Liver transplantation for unresectable colorectal liver metastases: a narrative review

Introduction

Surgery remains the cornerstone of treatment for colorectal liver metastases (CRLM), offering 5-year survival rates of approximately 20–45% (1-3). However, only about 20% of patients present with disease that is technically amenable to resection (4). For patients with unresectable CRLM (uCRLM), systemic therapy has traditionally been the mainstay of treatment. Unfortunately, systemic therapy alone yields poor long-term outcomes, with 5-year survival being exceedingly rare, primarily due to both the persistence of metastatic disease and the typically aggressive tumor biology in these patients (5,6).

Given these poor outcomes, liver transplantation (LT) has long been considered as a potential solution. However, LT for CRLM faced two major challenges: it had to outperform systemic therapy—a non-invasive option with fewer complications—and demonstrate outcomes comparable to those achieved for established LT indications such as hepatocellular carcinoma (HCC), where 5-year survival rates can reach approximately 75%, even exceeding those for resectable CRLM (7,8).

The first reports in the 1980s failed to reach those thresholds and consequently, interest in LT for CRLM waned for decades (9). This changed in 2013, when the prospective (but non-randomized) Norwegian Secondary Cancer (SECA) I study reported a 5-year survival rate of 60% following LT for uCRLM—a substantial improvement over the approximately 10% survival seen with systemic therapy alone in historic cohorts, though still inferior to outcomes for other LT indications (5). These promising results reignited global interest in transplant oncology and led to the initiation of several prospective trials, including randomized controlled trials (RCTs), aimed at refining patient selection criteria to further improve outcomes (10).

While previous reviews have summarized the evolving role of LT for uCRLM, this review is particularly timely for two reasons (11). First, it is among the first to incorporate results from the TransMet trial—the first RCT on this topic—published in 2024 (12). In this landmark study that one could compare to the landmark “Milan” study by Mazzaferro et al. for HCC LT (13), 5-year overall survival (OS) in the per-protocol analysis reached 73% in the LT-plus-chemotherapy group compared to 9% in the chemotherapy-alone group, a survival rate that also meets the benchmarks established for LT indications. Second, now that it may no longer be as critical to debate whether LT for uCRLM improves survival, but rather how best to implement it in real-world practice, optimizing patient selection criteria—such as optimal donor selection (living vs. deceased donors), primary tumor laterality (right- vs. left-sided), kirsten rat sarcoma viral oncogene homolog (KRAS) mutation status and the need for standardized candidate selection protocols—seems the most important next step and justifies a dedicated review article. We present this article in accordance with the Narrative Review reporting checklist (available at https://cco.amegroups.com/article/view/10.21037/cco-25-46/rc).

Methods

We conducted wide literature research on PubMed and Google Scholar to find relevant materials of prospective or retrospective studies on the outcomes of LT for uCRLM. The search included articles published between 2010 and 2025, using the following terms: liver transplantation, colorectal cancer, and colorectal liver metastasis. Only English-language studies, including RCTs and observational cohort studies, were included. Case reports, non-English publications, and duplicate or smaller retrospective studies from the same cohort were excluded. Further details regarding the search strategy and selection criteria are summarized in Table 1.

Results

After applying the inclusion and exclusion criteria, a total of eight studies published between 2017 and 2025 were deemed eligible for inclusion (9,12,14-19). The study and patient characteristics are reported in Table 2. Three studies came from European centers and five from North American centers. Five were single-center studies, while three were multi-center. Four were prospective, including one randomized controlled trial. Three studies used only living donor LT, three used both living and deceased donor LT, and two used only deceased donor LT. Primary tumor site information was available in six studies, including 146 patients in total; among them, 23 (15.8%) presented with right-sided tumors. KRAS mutation status was available in five studies, and the proportion of KRAS-mutated patients in each study was between 11.1% (one in nine patients) to 28.6% (two in seven patients). Five studies followed a single protocol (either institutional or trial-defined), one study included multiple protocols at its center, and two studies did not specify any selection criteria. Four among these five studies detailed on the definition of unresectability, and they all require multidisciplinary consensus between surgeons, oncologists, and radiologists based on tumor location and future liver remnant (12,15,16,18). One study noted that extensive resections such as Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy (ALPPS), two-stage hepatectomies, and parenchymal preserving procedures were considered (18). For the five studies using a single protocol, no studies included B-Raf proto-oncogene, serine/threonine kinase (BRAF)-mutated patients. In these five studies, 3-year OS ranged from 80% to 100%, or 5-year OS was 73%. As for recurrence-free survival (RFS), 3-year RFS ranged from 40% to 68.6%, or 5-year RFS was 19.9%. In the remaining studies, 3-year OS ranged from 62% to 64.9%, or 5-year OS was 50.4%. In these studies, 3-year RFS ranged from 38% to 46.3%, or 5-year RFS was 18.3%. Long-term follow-up after recurrence was reported in the Norwegian study and the TransMet trial (12,14). In the Norwegian study, 5-year OS from recurrence was 34.8%. In the TransMet trial, 5-year secondary RFS, defined as time from randomization to failure of curative-intent treatment for recurrence, was 36.1%.

