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

Abstract

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.

1. Introduction

Liver transplantation (LT) has undergone a fundamental transformation over the past three decades, evolving from a procedure in which malignancy was regarded as an absolute contraindication into an established, evidence-based therapeutic platform for selected primary and secondary hepatic malignancies [1,2]. This evolution has been driven by a deeper understanding of tumor biology, the emergence of immune checkpoint inhibitors and molecularly targeted therapies, and the development of prospective randomized evidence supporting the expansion of transplant indications beyond hepatocellular carcinoma [1,2,3,4]. The 2024 TransMet randomized controlled trial marked a defining milestone by demonstrating a fivefold improvement in 5-year overall survival (73% versus 9%) with LT plus chemotherapy compared with chemotherapy alone in carefully selected patients with unresectable colorectal liver metastases [2]. This represents the first Level 1 evidence supporting transplantation as a curative oncologic intervention in metastatic disease, provided patient selection is rigorously based on biologic behavior and treatment response. Alongside the established success of the Mayo Clinic protocol for perihilar cholangiocarcinoma and ongoing refinement of selection criteria for hepatocellular carcinoma and intrahepatic cholangiocarcinoma, the field has matured sufficiently to require a new paradigm for clinical trial design and research prioritization [1,3,4].

Despite these advances, major knowledge gaps continue to limit responsible expansion of transplant oncology. Comparative effectiveness data remain unavailable for many malignancies, while biomarker-driven selection strategies—including circulating tumor DNA, composite molecular risk models, and metabolic tumor volume assessment—still lack prospective validation in transplant-specific populations. Immunosuppression protocols are largely extrapolated from non-oncologic transplantation, and the integration of immune checkpoint inhibitors remains challenging because peri-transplant exposure is associated with rejection rates of 17–30% despite encouraging downstaging responses [3,4,5]. This manuscript addresses these limitations by proposing a comprehensive framework for transplant oncology clinical trials, including endpoint selection focused on overall/recurrence-free survival and transplant benefit, biomarker-integrated patient selection strategies, adaptive and randomized trial methodologies, immunosuppression optimization approaches, and structured surveillance and recurrence management protocols. Additionally, ethical considerations regarding organ allocation, requirements for international collaborative infrastructure, and a precision medicine roadmap for the future of transplant oncology are discussed. Proposed clinical trial frameworks spanning hepatocellular carcinoma, cholangiocarcinoma, combined tumors, rare vascular malignancies, colorectal liver metastases, and neuroendocrine liver metastases are presented to provide an actionable research agenda for the field [1,2,3,4,5].

2. Clinical Trial Design, Biomarker Integration, Immunosuppression, and Surveillance

2.1. Endpoint Selection

Traditional surgical oncology trials emphasize recurrence-free survival (RFS) as the primary endpoint, but this paradigm is poorly suited to transplant oncology, where the intervention is not solely oncologic but also life-restorative, resource-limited, and ethically constrained [1,2,6]. Overall survival (OS) consistently emerges as the most clinically meaningful and ethically defensible primary endpoint in this field.

Several key principles support prioritization of OS over RFS. First, transplant benefit—defined as the survival difference between transplantation and best alternative therapy—provides more relevant information than absolute survival rates when evaluating resource allocation decisions [2,6]. Second, quality-adjusted life years (QALYs) capture immunosuppression-related morbidity not reflected in OS alone [6]. Third, conditional and post-recurrence survival better reflect the longitudinal disease course in biologically favorable tumors such as NELM and HEHE (hepatic epithelioid hemangioendothelioma), where recurrence does not uniformly predict poor outcomes [7,8]. Fourth, RFS should be relegated to secondary analyses because recurrence does not equate to treatment failure in many transplant oncology contexts.

It is important to note, however, that the optimal primary endpoint may not be uniform across all transplant oncology indications. For HCC, RFS retains substantial clinical meaning because recurrence in this context often reflects underlying tumor biology—including microvascular invasion and tumor dedifferentiation—and directly informs decisions regarding surveillance intensity, immunosuppression modification, and salvage therapy. Endpoint selection should therefore be disease-specific rather than universally standardized: OS and transplant benefit remain the preferred primary endpoints for CRLM and NELM, where recurrence does not consistently predict poor outcomes, whereas RFS may reasonably serve as a co-primary or primary endpoint in HCC trials given its established prognostic and clinical management implications [9].

