Controversies in NEN: An ENETS position statement on the role of liver transplantation (LT) in patients with advanced small‐intestinal and pancreatic NETs

Abstract

Liver transplantation (LT) may offer survival or symptomatic benefit for highly selected patients with advanced, well‐differentiated small‐intestinal or pancreatic neuroendocrine tumours and unresectable liver‐dominant metastases. However, its role remains controversial, as LT is rarely curative, recurrence is common, and benefits must be weighed against perioperative risk, lifelong immunosuppression, alternative therapies, and organ allocation ethics. This ENETS position statement summarises current evidence and expert consensus, reframing LT within a transplant‐benefit model rather than fixed eligibility criteria. It outlines biologically informed selection principles and multidisciplinary assessment, as well as addressing the need for standardised characterisation, prospective registries, and long‐term outcome data to better define the net clinical benefit of LT in this rare patient population.

1. INTRODUCTION AND CONTEXT OF LT

Liver transplantation (LT) has been proposed as a potentially radical but rarely curative intervention for highly selected patients with metastatic well‐differentiated digestive neuroendocrine tumours (NETs) and liver‐dominant disease, yet its precise role and ethical positioning in organ allocation remain debated. Decisions must balance potential survival and quality‐of‐life gains against progression risk, perioperative morbidity, long‐term immunosuppression, and national transplant programmes. ¹ , ² Controversy still exists in this disease group as to whether sequencing of variable systemic treatment options in the advanced setting may lead to similar overall survival (OS) benefit.

While LT for hepatocellular carcinoma (HCC) has been established successfully and consistently since the mid‐nineties, LT for metastatic liver disease has been a matter of debate ever since. The increasing evidence for outcome improvement by LT in metastatic, unresectable colorectal liver disease, however, has fostered the broader field of transplant oncology. ³ , ⁴ , ⁵

This consensus statement will explore the role of LT in patients with advanced, well‐differentiated small intestinal (SI‐NET) and pancreatic (pan‐NET) NETs, and represents an ENETS‐aligned position statement aimed at providing a biologically informed framework for patient selection rather than prescriptive, evidence‐validated criteria.

The central premise of this paper is that LT should not be viewed through a validated eligibility‐based lens, but rather through an expected transplant‐benefit framework—identifying patients in whom LT is likely to provide meaningful survival or symptomatic advantage over contemporary non‐transplant therapies. The concept of transplant benefit therefore represents the expected incremental improvement in survival and/or quality of life compared with optimal contemporary non‐transplant therapy, rather than the likelihood of cure.

2. WHAT CURRENT OUTCOMES OF LT TELL US (INCLUDING MILAN NET EXPERIENCE)

Relatively large retrospective series (n > 50) in advanced gastro‐enteropancreatic (GEP)‐NET patients who have undergone LT report a 5‐year disease‐free survival (DFS) ~20–62%, and 5‐year OS ~47%–74%, typically without a survival plateau—suggesting that LT seldom achieves definitive cure. In 2018, the European Liver Transplant Registry reported 5‐, 10‐, and 15‐year OS of 67%, 54%, and 41%. ⁶ Limitations included heterogeneous case‐mix, imprecise liver tumour burden quantification, and non‐standardised imaging pre‐operatively and in follow‐up. ⁷ , ⁸ , ⁹ , ¹⁰ , ¹¹ , ¹² , ¹³ , ¹⁴ , ¹⁵ Deaths up to ~11% have been reported in some series highlighting negative predictors of outcome, for instance hepatomegaly and simultaneous pancreatic surgery. ¹⁶

Prospective experience from Milan—where selection criteria (the “Milan‐NET criteria” require Grade (G)1–G2 disease, hepatic tumour burden <50%, no extra‐hepatic disease (EHD), ≥6‐month stability) were consistently applied—reported z 5/10‐year DFS of 75%/52% and 5/10‐year OS of 95%/93%, respectively, again without clear plateaus. ¹⁷ , ¹⁸ , ¹⁹ An attempt was made to provide the results from a control group of patients, with similar baseline characteristics, who have benefited from liver resection (LR) instead of LT. However, these comparisons are intrinsically confounded by selection bias: LT cohorts typically require documented pre‐treatment stability and favourable tumour biology, whereas LR cohorts often include patients with more aggressive or recently progressive disease. As such, observed survival differences cannot be interpreted as evidence of treatment superiority. LT candidates were generally required to demonstrate pre‐treatment radiologic stability, whereas such criteria were not consistently applied in LR (LR) cohorts. The early DFS decline after LR likely reflects inclusion of patients with more aggressive or recently progressive disease, limiting the validity of direct OS comparisons. ¹⁷ , ¹⁸ , ¹⁹

