3 months from transplant assessment	Unresectable liver disease No evidence of extrahepatic disease No prior liver resection for CRLM No second primary malignancy (besides BCC/SCC) No rising CEA	Minimum 2 years chemotherapy with disease stability >30% reduction in disease volume by RECIST criteria within 3–6 months of induction chemotherapy If disease progression occurs, may still be relisted if criteria above met with switching chemotherapy regimen	-	-
SECA II (n=15)	Colorectal adenocarcinoma Primary tumor resected with negative margins	No evidence of extrahepatic disease Largest lesion <10 cm Fewer than 30 lesions, and largest lesion <5 cm *Prior liver resections not excluded, in fact patients with >2 prior resections referred to LT*	Minimum 1 year from diagnosis to LT >30% response by RECIST criteria if >30 lesions >10% response by RECIST criteria otherwise <10% response by RECIST criteria (if patients obtain at least 20% response after TACE or Y90	83%	35%
COLT (actively recruiting)	Colorectal adenocarcinoma <N2 disease BRAF mutation, MSI-h/MMR-d, and RAS mutations excluded FAP, Lynch syndrome excluded	Unresectable liver disease No evidence of extrahepatic disease CEA <50 *Unresectability defined as impossible to achieve R0, OR >5% mortality expected with resection/parenchymal growth, OR tumor burden score >=9*	Objective response to chemotherapy sustained for >4 months If disease progression occurs, may still be relisted if criteria above met with switching chemotherapy regimen Maximum 2 chemotherapy lines	Results pending	Results pending
TRANSMET (n=94)	Colorectal adenocarcinoma Primary tumor resected with negative margins BRAF mutation excluded	No evidence of extrahepatic disease CEA <80 or decrease >50% No second primary malignancy	Objective response (stable disease or partial response) by RECIST criteria for minimum 3 months If disease progression occurs, may still be relisted if criteria above met with switching chemotherapy regimen Maximum 3 chemotherapy lines	66%	33%
Early North American Cohort (LDLT, n=10)	Rochester Primary tumor resected with negative margins KRAS or TP53 mutations excluded Cleveland Clinic BRAF mutation excluded Toronto University Health Network BRAF mutation excluded	Rochester No evidence of extrahepatic disease CEA <80 Oslo score 0–2 Cleveland Clinic No evidence of extrahepatic disease CEA <100 Toronto University Health Network No evidence of extrahepatic disease Nonrising CEA	Rochester Minimum 1 year chemotherapy with response Cleveland Clinic Minimum 1 year from resection of primary to LT Minimum 6–12 months of chemotherapy with response Toronto University Health Network Minimum 6 months from resection of primary to LT Minimum 6 months chemotherapy with response	70%	60%
Toronto (LDLT, n=7)	Primary colorectal cancer stage >T4a >6 months from primary resection to LT BRAF mutation excluded	No evidence of extrahepatic disease No evidence of disease progression CEA <100 pretransplant No major vascular invasion No previous lung resection	Minimum 6 months from resection of primary to LT Minimum 6 months chemotherapy without disease progression No evidence of diseae in porta hepatis nodes 1 week prior to transplant	100%	69%

Graft Selection

With expanding indications for LT, an important consideration is a limited deceased donor allograft supply. LT for CRLM is unique in that the majority of patients are not transplanted for chronic liver failure with portal hypertension and are thus better positioned to tolerate marginal grafts. Furthermore, the pool of marginal grafts suitable for transplantation is growing thanks to technologies such as normothermic machine perfusion (NMP), which has been established to reduce ischemia/reperfusion injury and improve biliary outcomes in DCD transplant. From a transplant oncology perspective, NMP has specifically demonstrated increased utilization of marginal allografts that would be uniquely well suited for transplantation in noncirrhotic patients. ²⁵ Current experience with extended criteria donors in the setting of LT for CRLMs is limited. A prospective randomized trial from Sweden comparing LT with ECD versus best alternative care for unresectable CRLM will soon start recruiting patients (NCT04161092).