The CRLM experience illustrates this principle compellingly. Despite recurrence rates of 70% in some series, 5-year OS reached 73% in the TransMet trial versus 9% for chemotherapy alone [2]. In NELM, recurrence occurs in 50% of transplant recipients, yet median post-recurrence survival exceeds five years in many cohorts [7]. These findings demonstrate that recurrence-based endpoints would incorrectly classify highly successful interventions as failed treatments.

We recommend the following endpoint framework. The primary endpoint should be OS for all trials, with transplant benefit versus best alternative therapy as the primary metric for comparative trials [1,2]. Secondary endpoints should include RFS, quality of life and QALYs, graft survival, transplant-specific morbidity, and cost-effectiveness [6]. Exploratory endpoints should encompass conditional survival, post-recurrence survival, treatment-free survival, and ctDNA kinetics [10].

2.2. Patient Selection and Biomarker Integration

Patient selection represents the single most powerful determinant of transplant oncology outcomes. Accumulating evidence demonstrates that biologic behavior, not tumor burden alone, governs post-transplant success [4,11,12]. The transition from morphology-based criteria to biology-driven selection has enabled expansion of transplant indications while simultaneously improving outcomes through more precise risk stratification. Table 1 summarizes validated biomarkers across major hepatic malignancies that are applicable to transplant oncology [7,10,11,13,14,15,16].

Table 1. Validated biomarkers in transplant oncology across major hepatic malignancies.

Disease	Biomarker	Threshold	Impact on Outcomes	Clinical Utility Category
HCC	AFP	>1000 ng/mL	5-year RFS <50% vs. >85% if <100 ng/mL	Established in clinical practice
HCC	AFP-L3	>15%	C-stat 0.86 for recurrence prediction	Prospectively validated
HCC	DCP	>7.5 ng/mL	C-stat 0.81 for recurrence prediction	Prospectively validated
pCCA	CA 19-9	>500 U/mL	Higher dropout; inferior post-LT survival	Established in clinical practice
CRLM	RAS/BRAF	Mutant	2–3× higher recurrence vs. wild-type	Established in clinical practice
CRLM	ctDNA	Detectable post-chemo	5–10× increased recurrence risk	Investigational
CRLM	Metabolic Tumor Volume	High on PET	Predicts post-LT recurrence	Investigational
NELM	Ki-67	>20%	Excludes from transplant consideration	Established in clinical practice
NELM	68Ga-DOTATATE PET	Low uptake	Poor prognosis; extrahepatic disease likely	Established in clinical practice

Clinical utility categories: “Established in clinical practice” denotes biomarkers routinely incorporated into transplant candidacy decisions at most centers; “Prospectively validated” denotes biomarkers supported by prospective cohort data but not yet universally adopted; “Investigational” denotes biomarkers (including ctDNA and metabolic tumor volume) that remain under active study and should not yet be used as sole determinants of transplant eligibility outside of a clinical trial.

Dynamic biomarkers reflecting treatment response have emerged as particularly powerful selection tools. AFP dynamics during locoregional therapy, CA 19-9 kinetics during neoadjuvant treatment, and ctDNA clearance following systemic therapy demonstrate superior prognostic discrimination compared to static measurements [12,15,17]. Treatment response assessed over 6–12 months functions as a biologic stress test, identifying indolent disease suitable for transplantation [2,17]. The CRLM experience exemplifies this principle: patients achieving sustained chemotherapy response demonstrate 5-year OS of 73–83% post-LT, whereas those with progressive disease are universally poor candidates [2,17].

Future selection strategies should integrate composite models incorporating molecular profiling (RAS, BRAF, FGFR2, IDH1, microsatellite instability) [13,14,18,19], serum biomarkers (AFP, DCP, AFP-L3, CA 19-9) [4,11,15], functional imaging (metabolic tumor volume, receptor expression) [7,16], ctDNA for minimal residual disease detection [10,15], and treatment response by radiographic, biochemical, and pathologic criteria [2,17]. Composite models consistently achieve concordance statistics of 0.72–0.86 compared with 0.60–0.68 for single-parameter approaches [11,12], translating to 15–25% reductions in futile transplantation while simultaneously expanding access to biologically favorable patients currently excluded by traditional morphologic criteria.

