Clinical Outcomes of Initially Unresectable Hepatocellular Carcinoma Patients Receiving TACE/HAIC Plus Anti-Angiogenic Agents and Immune Checkpoint Inhibitors as Conversion Therapy, Achieving Complete Radiological Response or Resectability, Followed by Systemic Treatment or Surgical Resection: A Prospective Cohort Study
Conditions: Unresectable Hepatocellular Carcinom
Sponsor: Shanghai Zhongshan Hospital

 
 
 
Clinical Trial Study Protocol 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NCT number：Pending 
Document date：2025-07-08 
Clinical Outcomes of Initially Unresectable 
Hepatocellular Carcinoma Patients Receiving 
TACE/HAIC Plus Anti-Angiogenic Agents and 
Immune Checkpoint Inhibitors as Conversion 
Therapy, Achieving Complete Radiological 
Response or Resectability, Followed by Systemic 
Treatment or Surgical Resection: A Prospective 
Cohort Study 

 
 
1. PROJECT SUMMARY  
 
Title： 
Clinical Outcomes of Initially Unresectable Hepatocellular Carcinoma Patients 
Receiving TACE/HAIC Plus Anti-Angiogenic Agents and Immune Checkpoint 
Inhibitors as Conversion Therapy, Achieving Complete Radiological Response or 
Resectability, Followed by Systemic Treatment or Surgical Resection: A 
Prospective Cohort Study 
Research Description： 
Combined TACE/HAIC with anti-angiogenic drugs and immune checkpoint 
inhibitors (referred to as targeted immunotherapy) for initially unresectable 
hepatocellular carcinoma (uHCC) shows a high tumor response rate, 
potentially reducing tumor burden and successfully converting to resectable 
liver cancer, providing an opportunity for curative treatment, thus improving 
long-term survival. Current evidence shows that the conversion success rate 
of TACE/HAIC combined with targeted immunotherapy is between 22% and 
50%, demonstrating encouraging preliminary efficacy. However, there are 
still some unresolved issues. Whether surgical resection after achieving 
radiographic complete response (rCR) or meeting resectable criteria can 
provide a survival advantage for these patients remains controversial. 
Monotherapy with targeted immunotherapy can bring nearly 2 years of 
overall survival, with a median progression-free survival (PFS) of 7-9 
months, while long-term survival data for conversion therapy are still 
insufficient. In this prospective cohort study, we will evaluate and compare 
the clinical outcomes of uHCC patients who have achieved radiographic 
complete response or met resectable criteria after TACE or HAIC combined 
with anti-angiogenic drugs and immune checkpoint inhibitors, and then 
continue with systemic therapy or undergo surgical resection, aiming to 
further optimize the treatment strategy for liver cancer. 
Purpose and endpoint： 
 
primary purpose：   
! 
Median event-free survival (EFS) 
Secondary purpose：   
! 
2-year event-free survival rate (2-y EFS rate) 
! 
Overall survival (OS)  
! 
Security 
! 
Cost-effectiveness analysis of two treatment modes 
Study population and 
sample size： 
This study will enroll at least 278 newly diagnosed uHCC patients who have 
achieved radiographic complete response or resectability criteria after TACE 

 
 
or HAIC combined with anti-angiogenic drugs and immune checkpoint 
inhibitors. These patients will be divided into a systemic treatment group (at 
least 139 cases) and a surgery group (at least 139 cases). Potential subjects 
will be eligible to participate in this study after completing the screening 
examinations and procedures for study enrollment. 
Participating research 
institutions： 
Zhongshan Hospital,  Fudan University 
Research 
treatment/intervention： 
Systemic therapy (TACE or HAIC combined with anti-angiogenic drugs and 
immune checkpoint inhibitors) or hepatectomy 
Research period： 
24-36 months 
Subject participation 
period： 
up to 36 months 
 
 
 

 
 
2. RESEARCH PURPOSE AND ENDPOINTSPrimary research endpoint 
! Event-free survival (EFS)：Defined as the time from the date of achieving rCR or 
resectability criteria to the time of becoming inoperable, recurrence, progression, or death from 
any cause for uHCC patients. 
Secondary research endpoints 
! 2-year event-free survival rate (2-y EFS rate)：Defined as the rate of no events (recurrence, 
progression, or death from any cause) occurring in rCR patients over 2 years. 
! Overall survival (OS)：Defined as the survival time from the day of achieving rCR to death 
from any cause。 
! Security 
! Cost-effectiveness analysis of two treatment modes 
 
 

 
 
2. Research DesignThis study is a prospective cohort study aimed at observing the efficacy and 
safety of continuing systemic treatment or surgical resection in patients with initially unresectable 
hepatocellular carcinoma who achieve radiological complete remission or resectable standards after 
combined treatment with TACE/HAIC, anti-angiogenic drugs, and immune checkpoint inhibitors. 
According to the inclusion criteria (refer to the subject conditions), screen TACE/HAIC 
combined anti-angiogenic drugs and immune checkpoint inhibitors for patients with initially 
unresectable hepatocellular carcinoma who have reached rCR or resectable standards after conversion 
therapy, and subjects who meet the inclusion criteria can enter this study after signing an informed 
consent form. After the subject screening is qualified, patients are divided into surgical groups and 
systemic treatment groups according to the treatment plan chosen by the patient (surgery or continued 
systemic treatment). Patients are required to undergo regular check-ups every 3 months, including 
blood routine, liver and kidney function, tumor markers, thyroid function, myocardial enzymes, and 
liver enhanced CT/MRI. If tumor recurrence or progression is found, the original treatment plan is 
terminated, and the corresponding optimal treatment plan is provided. During the follow-up process, 
detailed records of any other anti-tumor treatments and survival status of the enrolled patients during 
the study period are kept. 
 