Another option for expanding the donor pool for CRLM is utilization of partial liver grafts, either with split grafts from deceased donors or partial grafts from living donors. In the absence of underlying liver disease in patients with unresectable CRLM, left donor hepatectomy may provide a suitable hepatic mass with reduced donor morbidity. Living donor liver transplant (LDLT) may present a particularly good solution for unresectable CRLM in geographic regions where there is scarcity of high-quality deceased donor allografts, such as North America. Interestingly, early mathematical models have demonstrated that adding patients with CRLM and healthy liver function to the deceased donor waitlist in Norway would have only a modest impact on waitlist time while increasing life-years gained by the population. ²⁶ This is likely driven by the peculiar situation in Norway, where the availability of deceased donor organs relative to the national need for liver transplantation is favorable. Recently, UNOS approved a MELD exception score of 15 for patients in the United States with CRLM. However, in most geographic areas of the United States this score is inadequate to allow access for a deceased donor organ. Thus, most patients will have limited access to a deceased donor allograft unless they develop decompensated liver disease and a high MELD related to untoward effects of chemotherapy. Early experience with the living donor liver transplant (LDLT) in this setting has been positive. The first North American trial conducted across three centers in the US/Canada reported a recurrence-free and overall survival at a median follow-up of 1.5 years of 62% and 100%. ¹⁶ Within the United States, between 2017 and 2022, 46 patients underwent liver transplant for CRLM across 15 different centers (56% underwent LDLT) with a 3-year OS >60%. ²⁷ There are no randomized trials comparing outcomes between living and deceased donor transplants, however in the heterogenous US population, 3-year OS was slightly higher in the living donor cohort (71.4% vs 51.4%) perhaps reflecting a cohort without underlying hepatic dysfunction. Since then, multiple centers have published their center specific protocols and experience with similar outcomes.^17,28,29 Currently there are several actively recruiting studies on LDLT for unresectable CRLM, including single arm LDLT trials from transplant groups in New York (NCT05248581, NCT04742621), Toronto (NCT04874259), South Korea (NCT04874259), and Italy (NCT05186116).

An interesting strategy to increase liver availability is the Resection and Partial Liver segment 2 and 3 transplantation with Delayed total hepatectomy (RAPID) protocol, which introduced two-stage transplant/hepatectomy. The primary advantage of the RAPID concept is that it does not reduce the liver donor pool. The technique uses a left lateral graft that usually would have had insufficient volume for a standard liver transplantation. The first stage consists of segment 1–3 resection, transplantation of a left lateral graft, and contralateral portal vein embolization. Flow modulation with ligation of the splenic artery or portocaval shunting is performed for elevated main portal pressure >20 mm Hg. The second stage consists of remnant right hepatectomy once the transplanted liver reaches 35–40% of standardized liver volume. A prospective study is currently recruiting patients at the Oslo University Hospital (NCT02215889), and a separate ongoing prospective study from Germany is using living donors for the RAPID concept (NCT03488953). Importantly, there do remain a subset of recipients with CRLM listed for transplant primarily for underlying liver failure secondary to systemic therapy or primary liver pathology. These patients with liver decompensation and portal hypertension would not be the ideal candidates for marginal or smaller grafts, including split liver grafts from living donors.

Current Pitfalls and Future Directions

The current literature suggests that liver transplantation offers reasonable overall survival and oncologic outcome in highly selected patients presenting with unresectable CRLM. Further, the publication of consensus guidelines provides a standardized guidance for best practices for future transplantation. However, the current literature and consensus raise several salient questions. The first issue is that the trials are of relatively small size and are performed in disparate environments with varying donor and recipient characteristics. This limits the generalizability of the current literature, and thus likely hamstrings the current guidelines.

A major concern is the large burden of recurrence (79% in the Norwegian study, 74% in the TRANSMET trial). Interestingly, total hepatectomy and LT have demonstrated the ability to modify the pattern of recurrence compared to patients undergoing liver resection. While intrahepatic recurrence is known to result in poorer outcomes, the majority of recurrence following LT presents as pulmonary metastases that can still be treated with curative intent. Even when not amenable to resection, several studies have demonstrated excellent long-term palliation for chemoresponsive metastases. ³⁰ Furthermore, these metastases progress less rapidly than liver metastases in patients who have not undergone liver transplantation, suggesting that posttransplant immunosuppression may not significantly worsen progression of metastatic pulmonary disease.^31,32,33 From an allocation standpoint, pulmonary metastasis after LT for CRLM presents a unique situation in which disease-free survival may not best reflect overall survival and thus benefit gained through transplantation.

