Liver transplantation changes the rules for colorectal liver metastases

In this single-center, retrospective study, Nakao et al. (1) compared the outcomes of patients with extensive bilobar colorectal liver metastases (CRLM), confined to the liver, who underwent either two-stage hepatectomy (TSH) or liver transplantation (LT), the latter performed within the TRANSMET protocol (2), between 2016 and 2023.

All patients received preoperative systemic chemotherapy. Patients were treated with TSH when complete resection was considered achievable, or by LT when they were deemed unresectable by a multidisciplinary expert surgical committee and fulfilled the inclusion criteria of the TRANSMET protocol.

Among the 640 patients treated for CRLM during the study period, 70 (11%) presented with extensive bilobar disease. Twelve patients had extrahepatic metastases and were excluded. Therefore, 58 patients with liver-only disease were analyzed: 42 were initially planned for TSH, and 16 for LT within the TRANSMET protocol. In the TSH group, 7 patients did not proceed to the second stage because of tumor progression, and 3 patients were secondarily referred for LT within the TRANSMET protocol. There were no dropouts among patients included in TRANSMET. Overall, the per-protocol (PP) analysis included 51 patients: 32 in the TSH group and 19 in the LT group.

The two groups were comparable, except for a higher frequency of RAS mutations in the TSH group (50% vs. 16%, P=0.01) and a higher number of liver metastases in the LT group (median 15 vs. 11 lesions, P=0.03). Analyses were performed both on an intention-to-treat (ITT) basis and in the PP population to compare the two surgical strategies.

Propensity score (PS) matching was performed to reduce selection bias related to baseline differences between groups. Matching was based on two covariates: RAS mutation status and the number of preoperative chemotherapy cycles. A 1:1 matching was performed between transplanted patients and patients undergoing TSH. A Cox proportional hazards model was used to analyze survival after matching.

The primary endpoint was to compare the long-term oncological outcomes of the two strategies, including overall survival (OS), recurrence-free survival (RFS), and time to surgical failure (TSF), defined as the time interval from the LT or the second-stage hepatectomy until either the first recurrence unfit for curative-intent treatment (by surgery or ablation) or death. LT was associated with significantly better OS, RFS, and TSF compared with TSH (5-year OS: 84% vs. 32%, P=0.003; 5-year RFS: 24% vs. 0%, P=0.0001; 5-year TSF: 61% vs. 7.7%, P<0.0001).

On multivariable analysis, LT [hazard ratio (HR) 0.20; P=0.01] and left-sided primary tumor location (HR 0.38; P=0.049) were identified as independent prognostic factors for improved OS. These results remained consistent after PS matching.

The excellent OS reported with LT in the TRANSMET trial raises the question of its potential benefit in patients with extensive bilobar CRLM who are technically resectable using a two-stage approach. The present study addresses the ongoing debate on the management of extensive bilobar CRLM by comparing two curative-intent strategies: LT and TSH.

TSH is associated with poor long-term survival, even among patients who successfully complete both stages. This approach is further limited by the high risk of early tumor progression preventing completion of the second stage (3).

Reported median OS is 42–65 months in patients completing both surgical stages (4-8), compared with less than 20 months when the second stage cannot be completed (7,8).

The Norwegian SECA1 and SECA2 studies reported 5-year survival rates of up to 83% in unresectable patients treated with LT (9,10). These favorable results were later supported by the TRANSMET trial, which demonstrated the superiority of LT for unresectable CRLM, thereby raising the question of its potential role in borderline patients theoretically eligible for complex surgical strategies such as TSH (2).

The present study fits within this perspective. Supported by a rigorous methodological framework (ITT, per-protocol, and PS-matched analyses), it demonstrates a clear advantage of LT, with significantly improved OS, RFS, and TSF (5-year OS: 84% vs. 32%; RFS: 24% vs. 0%; TSF: 61% vs. 7.7%).

The observed superiority of LT appears consistent with the tumor biology of CRLM. By replacing the entire hepatic parenchyma, LT eliminates undetected micrometastases responsible for early recurrence after TSH. Post-transplant recurrences are less frequent, occur later, and are predominantly pulmonary, with frequent access to curative treatment. In the TRANSMET trial, 46% of recurrences were accessible to curative treatment (surgical resection or percutaneous ablation), and the median secondary progression-free survival in the LT group was 35.4 months (2).

Several selection factors must nevertheless be considered. The interval between diagnosis and treatment was significantly longer in the LT group (20.1 vs. 11.3 months; P=0.01). A prolonged delay before LT acts as a biological filter, selecting patients with sustained disease control under chemotherapy and strictly liver-only disease.

Strict eligibility criteria restrict LT to a small subset of candidates. Moreover, while patients included in the TRANSMET trial had prioritized access to transplantation, this is no longer the case today. In the future, transplantation within acceptable timeframes may rely on the use of rescue allocation grafts (declined by at least five centers), together with prolonged waiting times, potentially impairing outcomes in this indication.

Additional data, preferably from multicenter randomized studies, are required to clarify these findings.

This study demonstrates a clear oncological advantage of LT over TSH in patients with extensive bilobar CRLM. However, these results are limited to a highly selected population with prolonged disease stability under chemotherapy and prioritized access to transplantation, which is not feasible in the setting of organ shortage.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, HepatoBiliary Surgery and Nutrition. The article has undergone external peer review.

Peer Review File: Available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2026-1-0005/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2026-1-0005/coif). The authors have no conflicts of interest to declare.

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