Across series, progression is common (≈31%–56% at 5 years) and continues to accrue over time (e.g., 60% recurrence at 10 years in a Milan cohort), reinforcing that LT in patients with NET is best framed as complete macroscopic disease clearance with potential long‐term palliation rather than universally curative. ¹⁸ , ¹⁹ , ²⁰

3. FROM CURATIVE TO SURVIVAL MODIFYING INTERVENTION

Given the persistent risk of recurrence despite apparent liver‐confined disease, LT in NET should be framed as a non‐curative, survival‐modifying intervention rather than a treatment expected to eradicate disease. Recurrence following LT does not necessarily imply treatment failure if transplantation substantially alters the natural history of disease and provides durable survival benefit. This concept mirrors contemporary transplant oncology, where recurrence after LT for colorectal liver metastases is common yet does not negate substantial long‐term survival benefit. Importantly, prolonged survival is often achievable without LT in patients with indolent disease, raising questions about the incremental benefit of transplantation in patients with favourable biology. ¹⁸ , ²¹ , ²² , ²³ , ²⁴

Importantly, recognising a survival‐modifying intervention from LT inherently alters the selection of patients. We propose, as an expert‐driven and hypothesis‐generating framework (not outcome‐validated), that LT may be most appropriate for patients in whom projected 5‐year OS without LT is <30%, and in whom transplantation could plausibly achieve an approximately 70% 5‐year OS. These reframing shifts focus from eligibility to incremental benefit, aligning LT with principles of transplant oncology and resource stewardship.

4. UNDERSTANDING PROGNOSTIC SPECIFICITIES IN ADVANCED NET AND CREATING THE HYPOTHESIS

Prognosis in metastatic well‐differentiated GEP‐NET is heterogeneous, with median OS frequently exceeding 5–10 years in selected populations. ²⁵ , ²⁶ , ²⁷ , ²⁸ , ²⁹ , ³⁰ , ³¹ , ³² , ³³ , ³⁴ , ³⁵ , ³⁶ , ³⁷ Excellent long‐term outcomes after LR have also been described in patients with favourable biology, emphasising selection bias when comparing LR vs. LT but also LR to medical options. ⁷ , ³⁸ Importantly, tumour burden is easily underestimated if suboptimal imaging techniques are used, and even employing up‐to‐date MRI protocols and PET‐Tracers, accurate staging and assessment of the LTB remains challenging. ³⁹

Undoubtedly, a proper prognostic stratification of GEP‐NET at the metastatic stage is lacking and would be expected to clarify this debate. More specifically, survival outcomes of patients with high grade/progressive tumours or low grade/slowly progressive tumours require additional prognostic investigations in separate cohorts of metastatic GEP‐NET. In addition, the presence of functional symptoms refractory to several lines of standard of care (SOC) therapy may refine the prognostic analysis. This is particularly the case for refractory carcinoid syndrome non‐responsive to somatostatin analogues (SSAs), and in much rarer cases, metastatic insulinoma may add to those who benefit from escalation in therapy (including LT).

Based on these considerations, we propose a biologically informed candidate profile identified on high‐quality whole‐body imaging:

• patients with slowly progressive tumours with, however, uncontrolled functioning syndromes

• and/or significant liver tumour burden (LTB) >25% without hepatomegaly (e.g. <70%LTB), not amenable to resection or other locoregional means.

• Limited extra‐hepatic disease (EHD) that is completely resectable or otherwise amenable to durable local control may be acceptable in selected cases following multidisciplinary review. Targetable EHD refers to metastatic deposits that can reasonably be eradicated or durably controlled by surgery, stereotactic radiotherapy, thermal ablation or other local therapies within a multidisciplinary strategy. Examples include isolated resectable lymph node metastases or solitary bone lesions amenable to local treatment. In contrast, diffuse skeletal disease, unresectable mesenteric root involvement, diffuse peritoneal disease, or brain metastases would generally remain incompatible with a transplant strategy.