Discussion

This study aimed to summarize the currently available literature on LT for uCRLM. Our review is distinct in several ways. First, we included only the study with the largest patient cohort from each institution, thereby avoiding the double-counting of individual patients observed in the previous systematic review (11,20). Second, we focused on factors not emphasized in earlier reviews but highly relevant to real-world practice as they relate to patient selection: the choice of donors (living or deceased), the prognostic role of primary tumor site (right or left) and KRAS mutations, and the consistent use of a single protocol for candidate selection.

Donor selection and availability

Donor availability has a major impact on LT feasibility for uCRLM. In Norway, an abundant supply of deceased donor organs enabled the University of Oslo group to perform all uCRLM LTs using deceased donors alone (5). Similarly, in the TransMet trial, patients randomized to LT received prioritization, ensuring access to a deceased donor liver within two months after chemotherapy completion (12).

In contrast, in North America, LT candidates are prioritized based on Model For End-Stage Liver Disease (MELD) scores, and patients with uCRLM—typically without decompensated liver disease—have low MELD scores, limiting their access to deceased organs (21). This limitation spurred the development of living donor LT strategies, beginning in the mid-2010s. Single-center studies from North America reported excellent results, with 3-year OS exceeding 80% (15). These results are encouraging for regions such as Asia, where deceased donor access is limited, and a multicenter living donor trial for uCRLM is currently underway in Japan (22).

Recently, opportunities for deceased donor LT in the US have improved through increased use of extended criteria donors and novel perfusion technologies, including normothermic machine perfusion (23-28). As a result, some US centers now report wait times under one month, comparable to European trials, and the number of deceased donor LTs for uCRLM [46] is now approaching that of living donor LTs [55] (19).

Evolution of patient selection criteria

Refinement of patient selection criteria has been central to improving LT outcomes for uCRLM. Comparing the early SECA studies to the recent TransMet trial reveals significant survival improvements, at least partially attributable to stricter eligibility requirements. Our results showed that centers using a single, consistent protocol—such as the Oslo Score—report 5-year OS rates exceeding 70% (5,12,15-18) (Table 3), whereas more heterogeneous national cohorts show lower outcomes (e.g., 3-year OS: 64.9% in the US) (9,19). To promote standardization, the US has established a national MELD exception review board for uCRLM (29), and a multicenter registry through the American Registry for Transplant Oncology (ARTx-Onc) is underway (30). The definition of “unresectable” were largely similar among studies, but the frequency with which extensive resections such as ALPPS are employed likely varies by center and country, and the current literature does not permit firm conclusions. A systematic comparison of these advanced hepatectomy strategies vs. LT remains an important topic for future study.

As to specific criterion, prognostic factors known from resectable CRLM have guided selection. Primary tumor laterality (right- vs. left-sided) is a well-established predictor of outcomes, with right-sided tumors associated with worse prognosis after liver resection (31-34). KRAS mutation status also carries prognostic importance, although the adverse effect of right-sided tumors appears limited to KRAS wild-type patients (35). In the TransMet trial, 17% of LT patients had right-sided primaries and 25% had KRAS mutations (12). Analysis from the University of Oslo demonstrated that right-sided tumors were associated with significantly lower 5-year OS (10% vs. 60.1%, P<0.001) (14). Their recent molecular analysis revealed that KRAS/TP53 co-mutations were significantly associated with outcomes (36). Some centers have responded by requiring extended observation periods (e.g., 18 months) for candidates with right-sided or KRAS-mutated tumors, achieving 3-year OS rates as high as 91% (18). Some other centers include metabolic tumor volume below 70 cm³—validated as a prognostic factor in Norwegian studies and two high-volume US centers—as a key selection criterion (37,38). Of note, current International Hepato-Pancreato-Biliary Association (IHPBA) guidelines do not exclude patients with right-sided primaries or KRAS mutations from LT candidacy (39). It is important to reiterate that OS and post-recurrence survival—not RFS/PFS—should guide transplant candidacy in uCRLM. Favorable survival after recurrence, for example following resection of pulmonary metastases, has been reported (12,14,40).