 

 
 
2. Eligibility Criteria 
 
Inclusion Criteria: 
1. Signed written informed consent. 
2. Age 18–75 years. 
3. Hepatocellular carcinoma (HCC) confirmed by histology/cytology or diagnosed according to the 
AASLD criteria. 
4. Initially unresectable HCC (uHCC), defined according to the Chinese Guidelines for Diagnosis 
and Treatment of Primary Liver Cancer (2024 edition) and the Chinese Expert Consensus on 
Conversion and Perioperative Therapy for Primary Liver Cancer (2024 edition): HCC considered 
unsafe for curative resection due to inability to ensure both oncological completeness (R0 resection) 
and functional hepatic reserve (adequate future liver remnant with good vascular supply and biliary 
drainage to maintain postoperative liver function and minimize morbidity and mortality). Mainly 
includes CNLC stage Ib–IIIa or potentially resectable cases. Some stage Ia patients may also be 
considered uHCC if the tumor is adjacent to major intrahepatic vessels or involves the first/second 
hepatic hilum making R0 resection infeasible, or if severe cirrhosis increases risk of postoperative 
liver failure and complications; these can be considered after successful conversion and supportive 
treatment. 
5. No prior systemic therapy before conversion treatment. 
6.Conversion therapy regimen must include TACE or HAIC plus anti-angiogenic agents and immune 
checkpoint inhibitors (ICIs). 
7. Anti-angiogenic agents may include lenvatinib, sorafenib, apatinib, donafenib, anlotinib, 
bevacizumab. 
8. ICIs may include pembrolizumab, atezolizumab, nivolumab, sintilimab, tislelizumab, toripalimab, 
penpulimab, cadonilimab, KN-046. 
9. After conversion therapy, hepatic lesions achieve radiological complete response (rCR) by 
mRECIST criteria on contrast-enhanced CT or MRI, or are assessed to have reached resectability 
criteria (eligible for curative hepatectomy or downstaging enabling safe surgery). 
10. After achieving rCR or resectability, patients must have received either liver resection or 
continued systemic therapy with scheduled follow-up. 
11. Child–Pugh class A or B liver function. 
12. Eastern Cooperative Oncology Group performance status (ECOG PS) 0–1. 
 
Exclusion Criteria: 

 
 
1. Presence of another primary malignancy in other organs. 
2. History of other malignancies. 
3. Recurrent HCC occurring <2 years after previous curative surgery or adjuvant therapy. 
4. Received treatments other than TACE or HAIC plus anti-angiogenic agents and ICIs during the 
conversion phase. 
5. Received treatments during postoperative or maintenance systemic therapy that differ from the 
initial conversion regimen. 
6. Severe organ dysfunction. 
7. Incomplete radiological assessment data after treatment. 
8. Child–Pugh class C liver function. 
9. Pregnant or breastfeeding women. 
10. Patients undergoing only functional future liver remnant (FLR) hypertrophy procedures (e.g., 
ALPPS or PVE) for insufficient FLR without other criteria for uHCC conversion. 
 
 

 
 
3. RESEARCH EVALUATION AND PROCEDURES 
Baseline/Pre-treatment 
Before enrollment, participants will undergo a screening evaluation to determine eligibility, 
including baseline medical history, physical examination, CBC, serum chemistry, urine analysis, 
EKG, serum tumor markers, history of neoadjuvant treatment, and baseline and neoadjuvant 
treatment-enhanced CT and/or MRI, etc. 
Systemic treatment for initially unresectable HCC: This study only included patients who received 
the following combined treatment regimens: TACE/HAIC + anti-angiogenic drugs + ICI. The main 
anti-angiogenic drugs were lenvatinib, sorafenib, apatinib, donafenib, anlotinib, bevacizumab. The 
main ICI drugs were pembrolizumab, atezolizumab, nivolumab, sintilimab, tiragolumab, 
tremelimumab, paminaplimab, cadonilimab, KN-046.  
The rCR was determined according to the mRECIST criteria. Two independent researchers assessed 
the tumor response and discussed discrepancies when they occurred. rCR was defined as the 
complete disappearance of the arterial enhancement area of all target lesions.  
Resectability standard assessment: Two independent researchers assessed the feasibility of surgical 
resection (R0 resection, sufficient remaining liver volume, and the surgery could obtain neoadjuvant 
tumor therapeutic effect compared to the initial treatment), and discussed discrepancies when they 
occurred. 
 
