Prospective Evaluation of a Locked Risk-Stratified Surveillance Strategy for Extrahepatic Metastasis in Hepatocellular Carcinoma
Conditions: HCC - Hepatocellular Carcinoma, Machine Learning, Evaluation
Sponsor: Tongji Hospital

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ClinicalTrials.gov Study Documents
Prospective Multicenter Observational Evaluation of a 
Locked Machine Learning-Guided Risk-Stratified 
Surveillance Strategy for Extrahepatic Metastasis in 
Hepatocellular Carcinoma
Study Protocol
Public-facing protocol summary aligned to the observational registry record
NCT Number
NCT07444905
Protocol ID
MLEHM-010
Document date
02 April 2026
Institution
Tongji Hospital, Tongji Medical College, Huazhong 
University of Science and Technology
Posting note: This public-facing document is intended to accompany the observational registry record. It summarizes the 
final locked study framework and should be interpreted together with the related study documents uploaded under the 
same NCT number.

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1. Administrative synopsis
Field
Summary
Study type
Observational; prospective multicenter cohort / patient 
registry
Overall design
Linked programme comprising retrospective model 
development and international external evaluation 
followed by a two-wave domestic prospective 
implementation programme
Retrospective programme
20,139 patients from 66 centres in 14 countries/regions 
(development cohort n=15,688; international external 
evaluation cohort n=4,451)
Prospective programme
15 domestic centres; pooled implementation cohort 
n=1,523 (wave 1: 11 centres, n=1,047; wave 2: 4 
centres, n=476)
Prospective enrolment window
February 2022 to February 2023
Comparative framework
Centre- and calendar-epoch-aligned usual care as the 
primary observational comparator; contemporaneous 
eligible no-tool episodes reserved for sensitivity 
analyses
Prospective study start date
February 2022 (actual)
Population scope
Adults with hepatocellular carcinoma without 
baseline extrahepatic metastasis across routine 
treatment pathways, including surgical resection, 
curative ablation/transplantation, transarterial 
locoregional therapy, systemic therapy, and best 
supportive care/no active anticancer therapy, as 
applicable at time zero
Registered outcome hierarchy
Primary registry outcome preserved as incident 
extrahepatic metastasis (EHM); registered 
secondary outcome preserved as overall survival; 
implementation and patient-important domains are 
prospectively specified as additional observational 
outcomes
2. Background and rationale
Hepatocellular carcinoma (HCC) is associated with substantial risks of recurrence and extrahepatic 
metastasis, particularly lung metastasis (LM) and bone metastasis (BM). Earlier identification of patients at 
increased risk of extrahepatic spread may support more appropriate surveillance intensity, earlier 
multidisciplinary review, and more timely downstream management. However, routine follow-up is rarely 
individualized to extrahepatic metastasis risk.
This registry-supporting protocol describes a locked machine learning-guided risk-stratified surveillance 
strategy intended for routine clinical use. The strategy is evaluated in an observational programme designed to 
assess model transportability, implementation fidelity, clinically actionable detection pathways, patient-
important downstream outcomes, and longer-term survival across routine HCC management pathways rather 
than a postoperative/curative-intent-only population.
3. Objectives

To evaluate transportability, discrimination, calibration, and threshold maintenance of the locked LM and 
BM risk modules in international and prospective settings.

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
To evaluate implementation performance, including completion of prespecified action, time to first action, 
and treatment activation within 60 days after the first eligible locked risk assessment.

To evaluate clinically meaningful detection patterns, including asymptomatic actionable LM/BM detection, 
symptom-driven detection, and detection while still clinically actionable at first discovery.

To evaluate patient-important downstream outcomes, including metastasis-related acute deterioration, 
metastasis-related emergency care or hospitalization, bone-metastasis catastrophic events, and overall 
survival.

