Study Setting {9}
This multi-institutional randomized controlled trial will be conducted in three hospitals of The Catholic University of Korea: Seoul St. Mary’s Hospital, Eunpyeong St. Mary’s Hospital, and Incheon St. Mary’s Hospital. The study design is depicted in Fig. 1.
Eligibility Criteria {10}
Inclusion criteria
- Patients ≥19 years of age with an established diagnosis of HCC by radiologic study in high-risk patient groups (e.g., hepatitis B or C, alcoholism, autoimmune liver disease) or pathologic examination.
- Single nodular HCC with a size of 5–8 cm.
- Dual nodular HCC with a maximal size of ≤8 cm.
- Triple nodular HCC with a maximal size of ≤5 cm.
- Patients meeting criteria (2) or (3) with viable HCC after first TACEa.
- Child-Pugh score of ≤8.
- No radiologic evidence of tumour invasion into the portal vein.
- No metastatic lesions outside the liver.
- No pathologic hematologic or renal functional abnormalitiesb.
- Eastern Cooperative Oncology Group performance score of 0 or 1.
aViable HCC will be evaluated within 4–6 weeks after first TACE. Viable HCC should be treated within 4 weeks of radiologic evaluation after first TACE. Patients with longer treatment delays will be excluded from trial enrolment.
bHemoglobin >8.5 g/dL, absolute neutrophil count >750/uL, platelets >30,000/uL, international normalized ratio ≤1.5, and serum creatinine level ≤1.5 mg/dL.
Exclusion criteria
- Patients with grade ≥3 AEs according to the Common Terminology Criteria for Adverse Events (CTCAE) after first TACE.
- Unfeasible location of viable HCC for RFA.
- Uncontrolled ascites.
- Uncontrolled hepatic encephalopathy.
- Recent variceal bleeding within 6 months.
- Prior organ transplant.
- Active gastric or duodenal ulcer.
- Other uncontrolled comorbidities or malignant neoplasms (except for tumours with CR more than 5 years prior).
- Positive for human immunodeficiency virus.
- Hematologic malignancy.
- End-stage renal disease: patients not in a haemodialysis state (eGFR <30 mL/min). Ongoing haemodialysis patients will be eligible for trial enrolment.
- End-stage heart failure (New York Heart Association stage 3 or 4 or history of myocardial infarction within prior 12 months).
- Brain metastasis.
Who Will Take Informed Consent? {26a}
Informed consent will be obtained by investigators (i.e., hepatologists) in the outpatient clinic at each hospital after the first TACE. A detailed explanation of the trial and information sheets will be given to patients before obtaining their informed consent.
Additional Consent Provisions For Collection And Use Of Participant Data And Biological Specimens {26b}
Not applicable.
Interventions
Explanation For The Choice Of Comparators {6b}
We hypothesize that tumour response will differ between patients with viable beyond-the-Milan HCC who receive combination TACE and RFA therapy versus TACE monotherapy.
Intervention Description {11a}
Before allocation
Patient eligibility will be evaluated after the first TACE. Patients with viable HCC after first TACE will be included in the trial. First TACE will be performed with ethiodized oil or drug-eluted beads with adriamycin (50–100 mg depending on tumour volume or liver function). The selection of ethiodized oil versus drug-eluted beads will be determined by discussion among physicians and interventional radiologists. All feeding arteries will be treated via superselective catheterization. Gelfoam particles will be used with ethiodized oil as is conventional for TACE.
Allocation
One month after first TACE, patients with viable tumour as revealed by computed tomography (CT) will be randomly allocated into combination therapy or monotherapy groups on the morning of the day of second TACE.
After allocation
All patients will undergo second TACE for the viable portion of the HCC with ethiodized oil and Gelfoam particles. Interventional radiologists performing second TACE will be blinded to patient allocation, and TACE will be performed in a conventional manner.
Patients in the combination TACE and RFA therapy group will be treated with additional RFA of the viable portion of the tumour under the guidance of fusion images from ultrasound and CT. RFA will be implemented within 1–2 days after second TACE. Whether RFA can be delayed for up to 1 month will depend on the medical condition of the patients. RFA will be performed by physicians at the three hospitals with more than 8 years of experience. A 17-gauge radiofrequency electrode system including three electrodes with a length of 150 mm and a 30-mm ablation zone (Octopus; STARmed, Goyang-si, Korea) will be used. The number of electrodes used will be determined based on the size of the viable tumour and the physicians’ discretion. However, physicians will attempt to obtain an ablation margin of at least a 1-cm perimeter around the viable tumour.