2.3. Trial Design Strategies

2.3.1. Randomized Controlled Trials

Randomized controlled trials (RCTs) remain the gold standard for establishing transplant benefit and are well-suited for situations where clinical equipoise exists, sufficient patient populations can be accrued, and ethical justification for randomization can be established [1,2]. The TransMet trial exemplifies this approach: direct comparison of LT plus chemotherapy versus chemotherapy alone demonstrated 5-year OS of 73% versus 9% (HR 0.37; p < 0.001), definitively reframing transplantation as a comparative oncologic intervention rather than experimental salvage therapy [2]. However, RCTs face inherent challenges, including small patient populations for rare malignancies [8,20], prolonged follow-up requirements of 5–10 years, and ethical concerns regarding organ allocation when preliminary data suggest substantial benefit [6].

2.3.2. Adaptive Platform Trials

Adaptive platform trials allow multiple disease cohorts or treatment strategies to be evaluated simultaneously under a unified trial infrastructure with dynamic modification of enrollment, shared control arms, and early stopping rules for futility or efficacy [1]. Their advantages in transplant oncology are substantial: they eliminate duplicate control arms, maximize data efficiency through shared infrastructure, and are particularly suited to evaluating multiple indications such as CRLM, iCCA, and NELM within a single framework. An example adaptive platform trial in CRLM could evaluate multiple neoadjuvant sequences, including chemotherapy alone [21], intensive locoregional therapy combining Y90 radioembolization with hepatic arterial infusion pump chemotherapy [22], and immunotherapy combinations for MSI-high tumors [1]. Interim analyses guide decisions on arm continuation, expansion, or termination based on accumulating efficacy and safety data.

2.3.3. Additional Methodological Considerations

Beyond adaptive platform trials, several additional methodological approaches merit consideration for transplant oncology research, given the rarity of many study populations. Adaptive enrichment designs allow prospective modification of eligibility criteria based on accumulating biomarker-outcome data, progressively concentrating enrollment on patient subgroups most likely to benefit while permitting early termination for subgroups showing futility [23]. Biomarker-stratified randomization—in which patients are randomized within predefined biomarker strata (e.g., ctDNA-positive versus ctDNA-negative, or molecular subtype)—enables simultaneous evaluation of overall treatment effect and biomarker-specific treatment interaction, directly supporting the precision-medicine selection paradigm proposed in this manuscript [23]. Registry-based randomized clinical trials, which embed randomization within existing national or multinational transplant registries (e.g., OPTN/UNOS and ELTR), offer a pragmatic and cost-efficient alternative for rare transplant oncology indications by leveraging existing data infrastructure, reducing trial-specific data collection burden, and improving generalizability through inclusion of real-world practice settings [24].

2.3.4. Prospective Registries with Embedded Hypotheses

Prospective registries represent an essential trial design for rare malignancies such as cHCC-CCA and HEHE where randomized studies are impractical [1,8,25]. Requirements include predefined inclusion and exclusion criteria, standardized treatment protocols, mandatory biomarker collection, including molecular profiling and ctDNA [10,19], central pathology review [19], uniform immunosuppression protocols [26,27], and predetermined statistical adjustment strategies [6]. An example registry trial for cHCC-CCA could require genomic sequencing of all enrolled patients, mandate neoadjuvant systemic therapy for six months, and stratify 3-year RFS by molecular subtype: hepatocellular-dominant, cholangiocarcinoma-dominant, and progenitor-like signatures [19].

2.3.5. Graft Sourcing and Allocation Ethics

Extended-criteria donors and living donor liver transplantation (LDLT) mitigate ethical concerns related to waitlist competition. Modeling studies demonstrate that carefully selected oncologic candidates transplanted with extended-criteria grafts do not adversely affect waitlist mortality [6]. Trial designs should incorporate explicit stratification by graft type, utilize out-of-sequence organ offers as employed in 68% of U.S. CRLM transplants [20], and establish living donor protocols for diseases requiring prolonged neoadjuvant therapy windows. Of the thirteen potential trial frameworks proposed in this review, eight employ RCT designs, two utilize adaptive platform frameworks, and three leverage prospective registry designs—reflecting varying levels of existing evidence, disease prevalence, and feasibility constraints across different malignancies.