Treatment phase 
For patients who achieve rCR, the multidisciplinary team (MDT, including surgeons, internists, and 
interventional radiologists) discusses the subsequent treatment plan after discussion and fully 
discusses the potential benefits and risks of surgical intervention with the patient, selects based on the 
patient's wishes, and is divided into surgical groups and systemic treatment groups. 
Continue systemic therapy: anti-angiogenic drugs and ICIs should be consistent with the preoperative 
conversion therapy selection, used according to their respective instructions, until disease progression 
(based on mRECIST criteria) or death or unacceptable toxicity. During treatment, TACE/HAIC can 
be performed as needed. 
The specimens of patients who undergo surgical resection are routinely evaluated for pathological 
response. Whether to receive adjuvant therapy after surgery is chosen based on the analysis of 
potential benefits and risks by the MDT team, combined with the patient's wishes (preventive 
TACE/HAIC or targeted drugs, immune checkpoint inhibitors, or any combination thereof).  

 
 
Patients in both groups were followed up every 3 months until tumor recurrence (based on mRECIST 
criteria) or death. 
In both groups, TACE/HAIC can be performed as needed. 
The routine follow-up program includes a comprehensive medical history, physical examination, 
blood routine, blood biochemistry, serological tumor marker assessment, coagulation function, 
thyroid function, myocardial enzyme profile, electrocardiogram, and chest plain CT and abdominal 
contrast-enhanced CT or MRI. Tumor progression is defined as the appearance of new lesions in any 
location, determined by contrast-enhanced CT or MRI based on the mRECIST criteria. 
 
After treatment 
For patients with tumor progression or recurrence, further treatment plans are decided after discussion 
by the MDT and consultation with the patient, and follow-up treatment and survival information 
continue until: 1) the subject's death; 2) the subject is lost to follow-up; or 3) the end of the study 
(follow-up period of 2 years). 
 
Termination criteria for the study： 
1) The participant withdraws the informed consent and requests to exit the clinical trial. 
2) The researcher determines that the trial is disadvantageous to the subject, including the following 
situations:： 
a) Clinically confirmed tumor progression, recurrence, or metastasis at any site (patients with 
progression or recurrence will be given the best treatment plan based on their condition) 
b) Clinically confirmed tumor progression, recurrence, or metastasis at any site (patients with 
progression or recurrence will be given the best treatment plan based on their condition) 
c) Progressive increase in tumor markers 
3) Unable to tolerate the adverse reactions of anti-angiogenic drugs or ICI 
 
 
 

 
 
3. EVALUATION INDICATORS AND STATISTICAL METHODS 
1、Primary endpoint: Event-free survival (EFS): defined as the time from the date of achieving 
rCR/resectability to intrahepatic recurrence, progression (based on mRECIST criteria), or death from 
any cause in patients who have achieved rCR/resectability. The Kaplan-Meier estimate of EFS and 
its corresponding 95% confidence interval will be calculated. The effect of the surgery group and the 
systemic treatment group on EFS will be evaluated using a Cox proportional hazards regression 
model, while controlling for other confounding factors. Point estimates of EFS based on exact 
binomial distribution and 95% confidence intervals, as well as the log-rank P-value for the 
comparison of EFS between the two groups, will be provided. A P-value < 0.05 is considered 
statistically significant. 
2、secondary endpoint： 
! 
2-year EFS rate: Defined as the rate of event-free (recurrence, progression, or death from any 
cause, based on mRECIST criteria) rCR patients at 2 years. The Kaplan-Meier estimate of the 2-
year EFS rate and its corresponding 95% confidence interval will be calculated. 
! 
Overall survival (OS): Defined as the time from achieving rCR to death from any cause. The 
Kaplan-Meier estimate of overall survival and its corresponding 95% confidence interval will be 
calculated. 
! 
Safety: The incidence of adverse events in the surgery group and the systemic therapy group. 
Adverse events recorded on the CRF will be mapped to preferred terms using the Medical 
Dictionary for Regulatory Activities (MedDRA). Severity, seriousness/grade, and the 
relationship with the study treatment will be assessed by the investigators. The seriousness/grade 
will be defined according to the National Cancer Institute (NCI) CTCAE v5.0. 
! 
Cost-effectiveness analysis of the two treatment modalities: The cost-effectiveness ratio (C/E) is 
defined as the ratio of time to an event (EFS) or overall survival (death) from rCR to all direct 
costs (medical expenses, including outpatient and inpatient), and will be compared between the 
two groups. 
 
3. SAMPLE SIZE CALCULATION 
The expected EFS for the control group patients is 12 months, and for the experimental group 
patients is 18 months (corresponding HR=0.67). The trial plans to enroll participants over 12 
months, with a 24-month follow-up. Considering a dropout rate of 20% for both the experimental 
and control groups, the trial would need at least 278 patients (at least 139 in each group) to achieve 
80% power to detect this difference at a significance level of α=0.1 (one-sided).