Chemotherapy with liver transplantation results in better OS and PFS compared to chemotherapy alone in unresectable colorectal liver metastases: TRANSMET trial

Based on scientific evidence up to the year 2000, liver transplantation was not considered for patients with colorectal liver metastases due to the low 5-year overall survival (OS) rate. However, significant progress in survival rates after liver transplantation over the past 20 years indicate that the survival rate for patients with colorectal liver metastases could be substantially improved, potentially exceeding the outcomes of modern chemotherapy. Due to the limited availability of organs for transplantation and the perception that local treatment has no role in advanced metastatic colorectal liver carcinoma, it is important to assess this benefit correctly. Thus, the TRANSMET study was conducted to assess the effectiveness and safety of combining chemotherapy with liver transplantation compared to chemotherapy alone for patients with unresectable colorectal liver metastases (uCLM). The results of this study were presented by dr. M. Gelli at the ESMO-GI 2024 congress.¹

Study design
TRANSMET was an international, open-label, randomized controlled trial conducted across 20 European centers. Patients with definitive uCLM from previously resected BRAF non-mutated colorectal cancer, who had responded to chemotherapy (≥3 months, ≤3 lines) and had no extrahepatic disease, were evaluated by an independent expert committee and randomly assigned (1:1) to receive either chemotherapy and liver transplantation (C+L arm) or chemotherapy alone (C arm). The primary endpoint was the 5-year OS. Secondary endpoints included progression-free survival (PFS), recurrence rate, health-related quality of life (HR-QoL), and safety.

Results
From February 2016 to July 2021, 157 patients from three countries were assessed for eligibility. Of these, 94 patients (60%) were randomly assigned to the C+L arm (N=47) or the C arm (N=47). Of these, respectively 11 (most prevalent reason due to tumor progression) and 9 (most prevalent reason due to liver resection) patients did not receive the allocated treatment, resulting in 36 patients in the C+L arm and 38 patients in the C arm. At baseline, both groups had a median of 20 nodules, with median maximal diameters of uCLM being 55 mm (43-76) and 50 mm (27-83), respectively. Objective response at randomization was achieved after a median of 21 chemotherapy cycles in the C+L arm and 17 cycles in the C arm. The 5-year OS was 73% versus 9% in the C+L arm compared to the C arm (HR [95%-CI]: 0.16 [0.07-0.33]; p<0.0001), and the 5-year PFS was 20% versus 0% (HR [95%-CI]: 0.34 [0.20-0.58]; p<0.0001). Both the OS and the PFS were significantly longer in the C+L arm compared to the C arm. Among transplanted patients, 28 (74%) experienced recurrence, with 46% treated by surgery or local ablation. Ultimately, 15 (54%) patients were disease-free. QoL analyses showed a trend towards a decline in physical functioning in the C arm compared to the C+L arm, but this was not statistically significant.

Post-liver transplantation adverse events (AEs) of grade 3 or higher within 3 months were reported in 13 patients in the C+L arm (34%), with three requiring retransplantation and one death occurring. Postoperative chemotherapy-related AEs of grade 3 or higher were reported in 8 patients (36%) in the C+L arm. The percentage of patients experiencing at least one AE was 90% in the C+L arm versus 54% in the C arm, while the percentage of patients experiencing at least one serious AEs was 80% in the C+L arm and 83% in the C arm.

Conclusions
Combining liver transplantation with chemotherapy improves the OS and the PFS in a selected group of patients with unresectable colorectal liver metastases compared to chemotherapy alone. However, no major long-term statistically significant imporvements in QoL were observed. Post-liver transplantation chemotherapy appears feasible with acceptable toxicity and may become a new standard option in the treatment strategy for liver-only uCLM patients.

Reference

1. Adam R, et al. Chemotherapy and liver transplantation versus chemotherapy alone in patients with definitively unresectable colorectal liver metastases: Updated results from the randomized TRANSMET trial. Presented at ESMO GI 2024; Abstract 10.