To describe workflow and resource implications of model-enabled risk stratification in routine practice.
4. Study design and setting
This is a multicenter prospective observational cohort study conducted in routine care. The study does not 
assign treatment or surveillance strategies on a protocol basis. Treating clinicians retain responsibility for all 
diagnostic, surveillance, and management decisions. The prospective programme follows multicenter 
retrospective development and independent international external evaluation, and the prospective cohort 
spans eligible HCC management pathways represented at time zero rather than a postoperative-only design.
The live implementation programme is structured in two waves. Wave 1 introduced the locked package into 11 
domestic centres. Wave 2 was a prespecified independent new-centre prospective replication in 4 additional 
domestic centres using the unchanged v1.0 package carried forward from the pre-live freeze dossier. No 
retraining, threshold revision, or SOP remapping was permitted during the primary implementation phase.
5. Study population
Adults aged 18 years or older with HCC and without baseline extrahepatic metastasis at the first eligible 
locked LM/BM risk assessment are enrolled and followed under routine clinical practice at participating 
centres. The cohort is not restricted to postoperative or curative-intent populations and may include patients 
entering follow-up from surgical, ablative/transplant, locoregional, systemic, or supportive-care pathways, as 
applicable in routine practice.
6. Locked strategy package
The locked package comprises endpoint-specific LM and BM first-site competing-risk modules, frozen 
preprocessing rules, fixed 12-month risk thresholds, and linked standard operating procedure (SOP)-based 
surveillance and management pathways.
Component
Specification
LM thresholds
T1 = 8%; T2 = 12%
BM thresholds
T1 = 4%; T2 = 6%
Low-risk pathway
Routine surveillance at the usual interval; no automatic 
MDT; no immediate directed LM/BM work-up unless 
symptoms or new abnormalities emerge
Intermediate-risk pathway
Reassessment within 8-12 weeks; MDT if imaging 
changes or symptoms occur; directed evaluation as 
indicated
High-risk pathway
Expedited imaging and MDT review within the 
prespecified window, with endpoint-specific directed 
evaluation and downstream management planning
Discordant LM/BM strata
Overall pathway intensity follows the higher operational 
stratum; directed work-up remains endpoint-specific
7. Governance and implementation chronology

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Milestone
Timing
Summary
Pre-live freeze dossier
January 2022
Protocol, thresholds, SOP-linked 
pathway rules, and SAP frozen 
before first live implementation
v1.0 release
Before first wave 1 go-live
Locked package released for live 
use
Prospective implementation window
February 2022 to February 2023
Two-wave live programme operated 
under the locked package
Wave 2 carry-forward
During prospective implementation
Prespecified independent new-
centre prospective replication used 
unchanged v1.0 package
Governance audit
Wave 2 period
Audit-only review; no deployment 
change allowed during the primary 
implementation phase
8. Outcomes and assessment windows
Registry-facing outcome domains are organized as registered outcomes and additional prospectively specified 
implementation and clinical-utility domains. Definitions and adjudication rules are detailed in the accompanying 
Endpoint Definitions and Adjudication Charter.

Registered primary outcome: incident extrahepatic metastasis, including site-specific ascertainment of lung 
and bone metastasis where applicable, up to 36 months.

Registered secondary outcome: overall survival up to 36 months.

Implementation, patient-important, and long-term comparative outcomes are additional prospectively 
specified observational domains and do not replace the preserved registry primary outcome hierarchy.

Implementation outcomes: completion of prespecified action within 60 days, time to first prespecified action, 
treatment activation within 60 days, and strategy-nonconcordant intensified action among low/intermediate-
risk episodes.

Patient-important comparative outcomes: asymptomatic actionable LM/BM detection, symptom-driven 
LM/BM detection, metastasis-related emergency department visit or hospitalization, metastasis-related 
acute deterioration composite, detection while still clinically actionable at discovery, and the bone-
metastasis catastrophic event composite.
9. Comparative analysis framework
Comparative implementation analyses are observational and use centre- and calendar-epoch-aligned usual-
care episodes as the primary comparator under an emulated target-trial framework. The first valid locked 
LM/BM risk assessment defines time zero. A 0-7-day implementation grace period is allowed. Primary 
implementation outcomes are assessed through day 60; long-term survival outcomes are anchored to the 60-
day landmark when prespecified to reduce immortal-time bias.
All comparative estimates are observational and should not be interpreted as randomized treatment effects.
10. Ethics and dissemination
The study is conducted under institutional ethics approval and routine-care governance procedures. 
Participants receive standard clinical management, and no study-mandated treatment allocation is performed. 
Public registry posting includes this protocol summary, the Statistical Analysis Plan, the Endpoint Definitions 
and Adjudication Charter, and the Model Lock and Version Governance Note.
No formal data monitoring committee is constituted because this is a non-interventional observational 
programme and no study-mandated treatment allocation is performed.