A key to reducing recurrence after LT may lie in patient selection. Prior studies have demonstrated significant discrepancies between individual centers and independent multidisciplinary committees regarding patient eligibility for transplant, with up to 40% of patients being excluded upon second review for disease progression. Going forward, the use of an independent evaluation committee may exclude bias favoring compassionate LT for young patients with an anticipated poor outcome, but no other chance of curative treatment. ²⁹ Centralized database of patients undergoing LT for unresectable CRLM are needed to explore which other patients would stand to benefit from LT. Furthermore, as recipient factors associated with favorable outcomes become more established, an increased standardized exception MELD score should be adopted to prioritize allograft allocation to this small group of patients who stand to benefit from liver transplantation. In the future, circulating tumor DNA (ctDNA) may identify patients at risk of developing recurrence after liver transplant. ctDNA is already widely utilized for colorectal cancer in the nonmetastatic setting. It can guide the need for adjuvant chemotherapy after resection of stage II disease and identify subclinical recurrence months before radiologic detection. Recently, it has been applied to the liver metastasis setting with early studies demonstrating both the ability to clear ctDNA with liver resection/transplant and a strong correlation between the presence of postop ctDNA and clinical recurrence. ³⁴ With further study, ctDNA may be used for patient selection, posttransplant surveillance, and for guiding the need for early chemotherapy after liver transplant in the absence of radiologically detectable disease. In addition, a better understanding of the mechanism of tropism of metastatic colorectal cancer to specific organs may help better select patients that are most likely to benefit from transplantation.

There is much that remains unknown about LT for unresectable CRLM. There is little known about the impact of starting immunosuppression on patients who underwent marrow suppressing chemotherapy prior to transplant. Small reviews of have demonstrated no increase in marrow toxicity and no increased risk for rejection. ³⁵ Another concern is regarding the increased risk of rejection in patients receiving immune-checkpoint inhibitor (ICI) immunotherapy preoperatively. ICI immunotherapy has doubled progression-free survival compared to standard chemotherapy when received as first-line therapy for MSI-h/dMMR metastatic colorectal cancer.^36,37 Given the high rate of durable responses and prolonged survival outcomes (approximating 70% at 3 years), some centers have been hesitant to allocate scarce liver allografts to patients with MSI-h/dMMR primary tumors (exclusion criterion per IABHA guidelines). Early US trials have suggested higher rates of rejection after LT for patients treated with ICIs. Further studies may clarify whether there is a safe window period after which it may be safe to pursue LT for patients treated with ICIs. Additionally, CAR-T cells and adoptive T cell therapies may prove to be a possible therapeutic option post-transplant.^15,16 This may reduce the risk of recurrence after transplantation and thus further improve outcomes. It is also unclear if posttransplant chemotherapy will improve oncologic and survival outcomes. Finally, unresectable CRLM is not a fixed indication for LT. Changes in allograft scarcity, transplant outcomes, and advancements in systemic therapies such as chemotherapy and immunotherapy should always encourage comparison of different treatment modalities to ensure the greatest survival benefit and quality of life for patients.

Conclusion

In highly selected patients with unresectable colorectal liver metastases and no evidence of extrahepatic disease, liver transplantation significantly improves overall survival compared to chemotherapy alone with 5-year overall survival approximating 70% compared to <10% with chemotherapy alone. The Achilles heel of LT for CRLM remains a high burden of disease recurrence, primarily presenting as treatable pulmonary metastases. A primary consideration is careful patient selection. Although selection criteria vary, nearly all landmark trials and international guidelines mandate an R0 resection of the primary tumor with histology confirming colorectal adenocarcinoma and specify a minimum time period between diagnosis and transplant during which candidates undergo neoadjuvant chemotherapy and are excluded if there is concern for disease progression either by surveillance imaging or CEA. Since the initial European experience with LT for CRLM, several North American cohorts have demonstrated the safety and efficacy of this approach in living donor liver transplant as well. As integration of LT into treatment protocols for CRLM gains traction, challenges will include standardizing eligibility criteria and ensuring equitable access to high quality allografts.