The following critical appraisal of existing evidence and empirical knowledge is further based on the assumption that such a population of patients is expected to deal with a 5‐year OS <30% without LT. Future candidate selection is likely to evolve beyond clinic‐pathological variables alone. Emerging biomarkers—including circulating tumour DNA, methylation profiling, transcriptomic signatures, radiomics, AI‐assisted imaging analysis and integrated dual SSTR/FDG PET phenotyping—may further refine the prediction of tumour biology and transplant benefit. However, none has yet been prospectively validated for liver transplantation candidate selection.

5. PRE‐TRANSPLANT TUMOUR CHARACTERISATION

1. Imaging Standards: A minimal contemporary imaging set for LT evaluation should include contrast‐enhanced CT (chest/abdomen/pelvis; triphasic protocol for the liver), contrast‐enhanced liver MRI (preferably using liver‐specific contrast media and including DWI, diffusion‐weighed imaging), and SSRT‐PET/CT. In SI‐NET, ¹⁸F‐DOPA PET/CT may complement SRI‐PET/CT in the future. Ideally, this imaging should be repeated within 3 months of LT consideration. ¹⁰ , ¹⁸ , ⁴⁰ , ⁴¹ , ⁴²

   Detection of EHD using whole‐body functional imaging is critical, as modern PET techniques have reduced the proportion of truly “liver‐only” cases compared with pre‐PET eras. Discordance between SSRT‐PET and CT/MRI (e.g., SSRT‐negative or heterogeneous, but morphologically visible disease) may signal aggressive biology and tumour heterogeneity; ¹⁸FDG‐PET can help further characterise such cases. ¹⁸FDG negativity may help identify patients with more indolent disease biology.

2. Dynamic prognostic classification: serial and whole body, modality‐consistent imaging is recommended to document disease stability before listing. Historically, most transplant series have required ≥6 months of stable disease prior to consideration of listing, and waiting‐list time often provides an additional biological “test of time”. Some members of the panel have proposed longer observation, especially in tumours with higher proliferative indices or uncertain kinetics. Therefore, prolonged observation strategies should be considered biologically motivated but not evidence‐validated selection criteria.

6. CURRENT SELECTION CRITERIA—STRENGTHS AND LIMITATIONS

1. Milan NET Criteria and Inadvertent Selection Bias: Traditional criteria (G1–G2 disease, hepatic tumour burden <50%, no EHD, ≥6‐month stability) identify patients with excellent tumour biology and favourable pre‐ and post‐transplant survival. Indeed, these same patients often experience prolonged survival if receiving non‐transplant multimodal therapy. ³² , ⁴⁰ , ⁴³ , ⁴⁴ , ⁴⁵ , ⁴⁶

2. Prognostic Factors: Higher tumour grade predicts poorer outcomes, although assessment may be affected by sampling limitations. Liver tumour burden (LTB) is prognostic in pan‐NET, but appears less dominant in SI‐NET, where the volume of mesenteric nodal disease and resectability are often more relevant. Extensive liver replacement (>70%) has historically been associated with poor outcomes, although this does not necessarily correlate with hepatomegaly. Bone metastases are relatively common; in SI‐NET, however, a limited number of bone metastases (oligometastatic disease) may not independently worsen overall survival in all series, whereas diffuse skeletal involvement is consistently associated with poorer outcomes. ⁷ , ¹⁵ , ⁴⁷ , ⁴⁸ , ⁴⁹ , ⁵⁰ Age may also influence prognosis.

7. UPDATED (ENETS) RECOMMENDED SELECTION PRINCIPLES FOR LIVER TRANSPLANT

Conceptual Framework: In the absence of the demonstration of any curative role of LT, evolving ENETS‐aligned thinking focuses on creating transplant benefit vs. SOC. This goes along with the recognition of a survival‐modifying intervention role of LT, yielding the selection of patients whose survival or symptom burden is likely to be meaningfully improved by LT compared with non‐transplant therapy. The following principles should therefore be viewed as a biologically informed framework rather than rigid evidence‐based criteria (Table 1). Many of these principles derive from retrospective series and expert consensus rather than prospective validation.