Importance of early referral

Referral timing critically impacts LT eligibility. Referral practices vary substantially between countries and medical specialties (18,41-43). Earlier referral correlates with greater transplant eligibility, whereas late referrals after extensive systemic or liver-directed therapies often result in liver dysfunction, compromising transplant candidacy (41). Other liver-directed treatments—including hepatic artery infusion pump (HAIP) therapy, radiofrequency ablation (RFA), Y-90 radioembolization (TARE), and stereotactic body radiation therapy (SBRT)—should be pursued with potential LT eligibility in mind (44-46).

Future directions: incorporating tumor biology and interpretable AI approaches

We have provided a comprehensive review of currently available reports on the outcomes of LT for uCRLM. What remains debated is the role of adjuvant chemotherapy. The TransMet trial achieved excellent outcomes with more than 60% of patients receiving adjuvant systemic therapy, yet no clear additional survival benefit from adjuvant chemotherapy was demonstrated, and 60.5% (23/38) of LT recipients were unable to start or complete more than six courses of adjuvant chemotherapy. Norwegian and US studies have shown comparable results without adjuvant therapy (12,18,47). RCTs have consistently demonstrated that adjuvant therapy after liver resection for CRLM provides no overall-survival benefit and only a modest gain in RFS (48-50). Furthermore, standardizing adjuvant regimens after LT is equally challenging because most patients have already received prolonged, heterogenous systemic therapy before LT. Further multicenter collaboration is needed to clarify the impact of adjuvant chemotherapy in LT for uCRLM. Additionally, while encouraging results have been reported from European and North American centers with stringent selection protocols, further research is needed to refine selection based on tumor biology. To this end, insights from the resectable CRLM literature may offer valuable guidance. One potential approach is to shift from selection criteria (Oslo criteria) that resemble the traditional Fong score and instead adopt biologically informed risk scores—such as the modified Clinical Risk Score (m-CRS) or the GAME score—developed for resectable CRLM, both of which incorporate KRAS mutation status (51,52). Notably, emerging evidence from resectable CRLM studies suggests that not all KRAS mutations confer poor prognosis; in fact, certain mutations may even be associated with more favorable outcomes (53). Similarly, while BRAF mutations are often regarded as a contraindication for LT, research in resectable CRLM shows that approximately 20% of BRAF-mutated tumors may have a protective rather than deleterious effect (54). Blanket exclusion of all BRAF-mutated patients may therefore be overly restrictive. Given that current LT studies are underpowered to stratify by specific KRAS mutations (e.g., exon or codon-specific variants) or other granular prognostic factors, a promising strategy, although still highly hypothetical, would be to develop AI-based decision tree models that flexibly combine prognostic factors, thereby maximizing patient inclusion without compromising outcomes (55). For example, rather than excluding all patients with right-sided primaries or any KRAS/BRAF mutations—an approach that may deny LT to patients with favorable subtypes—machine learning models could identify nuanced subgroups with potential benefit. Similarly, although LT is not currently offered for resectable CRLM, some patients might achieve better OS with transplantation than with resection. Accordingly, robust comparisons of transplantation and resection—using advanced statistical techniques or machine-learning methods—might be needed. In particular, a patient-level meta-analysis could provide the larger sample size necessary to apply machine learning methods such as Optimal Policy Trees (56), enabling the discovery of combinations of factors that determine which subsets of patients are most likely, or unlikely, to benefit from LT. The need for more sophisticated, data-driven stratification that balances the goal of improving expected outcomes with the risk of excluding patients who could benefit from LT is underscored by the interim analysis of the SECA II trial, which, in its effort to identify a highly favorable subgroup, included only 15 patients—potentially excluding others who may have derived meaningful benefit (47).

Conclusions

LT for uCRLM has emerged as a viable treatment for selected patients, with survival outcomes comparable to established LT indications. As the field moves beyond proof-of-concept, optimizing candidate selection based on tumor biology, refining eligibility criteria, and standardizing protocols across centers are essential. Future research should focus on incorporating molecular markers and data-driven approaches to identify patients most likely to benefit from transplant while minimizing the risk of excluding those with favorable subtypes.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://cco.amegroups.com/article/view/10.21037/cco-25-46/rc

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-25-46/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-25-46/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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