Graft source also carries substantial implications for transplant oncology trial design that extend beyond ethical allocation considerations. In much of Asia, particularly Japan and Korea, LDLT constitutes the predominant—and in some centers, near-exclusive—modality for HCC transplantation, reflecting persistent deceased donor organ scarcity in these regions [28]. This creates a fundamentally different trial landscape compared with DDLT-predominant systems such as the United States and much of Europe: LDLT programs can offer substantially shorter waiting times, enabling earlier transplantation before tumor progression and reducing dropout from the transplant list, but they introduce donor-specific ethical considerations, variable graft-to-recipient size matching, and different biologic selection pressures since candidates are not subject to deceased-donor allocation priority systems [28]. Future transplant oncology trials should explicitly stratify by graft source (LDLT versus DDLT) or, where feasible, be designed and powered separately for each system, since waiting-time-dependent tumor progression, dropout-corrected intention-to-treat analyses, and comparative transplant benefit calculations may differ substantially between LDLT- and DDLT-based cohorts. International collaborative trials spanning both graft-source paradigms will be essential to generate globally generalizable evidence applicable across differing donor-availability contexts.

2.4. Immunosuppression Strategies

Emerging evidence supports tailored immunosuppression based on tumor biology to minimize oncologic risk while maintaining adequate graft protection [26,27,29]. The tension between preventing allograft rejection and avoiding excessive immunosuppression that may permit tumor recurrence represents a fundamental challenge in transplant oncology.

2.4.1. mTOR Inhibitors vs. Calcineurin Inhibitors

The SILVER trial in HCC demonstrated that sirolimus-based immunosuppression improved 5-year RFS compared with CNI-dominant regimens (77% vs. 68%; HR 0.63; p = 0.009), attributed to mTOR inhibitors’ anti-angiogenic and antiproliferative properties that may suppress micrometastatic disease [30]. However, subsequent meta-analyses yielded mixed results, with some failing to confirm survival benefits and others demonstrating increased complications, including impaired wound healing and proteinuria, with early mTOR introduction [27,29]. Current practice at most centers employs CNI minimization with consideration of mTOR introduction at 3–6 months post-LT in high-risk patients defined by AFP > 100 ng/mL, microvascular invasion on explant pathology, or poor tumor differentiation [4,29]. Level 1 evidence supporting universal adoption is lacking, highlighting the need for prospective trials comparing standard tacrolimus-based immunosuppression with early mTOR conversion at month three, stratified by tumor biology including AFP level, RAS mutation status, molecular subtype, tumor burden, and vascular invasion [4,19,26,27,31]. The primary endpoint would be 5-year RFS, with secondary endpoints including OS, rejection rates, and post-transplant complications.

2.4.2. Immunotherapy-Related Immunosuppression Considerations

For patients receiving pre-transplant immunotherapy, specific immunosuppression modifications may be warranted [3,5,32]. These include higher baseline immunosuppression immediately post-LT to counteract residual immune activation from checkpoint inhibitor exposure [5], prolonged steroid tapers beyond standard protocols, intensive rejection surveillance with protocol biopsies at 1, 3, and 6 months [32], and avoidance of T-cell-depleting induction agents, which may paradoxically increase rejection risk [5]. These strategies remain empiric and require prospective validation.

2.5. Surveillance and Recurrence Management

2.5.1. Post-Transplant Surveillance Protocols

Standard surveillance for all malignancies should include cross-sectional imaging (CT or MRI) every three months for two years, then every six months for three additional years, then annually [29,33]. Tumor markers (AFP, CEA, and CA 19-9 as appropriate) should be measured monthly for one year, then every three months for four years, and then every six months indefinitely [4,15,17]. Chest imaging should be performed every six months for five years, given that pulmonary metastases are common in CRLM and HCC recurrence patterns [17,33]. ctDNA monitoring can detect recurrence 2–6 months before radiographic detection, though prospective validation of ctDNA-guided intervention strategies is ongoing [10]. Liquid biopsy from bile is under investigation specifically for iCCA and pCCA surveillance, potentially offering disease-specific early detection [10,18].