1. Tumour grade: Confirmation of low‐ or intermediate‐grade disease (G1–G2) is recommended whenever feasible, acknowledging sampling limitations. Imaging surrogates of indolent biology include a baseline, ileal primary, low grade, strong SSRT uptake, ¹⁸FDG negativity, and is complemented by dynamic imaging follow‐up and slow morphological progression.

2. Primary tumour factors: portal‐drained primaries (SI‐NET/pancreas) favoured and definitive resection of the primary/locoregional disease prior to LT consideration.

3. Liver tumour burden (LTB): Low LTB (<10–25%) is frequently associated with favourable natural history with non‐transplant therapy and may represent overtreatment with LT. Conversely, patients with substantial, liver‐dominant disease may derive the greatest survival benefit from transplantation. Consideration is strongest in patients with LTB in the range of approximately 25–70%, particularly when metastases are large, unresectable within the liver, and/or symptom‐producing, and when alternative liver‐directed options have been exhausted. Extreme tumour replacement (>70%) or marked hepatomegaly has historically been associated with poorer outcomes and may represent a relative contraindication due to both biological and technical factors.

4. Extra‐hepatic liver disease (EHD): Replace “no EHD” with “no macroscopic, non‐targetable EHD”. Contraindications may include unresectable mesenteric nodes, spinal metastases, or brain metastases. Recognise practical limits in detecting micrometastases.

5. Need for tumour stabilisation on imaging before listing: Maintain strict stability before LT; systemic therapy during the waiting period can be used to ensure disease stability, prioritising SSA or Peptide Receptor Radionuclide Therapy (PRRT) in slowly progressive disease; everolimus is a reasonable option (and may dovetail with post‐LT immunosuppression). ⁵¹ The duration of pre‐listing observation remains empirical. While ≥6 months of stable disease has historically been used, longer observation has been proposed in tumours with higher proliferative indices based on theoretical concerns regarding delayed progression.

6. Age: <60 years as a relative consideration.

7. In uncontrolled functioning NETs (e.g., carcinoid syndrome; insulinoma, VIPoma), LT may be considered as a symptom‐relieving intervention. In this context, the risk–benefit balance differs from non‐functioning tumours, and shorter periods of demonstrated stability may be acceptable. Additional studies are needed to define the role of LT in refractory carcinoid syndrome with or without carcinoid heart disease. This approach is driven by clinical necessity and expert experience rather than outcome‐validated criteria. ¹⁰

TABLE 1.

Proposed updated criteria for liver transplantation in patients with advanced GEP‐NET.

