Adjuvant Anti-PD-1 Therapy in Resected Hepatocellular Carcinoma

Efficacy of Postoperative Adjuvant PD-1 Inhibitors Guided by a Deep Learning Model: a Multicenter, Prospective Cohort Study

Early hepatocellular carcinoma (HCC) recurrence (driven by residual tumors) and late recurrence (driven by de novo tumors) exhibit distinct biological behaviors, suggesting differential therapeutic vulnerabilities. The beneficiaries of adjuvant PD-1 inhibitors (aPD-1) and their efficacy across these temporally divergent recurrence patterns remains unestablished.

Study Overview

• Status: Not yet recruiting
• Conditions: Recurrence; HCC; Adjuvant Therapy; Immune Checkpoint Inhibitor
• Intervention / Treatment: Drug: PD-1 Inhibitors

Detailed Description

Hepatocellular carcinoma (HCC), a leading cause of global cancer-related mortality, continues to rise in incidence and lethality despite advancements in early detection and surgical techniques. Curative liver resection, while the cornerstone of therapeutic management, is frequently undermined by postoperative recurrence, a phenomenon observed in up to 70% of patients within five years, with early (≤2 years) and late (>2 years) recurrences reflecting distinct biological origins. Early recurrences predominantly stem from residual micro-metastases of the primary tumor, strongly associated with aggressive histopathological features such as microvascular invasion (MVI), multifocality, and satellite nodules. In contrast, late recurrences often arise de novo from the cirrhotic liver microenvironment, driven by persistent viral activity or chronic hepatic inflammation rather than the index tumor's biological behavior. Despite decades of research, postoperative adjuvant strategies, including antiviral therapy, transarterial chemoembolization, and traditional agents like Huaier granules, have yielded inconsistent results or lack robust evidence for standardization. The emergence of immune checkpoint inhibitors (ICIs) has reignited hope, yet recent randomized controlled trials (RCT) underscore unresolved challenges. The IMbrave050 trial initially demonstrated reduced recurrence with adjuvant Atezolizumab-Bevacizumab (median follow-up of 17 months). However, with longer follow-up (35 months), results shifted to negative. Another RCT has shown promising outcomes for patients with MVI-positive HCC who received adjuvant therapy with Sintilimab. Nevertheless, the median follow-up was only 23 months, which does not provide adequate resolution of late recurrence. Similarly, a recent prospective cohort study reported positive results of adjuvant immunotherapy in high-risk patients. These studies, limited by follow-up durations insufficient to capture late-recurrence dynamics, leave critical questions unanswered: Do adjuvant ICIs durably suppress recurrence, or merely delay its onset? In addition, there is currently no gold standard for defining high recurrence risk. Common pathological factors include MVI and satellite nodules13, but the same patient may have multiple high-risk factors simultaneously. Machine learning (ML) is increasingly being used in the construction of predictive models, and its performance often exceeds that of models based on standard statistical methods and traditional staging systems14, 15. Therefore, there is great potential for using ML to integrate clinical and pathological characteristics and quantify these risk factors to accurately identify high-risk populations and guide postoperative management strategies.

In order to fill these research gaps, we constructed an ML model to predict the risk of HCC recurrence through previous studies, and found that high-risk groups were more likely to be the potential benefit population of HCC. Therefore, this study aimed to verify the value of ML model in guiding postoperative adjuvant PD-1 inhibitors.

• Study Type: Observational
• Enrollment (Estimated): 300

Contacts and Locations

• Study Contact: Name: Wanguang Zhang, PhD; Phone Number: +8613886195965; Email: wgzhang@tjh.tjmu.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: N/A

• Sampling Method: Probability Sample

Study Population

The target population was patients with hepatocellular carcinoma who were undergoing curative surgery as initial treatment and who were receiving active surveillance or adjuvant PD-1 inhibitors postoperatively.

Description

Inclusion Criteria:

• Aged between 18 and 75;
• achieved complete tumor resection;
• histological verification of HCC;
• liver function classified as Child-Pugh grade A or B;
• No other serious systemic disease or organ dysfunction.

Exclusion Criteria:

• history of other malignancies or recurrent HCC;
• extrahepatic metastasis;
• prior treatments for HCC;
• ongoing severe postoperative complications;
• mixed or other types of liver cancer;
• received other adjuvant therapy.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Active surveillance cohort
Adjuvant PD-1 inhibitor cohort	Drug: PD-1 Inhibitors; Patients in the adjuvant cohort received at least one cycle of PD-1 inhibitors.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Disease free survival	From date of surgery until the date of first documented recurrence or date of death from any cause, whichever came first, assessed up to 96months.

Secondary Outcome Measures

Outcome Measure	Time Frame
Overall survival	From date of enrollment until the date of death from any cause, assessed up to 96 months.

Collaborators and Investigators

• Sponsor: Tongji Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): January 31, 2026
• Primary Completion (Estimated): December 31, 2029
• Study Completion (Estimated): December 31, 2031

Study Registration Dates

• First Submitted: January 23, 2026
• First Submitted That Met QC Criteria: January 23, 2026
• First Posted (Actual): January 30, 2026

Study Record Updates

• Last Update Posted (Actual): January 30, 2026
• Last Update Submitted That Met QC Criteria: January 23, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Pathological Conditions, Signs and Symptoms; Recurrence; Antineoplastic Agents, Immunological; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Therapeutic Uses; Immune Checkpoint Inhibitors
• Other Study ID Numbers: MLbased-adjuvant01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No