2.5.2. Management of Oligometastatic Recurrence

Oligometastatic recurrence—defined as 1–3 lesions confined to a single organ system—may be amenable to aggressive local therapy with curative intent or prolonged disease control [7,17]. Pulmonary metastasectomy is an important option for CRLM; post-LT pulmonary metastases occur in 40–60% of CRLM recurrences, and retrospective SECA data demonstrate that metastasectomy yields median post-recurrence survival exceeding five years in carefully selected cases [17]. SBRT offers an alternative for unresectable oligometastatic recurrence. For HCC recurrence, lenvatinib or sorafenib is preferred over immune checkpoint inhibitors due to rejection risk [33,34]; for CRLM recurrence, chemotherapy with or without targeted therapy combined with immunosuppression minimization is standard [17,21]; and for cholangiocarcinoma recurrence, molecular profiling should identify targetable FGFR2 fusions and IDH1 mutations [35,36,37]. Early palliative care integration for diffuse recurrence improves quality of life and may paradoxically extend survival through optimization of symptom management and reduction in treatment-related toxicities [6].

3. Discussion and Future Directions

3.1. Transplant Benefit and Ethical Justification

The central ethical question in transplant oncology extends beyond whether acceptable survival can be achieved. Rather, we must ask whether transplantation provides a meaningful survival advantage over the best available alternative therapy to justify utilization of scarce donor organs [2,6]. The TransMet trial provides the definitive answer for CRLM: 5-year OS of 73% versus 9% for chemotherapy alone (an absolute advantage of 64 percentage points; HR 0.37), far exceeding thresholds considered practice-changing in oncology [2].

Comparative transplant benefit varies substantially across diseases. For CRLM, the absolute 5-year OS advantage of 60–70% versus chemotherapy represents a transformative benefit clearly justifying organ utilization [2]. For pCCA, the absolute advantage of 50–70% over palliative chemotherapy is similarly compelling, though outcomes are comparable to resection in technically feasible cases, suggesting transplantation should be reserved for unresectable disease [38,39,40]. For HCC within Milan criteria in patients with cirrhosis, the absolute 5-year OS advantage of 15–30% over resection is driven primarily by prevention of de novo HCC in the remnant cirrhotic liver [4,41]. For iCCA and NELM, insufficient comparative data exist to quantify transplant benefit, motivating the proposed comparative trials [7,40].

Organ allocation ethics demand consideration of alternative graft sources to minimize impact on standard allocation systems [6]. The U.S. CRLM experience demonstrates feasibility: 68% of transplants utilized out-of-sequence deceased donor offers, and 48% employed living donors [20]. Three policy recommendations follow. First, oncologic indications should preferentially utilize extended-criteria grafts and LDLT, reserving ideal deceased donor organs for acute liver failure or decompensated cirrhosis [6]. Second, out-of-sequence allocation for oncologic candidates should be acceptable when substantial transplant benefit has been established through prospective trials [2,20]. Third, minimum transplant benefit thresholds (HR < 0.5 versus best alternative therapy) should guide policy decisions regarding new indication approval [2].

3.2. Knowledge Gaps and Research Priorities

Despite substantial progress, five critical deficiencies limit responsible expansion and motivate future research.

3.2.1. Priority 1: Comparative Effectiveness Trials

The most critical need is for RCTs comparing LT with best alternative therapies where transplant benefit remains unquantified [1,2]. For iCCA, trials should compare LT versus resection for early disease (solitary tumors 2–3 cm) [40,41] and LT versus targeted therapy for FGFR2- or IDH1-mutant unresectable disease [35,36,37]. For pCCA, trials should compare the Mayo protocol with modern systemic therapy combinations including immunotherapy [38,39,41].

Two ongoing prospective Italian trials directly address these evidentiary gaps for cholangiocarcinoma. LIRICA (NCT06098547) is evaluating LT for unresectable iCCA following a minimum of six months of disease control on standard-of-care chemotherapy, incorporating pre-transplant PET-MR for lymph node assessment and biomarker collection to identify predictors of post-transplant prognosis. LITHALICA (NCT06125769) is a companion nationwide Italian trial evaluating LT for unresectable pCCA, retaining the Mayo Clinic’s selection criteria but substituting standard-of-care chemotherapy for the traditional neoadjuvant radiochemotherapy regimen, with results anticipated from 2028 onward [42,43]. These registry-embedded prospective studies exemplify the trial design principles advocated in this manuscript and will provide important comparative data as the field awaits results. Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) similarly warrants expanded consideration given its mixed histology and heterogeneous molecular behavior; molecular subtyping into hepatocellular-dominant, cholangiocarcinoma-dominant, and progenitor-like signatures is likely essential for identifying the subgroups of cHCC-CCA most likely to benefit from transplantation, given the historically poor outcomes observed when this entity is treated as a single homogeneous group rather than a biologically heterogeneous spectrum spanning both parent tumor types.