Domain	Proposed considerations	Rationale
Tumour Grade & Biology	Confirmed low‐ or intermediate‐grade (G1–G2) NET. When sampling is limited or grade increased, imaging and kinetic surrogates may refine assessment of tumour prognosis (e.g., strong SSRT‐PET uptake, FDG‐PET negativity, and slow morphologic progression). Pre‐listing stability of ≥6 months is generally recommended; longer observation may be considered in tumours with uncertain kinetics, but this approach is biologically motivated rather than outcome‐validated.	Tumour grade is the strongest predictor of survival. Imaging characteristics and growth rate may compensate for sampling limitations and refined tumour behaviour. Indolent biology is essential for potential LT feasibility and benefit.
Primary Tumour Management	Portal‐drained primaries (SI‐NET or pan‐NET) should ideally be definitively managed before LT consideration.	Control of the primary and locoregional disease may reduce ongoing dissemination risk and aligns with known prognostic relevance of primary site.
Liver Tumour Burden (LTB)	Very low LTB (<10%–25%) may represent overtreatment with LT, given favourable natural history if receiving non‐transplant therapy. Consideration is strongest in patients with substantial, liver‐dominant disease (e.g., 50%–70% replacement, or ≥25% with bulky, unresectable, and/or symptomatic liver metastases and indolent biology. Hepatomegaly is an adverse feature.	LTB reflects total tumour burden and influences prognosis. Patients with high but liver‐dominant burden may derive the greatest survival advantage from LT relative to non‐transplant management.
Extrahepatic Disease (EHD)	Replace the concept of “no EHD” with “no macroscopic, non‐targetable EHD.” Limited, completely resectable or otherwise controllable EHD may not be an absolute contraindication. Unresectable mesenteric nodal disease, certain bone metastases (e.g., posterior spinal involvement), or brain metastases remain high‐risk features.	Complete exclusion of all EHD is often unrealistic with modern imaging and correlation between high LTB and EHD in GEP NET. A nuanced, biology‐driven approach may optimise candidate selection without clearly compromising outcomes. High‐quality whole‐body imaging is essential.
Disease Stability Before Listing	Demonstrated radiologic stability on serial, modality‐consistent imaging is required before LT listing. A minimum of ~6 months of stable disease has historically been used and serves as a practical baseline “test of time.” Longer observation may be reasonable in tumours with uncertain kinetics, Systemic therapy during evaluation (e.g., SSA, PRRT, everolimus) may support disease control while preserving transplant candidacy.	Disease progression before LR is strongly associated with post‐transplant recurrence and poorer survival. Demonstrating stability helps identify indolent tumours and reduces the risk of futile transplantation. The role of disease progression as marker of prognosis stratification is acknowledged by its role as an inclusion criteria in GEP NET phase III medical trials
Age	Age <60 years may be considered a relative, not absolute, factor.	Reflects graft stewardship and expected post‐transplant survival while allowing individualised assessment.
Functioning Syndromes	In refractory functioning NETs (e.g., uncontrolled carcinoid syndrome), LT may be considered partly for symptom control. In selected cases, this may justify greater flexibility in stabilisation duration or LTB thresholds.	Hormone‐mediated complications contribute independently to morbidity and mortality; LT may improve quality of life and reduce endocrine‐driven risks. This approach reflects clinical necessity rather than outcome‐validated criteria.
Overall Target Population	Medically fit patients with unresectable, liver‐dominant, slowly progressive disease and poor projected survival without LT (e.g., 5‐year OS <30%), in whom LT could plausibly achieve substantially improved survival (e.g., ≥70% at 5 years), and without macroscopic, non‐targetable EHD.	Focuses on patients most likely to derive incremental survival or symptomatic benefit relative to contemporary non‐transplant therapies.
Programmatic Considerations	Early involvement of NET multidisciplinary teams and transplant specialists; standardised imaging protocols; coordinated systemic therapy during evaluation.	Enhances treatment sequencing, reduces variability, and supports equitable and biologically informed graft allocation.

Abbreviations: EHD, extra‐hepatic disease; GEP‐NET, gastroenteropancreatic neuroendocrine tumour; LT, liver transplantation; LTB, liver tumour burden.

8. LT WITHIN THE MULTIMODAL TREATMENT LANDSCAPE

Systemic therapy options for patients with advanced GEP‐NET may include SSAs and PRRT (peptide receptor radionuclide therapy), everolimus, sunitinib, and cabozantinib, capecitabine with temozolomide (CAPTEM), and other chemotherapies, depending on the primary site. Everolimus, MKI (multikinase inhibitors), or chemotherapies were mostly developed and validated in patients with progressive disease, which does not fit with the population expected to benefit from LT. In contrast, SSA and PRRT anti‐tumour activity were validated in patients with slowly progressive disease and could serve as alternatives or treatment while awaiting LT. Everolimus may play a dedicated role both as an anti‐tumour and immunosuppressive agent. MKI, chemotherapies, and PRRT may downstage the tumour burden in some patients. However, no OS benefit has been demonstrated, and long‐term adverse events may occur with PRRT and cytotoxic chemotherapy. Taken together, well tolerated and/or adjusted systemic therapy options providing robust stabilisation with no or minimal long‐term adverse events (AEs) should be favoured. Locoregional measures (surgery, ablation, embolisation) can potentially debulk liver disease, but remain a survival modifying intervention. ⁴³ , ⁵¹ , ⁵² , ⁵³ , ⁵⁴ , ⁵⁵ Trans‐arterial chemo‐embolisation (TACE) may complicate tumour‐load measurements and operative planes, though recent work found no correlation with arterial LT complications. ⁵⁶ There is phase III evidence of tumour control with systemic therapy options, whereas most locoregional data are retrospective.

