Transforming Liver Transplant Oncology: A Comprehensive Framework for Clinical Trial Design and Precision Transplantation

Liver transplantation (LT) has evolved from a contraindicated procedure for malignancy into an established oncologic therapy for selected primary and secondary hepatic cancers. Advances in tumor biology, molecular profiling, immunotherapy, and peri-transplant management have expanded transplant indications beyond hepatocellular carcinoma (HCC) to include perihilar cholangiocarcinoma, intrahepatic cholangiocarcinoma, colorectal liver metastasis (CRLM), neuroendocrine liver metastasis (NELM), and rare hepatic malignancies. The 2024 TransMet randomized controlled trial, demonstrating a 5-year overall survival (OS) of 73% with LT plus chemotherapy versus 9% with chemotherapy alone for unresectable CRLM, established the first Level 1 evidence supporting transplantation as a curative oncologic intervention in metastatic disease. These advances necessitate a modern framework for clinical trial design and research prioritization in transplant oncology. This manuscript proposes a comprehensive framework for future transplant oncology trials addressing endpoint selection, biomarker-driven patient selection, trial methodology, immunosuppression optimization, surveillance strategies, and ethical organ allocation. OS and transplant benefit are emphasized as the preferred primary endpoints for CRLM and NELM, whereas recurrence-free survival is recognized as retaining distinct clinical and prognostic value in HCC, underscoring that endpoint selection should be disease-specific rather than universally standardized. Emerging biomarkers—including circulating tumor DNA, AFP dynamics, and molecular and functional imaging profiling—are stratified into established, prospectively validated, and investigational categories to clarify their current clinical applicability. Randomized controlled trials, adaptive platform and enrichment designs, biomarker-stratified randomization, registry-based trials, and prospective registries are presented as complementary strategies tailored to disease prevalence and feasibility, alongside explicit consideration of how graft source—particularly the predominance of living donor liver transplantation in Asia versus deceased donor systems elsewhere—shapes trial design and interpretation. The manuscript further examines tumor biology-based immunosuppression, immune checkpoint inhibitor integration, and management of post-transplant recurrence. A precision medicine vision is proposed in which transplant candidacy is determined by biologic behavior and molecular signatures rather than morphology alone, with proposed trial frameworks offering an actionable research agenda for the next decade of transplant oncology.