For NELM, trials should evaluate LT versus PRRT sequencing strategies [7,40]. Establishment of transplant benefit takes priority over demonstrating feasibility to justify organ allocation and inform evidence-based clinical practice guidelines [2,6].

3.2.2. Priority 2: Biomarker-Driven Selection

Prospective validation of biomarkers identified in retrospective studies represents an urgent need. ctDNA should be evaluated prospectively as a gatekeeper biomarker for transplant eligibility across all malignancies, as retrospective data suggest ctDNA-negative status after neoadjuvant therapy strongly predicts favorable outcomes [10,15]. Composite risk models integrating molecular profiling, serum biomarkers, functional imaging, and treatment response should be validated in multicenter cohorts [11,12]. Metabolic tumor volume on PET should be evaluated as a quantitative selection metric given emerging prognostic data in CRLM [16]. Prospective biomarker validation could reduce futile transplantation by an estimated 15–30% while simultaneously expanding access to patients currently excluded by traditional criteria [11,12].

3.2.3. Priority 3: Immunotherapy Integration

Prospective trials defining safe and effective immunotherapy integration into transplant protocols represent a critical unmet need [3,41]. Optimal ICI washout periods require prospective definition, as current consensus recommendations of 90 days or longer are based on limited retrospective data [5,32]. Safe neoadjuvant ICI regimens for HCC and cholangiocarcinoma should be evaluated in prospective trials with standardized rejection monitoring, predetermined stopping rules, and comparison against current standard-of-care bridging strategies [3]. Post-LT ICI strategies for recurrence require dedicated safety and efficacy trials given high rejection rates in case series [33,34]. The cautionary experience of IMbrave050—where initially promising adjuvant immunotherapy benefits failed to persist with longer follow-up—underscores that extrapolation from non-transplant settings is fraught with risk and potential patient harm [41].

3.2.4. Priority 4: Immunosuppression Optimization

RCTs evaluating tumor biology-tailored immunosuppression regimens could substantially improve oncologic outcomes. For HCC, CRLM, and iCCA, trials should compare mTOR-based regimens with CNI-dominant approaches stratified by molecular and biologic risk factors [4,19,26,27,31]. Optimal timing of immunosuppression modification requires definition: early conversion at month three versus late conversion at month six or twelve, delayed conversion based on ctDNA-detected minimal residual disease [10], and risk-adaptive strategies that personalize conversion timing to individual risk profiles. Trade-offs between rejection and recurrence risk should be quantified prospectively with standardized monitoring, as current protocols are extrapolated from non-oncologic transplantation [26,27,29].

3.2.5. Priority 5: Cost-Effectiveness and Quality of Life

Comprehensive economic analyses and patient-reported outcomes should be integrated into all future transplant oncology trials [6]. For TransMet-based CRLM transplantation, formal cost-effectiveness analysis comparing LT with chemotherapy should inform insurance coverage and healthcare policy [2]. For NELM, cost-effectiveness should compare transplantation with PRRT and combined strategies, incorporating long-term outcomes and disease-specific quality-of-life measures [7,40]. Survival metrics alone inadequately capture the value of transplant oncology interventions; resource allocation decisions require comprehensive understanding of cost-effectiveness and patient-centered outcomes beyond traditional endpoints [6].

3.3. International Collaboration and Infrastructure

The rarity of transplant oncology populations necessitates international collaboration to achieve adequate sample sizes. The TransMet trial illustrates this requirement, enrolling 94 patients across 17 European centers over five years [2]. Existing frameworks provide infrastructure: the International Liver Transplantation Society (ILTS) Transplant Oncology Consensus Conference, the European Liver and Intestine Transplant Association (ELITA), and the American Society of Transplantation (AST) Liver and Intestinal Community of Practice [1,20]. These organizations should establish harmonized eligibility criteria across centers, develop centralized biorepositories for tissue, blood, and ctDNA banking, implement shared control arms and master protocols, and create real-time data sharing platforms enabling adaptive trial modifications [1,10].