Although LT may theoretically be considered as an alternative to LR in selected scenarios, it is currently reserved for patients in whom liver disease is not amenable to resection or other locoregional approaches. This reflects both the limited quality of evidence demonstrating a survival advantage of LT and the constraints imposed by the donor organ pool.

9. PERI‐ AND POST‐TRANSPLANT CONSIDERATIONS AND RISKS

Fitness and ability to adhere to complex clinical pathways are essential. Early mortality remains an issue (~10%–15% within 90 days), driven by infection and vascular events. ¹⁶ Long‐term immunosuppression increases the risk of de novo malignancy (≈2‐fold for solid tumours; ~30‐fold for haematologic malignancies), which in some series is a leading cause of death. ⁵⁷ Graft‐ and drug‐related morbidities (renal dysfunction, diabetes, neuropathy, graft failure) may present post‐transplant, especially in younger patients who may otherwise have relatively long survival with non‐transplant care. ⁵⁸ In addition, all systemic treatment options may have tolerability interactions with immunosuppression. ⁵²

10. QUALITY OF LIFE (QoL)

There is a paucity of QoL data specific to patients with a NET diagnosis who have had a LT. ⁵⁹ In general LT populations, QoL improves versus pre‐LT and can remain better for decades; anxiety/depression also improve within a yea, findings that may not fully extrapolate because many patients with NET have preserved liver function pre‐LT. ⁶⁰ , ⁶¹ NET‐specific QoL tools should address cancer survivorship and transplant domains (e.g., graft function, fatigue, recurrence anxiety) and distinguish functioning vs. non‐functioning NETs, as symptom resolution can result in overestimated QoL gains.

11. PROGRAMMATIC AND ETHICAL CONSIDERATIONS

Patients with advanced NEsT comprise roughly 0.5% of all LTs. ⁶ Early multidisciplinary involvement—including transplant surgeons—and early referral of selected candidates for consideration of LT can lead to better synchronisation of systemic/locoregional plans with listing policies and organ availability. National programmes (e.g., UK/Ireland) offer frameworks for equitable review, research integration, and consistent allocation; international collaboration and registries (e.g., ENETS) with long‐term follow‐up (>10 years) are essential. ⁶² Living donor liver transplantation (LDLT) may become an attractive strategy for selected NET patients because it avoids competition with deceased donor allocation and permits transplantation to be scheduled according to tumour biology rather than organ availability. However, experience remains limited, donor safety remains paramount, and current evidence is insufficient to recommend LDLT outside experienced centres or prospective evaluation.

12. PRACTICAL PROPOSAL—WHICH PATIENTS WITH A NET DIAGNOSIS TO CONSIDER NOW FOR LIVER TRANSPLANT?

From a practical standpoint, LT should be considered in a highly selected subgroup of patients in whom transplantation is expected to confer a meaningful survival or symptomatic benefit over non‐transplant therapy. The primary target population comprises medically‐fit patients with slowly progressive, well‐differentiated tumours whose estimated 5‐year OS without LT is poor (e.g., <30%), based on an integrated assessment of tumour grade, growth kinetics, hepatic and extra‐hepatic tumour burden, and functional imaging. In such patients, LT may be expected to deliver a post‐transplant 5‐year OS in the range of ≥70%, provided that macroscopically non‐targetable EHD is absent. Certain clinical scenarios may act as pragmatic triggers for transplant evaluation rather than strict eligibility thresholds. These include uncontrolled functioning syndromes and substantial liver tumour replacement (e.g., 50%–70%, or >25% in the setting of bulky, unresectable, and/or symptomatic liver disease). In this context, disease burden or symptom severity may limit long‐term survival or QoL, despite otherwise indolent tumour biology ¹⁸ , ¹⁹ , ⁴⁸ (see also: Table 1).

During the evaluation and waiting period, systemic therapy plays a dual role in disease control and biological assessment. Somatostatin analogues, PRRT, and everolimus are commonly favoured options to help maintain radiologic stability while minimising treatment‐related complications that could jeopardise transplant candidacy. Treatment selection should therefore balance oncologic control with preservation of surgical fitness. ⁵¹

With respect to EHD, a nuanced approach is increasingly adopted. State‐of‐the‐art SSRT‐imaging and conventional imaging, and eventually, further PET tracers play a pivotal role. Limited, resectable, or otherwise targetable EHD may not represent an absolute contraindication. In contrast, macroscopically evident disease that cannot be eradicated or durably controlled—such as spinal involvement, brain metastases, or unresectable mesenteric nodal disease—generally remains incompatible with a transplant strategy.

13. KEY MESSAGES

• LT in NET is rarely curative and should be framed as a survival‐modifying intervention.

• Selection should prioritise transplant benefit vs. standard care, not eligibility alone.

• Tumour biology (grade, kinetics, imaging phenotype) is the dominant determinant of outcome.

• Milan criteria preferentially select favourable biology, not necessarily maximal transplant benefit.

• Decisions regarding extra‐hepatic disease and functioning tumours remain MDT‐driven.

• Prospective validation of selection strategies is lacking.

14. CONCLUSIONS AND FUTURE DIRECTIONS

Liver transplantation for advanced SI‐NET and pan‐NET represents a high‐value intervention for a narrow but clinically important subgroup of patients. Contemporary selection thinking is evolving from static, anatomy‐based filters towards a framework that integrates tumour biology, growth kinetics, and advanced imaging phenotypes. This shift reflects the need to prioritise patients unlikely to achieve comparable survival without LT, while also recognising the persistent risks of post‐transplant recurrence and lifelong immunosuppression.

Future progress depends on prospective, collaborative efforts that apply standardised imaging protocols, dynamic measures of disease stability, and biological correlates of tumour behaviour. NET‐specific QoL endpoints should be incorporated alongside survival outcomes to better define net clinical benefit. National pilot frameworks and international registry initiatives will be essential to capture long‐term outcomes exceeding 10 years, thereby reflecting the true survivorship patterns and recurrence trajectories characteristic of this disease. ⁶²

AUTHOR CONTRIBUTIONS

Peter Stålberg: Conceptualization; writing – original draft; writing – review and editing. Beata Kos‐Kudla: Writing – review and editing. Clarisse Dromain: Writing – review and editing. Nehara Begum: Writing – review and editing. Raj Srirajaskanthan: Conceptualization; writing – review and editing. Mairéad G. McNamara: Writing – review and editing. Eric Baudin: Conceptualization; writing – original draft; writing – review and editing. Wendy Martin: Writing – review and editing. Timm Denecke: Writing – review and editing. Simona Grozinsky‐Glasberg: Writing – review and editing. Andreas Pascher: Writing – review and editing. Stephanie Alband: Writing – review and editing.

CONFLICT OF INTEREST STATEMENT

Mairéad G. McNamara has received research grant support from Astra Zeneca, Servier, Ipsen, and NuCana. She has received travel and accommodation support from Bayer and Ipsen, and speaker honoraria from Pfizer, Ipsen, NuCana, Mylan, and AAA. She has served on advisory boards for Celgene, Ipsen, Sirtex, Baxalta, Incyte, and Astra Zeneca.

Beata Kos‐Kudla has received honoraria or consultation fees from Merck, Ipsen, Novartis, Pfizer, and has participated in company sponsored speaker bureaus for Merck, IBSA, Ipsen, Novartis, and Pfizer.

Timm Denecke reports research funding by Bayer and honoraria from Bayer, Siemens, Canon, AAA, Merck, Roche, IPSEN, Novartis, AstraZeneca, Parexel, Perceptive, and Calyx for scientific lectures and expert reports.

Nehara Begum has served on advisory boards for ESTEVE and Ipsen Pharma, and has received speaker honoraria from ESTEVE, Ipsen Pharma, and Recordati.

Raj Srirajaskanthan has received grants/research supports from Novartis and Ipsen, and honoraria or consultation fees from Novartis, Ipsen, Terumo, ITM, Advanz.

Eric Baudin reports grant funding from Novartis, HRA, consulting fees from Novartis, support from HRA, Novartis, Enterome; and participation on advisory boards of Ipsen, Novartis, AAA, Pfizer.

All other authors declare no conflicts of interest.

DATA AVAILABILITY STATEMENT

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.