Engagement with regulatory bodies, including the FDA and EMA, is essential to define acceptable trial designs for rare populations, establish surrogate endpoints predicting long-term survival, and accelerate approval pathways for oncologic transplant indications [6]. Precedent exists in the accelerated approval of targeted therapies such as pemigatinib and ivosidenib based on Phase II data [35,36], and similar frameworks could apply to transplant protocols demonstrating exceptional response rates in biomarker-selected populations.

3.4. The Future of Transplant Oncology: Precision Medicine

The next decade will witness the convergence of transplantation, molecular oncology, and immunotherapy into an integrated precision medicine framework in which transplant candidacy is determined not by tumor size or anatomical location but by comprehensive biologic characterization [4,18,19]. Transplant candidacy will be determined by molecular profile including actionable mutations, immune phenotype, and stem cell signatures predicting aggressive behavior [18,19]; functional imaging assessing metabolic activity and receptor expression [7,16]; and treatment response measured radiographically, biochemically, pathologically, and by ctDNA clearance [10,15]. Minimal residual disease negativity after neoadjuvant therapy will serve as a gatekeeper for transplant eligibility.

The implications are profound. Patients with biologically aggressive HCC beyond Milan criteria but demonstrating favorable biomarkers—AFP below 15 ng/mL, sustained treatment response, and ctDNA-negative status—may become excellent transplant candidates despite morphologic exclusion [4,10,11]. Conversely, patients with anatomically small iCCA harboring poor molecular features such as KRAS mutations, high Ki-67, or detectable ctDNA despite therapy may be inappropriate candidates despite meeting size criteria [18,40]. This represents a fundamental shift where biology supersedes anatomy as the primary determinant of transplant suitability. Enabling technologies—next-generation sequencing of tissue and liquid biopsies [18,19], radiomics and AI-enhanced imaging [16], organoid ex vivo drug sensitivity testing, and machine perfusion graft biomarker assessment—will facilitate this transition [1,10].

4. Conclusions

In conclusion, transplant oncology has entered a transformative era in which liver transplantation is increasingly defined not by rigid morphologic constraints but by biologic precision, comparative transplant benefit, and multidisciplinary integration of surgery, systemic therapy, molecular diagnostics, and immunology. The emergence of randomized evidence, such as the TransMet trial, combined with advances in biomarker-driven patient selection, targeted therapies, immunotherapy, and an expanding methodological toolkit spanning randomized controlled trials, adaptive platform and enrichment designs, biomarker-stratified randomization, and registry-based trials, has fundamentally redefined transplantation as a potentially curative oncologic platform for carefully selected hepatic malignancies. Critically, this framework must be applied with disease-specific nuance rather than uniform standardization: endpoint selection, biomarker validation status, and even graft source—particularly the choice between living and deceased donor liver transplantation—each carry distinct implications depending on the malignancy under study. At the same time, the field faces substantial unresolved challenges involving ethical organ allocation, optimization of immunosuppression, integration of immune checkpoint inhibitors, and validation of molecular and liquid biopsy-based selection strategies.

Future progress in transplant oncology will depend on international collaboration, prospective biomarker-driven trials that clearly distinguish established, prospectively validated, and investigational tools, and the development of precision medicine frameworks capable of balancing oncologic efficacy with responsible stewardship of scarce donor organs. The proposed clinical trial structures and research priorities outlined in this manuscript—extending across hepatocellular carcinoma, intrahepatic and perihilar cholangiocarcinoma, combined hepatocellular-cholangiocarcinoma, colorectal liver metastases, neuroendocrine tumors, and rare hepatic malignancies—provide a practical roadmap for advancing evidence-based expansion of transplant indications. Ultimately, the future of the field will be defined by its ability to integrate molecular biology, dynamic treatment response, disease- and region-specific trial design, and individualized risk assessment into a unified transplant strategy that maximizes long-term survival, quality of life, and ethical allocation of transplant resources.