Patients in the TACE monotherapy group will be discharged from the hospital without further intervention if they experience no AEs.
Follow-up and primary endpoint evaluation
All patients will be followed for 4–6 weeks after admission for second TACE on an outpatient basis. Magnetic resonance imaging (MRI) with gadoxetic acid (Primovist; Beyel-Shering Pharm, Beyel, Germany) and laboratory tests, including tumour markers and a liver battery, will be performed. Tumour response according to modified Response Evaluation Criteria in Solid Tumours (mRECIST) criteria will be assessed by two independent radiologists blinded to patient allocation (Asan Imaging Metrics, Seoul, Korea). In the case of disagreement, a third independent radiologist will review the imaging results and make a final decision.
Criteria For Discontinuing Or Modifying Allocated Interventions {11b}
Patients who are assigned to the combination therapy group and do not receive RFA within 2 days after second TACE without consent of the investigator will be excluded. However, RFA can be delayed up to 1 month for patients with severe post-embolization syndrome depending on the hepatologist’s discretion.
Strategies To Improve Adherence To Interventions {11c}
To prevent loss of follow-up between combination therapies, both second TACE and RFA will be performed during a single hospital admission unless the patient is unable to undergo RFA due to severe postembolization syndrome.
Relevant Concomitant Care Permitted Or Prohibited During The Trial {11d}
According to the nationwide health insurance system, additional use of systemic chemotherapy is not reimbursed during locoregional treatment and its evaluation period (4–6 weeks). Although external radiation can be applied in patients with malignant portal vein thrombosis, this study will not include patients with portal vein thrombosis. Therefore, there is little chance of concomitant care during the intervention and evaluation period. After evaluation of the primary endpoint, other systemic or locoregional treatments can be applied according to patients’ disease status.
Provisions For Post-trial Care {30}
During the intervention period, patients will be closely monitored by investigators. Regular vital signs and biochemical laboratory tests will be performed. After the intervention and evaluation period, patients will undergo a conventional treatment course. Investigators will attempt to attenuate any damage from the interventions. When it is impossible to recover from irreversible injury, an insurance program associated with this trial will provide compensation. Patients will not be compensated for their participation in this trial. After evaluating primary endpoint, patients will be followed by their own treatment plan (local or systemic therapy) based on disease status.
Outcomes {12}
The primary endpoint is 4–6-week CR in patients with viable tumour after first TACE. Tumour response rate will be evaluated in accordance with mRECIST [8]. In patients with multiple tumours, the sum of the largest diameters of viable lesions will be calculated.
Secondary outcomes include: (1) progression-free survival, defined as the time between random allocation and first progression; (2) overall response rate, defined as CR + partial response; (3) number of treatments (i.e., TACE) until achieving CR; (4) overall survival rate (i.e., 6-, 12-, and 24-month) and cause of death; and (5) change in liver function within 6 months based on liver function tests and Child-Pugh score.
Participant Timeline {13}
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STUDY PERIOD
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Enrolment
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Allocation
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Post-allocation
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Close-out
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TIMEPOINT**
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-1 to -2 w
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0
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2 w
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1 m
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2 m
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6 m
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12 m
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24 m
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ENROLMENT:
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Eligibility screen
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X
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Informed consent
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X
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Laboratory tests
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X
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Allocation
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X
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INTERVENTIONS:
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TACE + RFA
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X
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TACE
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X
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ASSESSMENTS:
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Baseline MRI
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X
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CT after first TACE
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X
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Follow-up MRI
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X
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Regular follow-up (lab, CT or MRI)
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X
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X
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X
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X
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Sample Size {14}
A previous study reports that the rate of CR after combination TACE and RFA therapy was 53% for patients with HCC tumours > 5 cm [9]. By contrast, the CR rate after TACE monotherapy was 26% for patients with intermediate-stage HCC [10]. Thus, we assume that the difference in CR rate between groups may be 28%. In this trial, we calculated that 48 patients per group are needed to achieve a two-sided α level of 0.05 and statistical power of 80%. A total of 120 patients will be included in this trial (i.e., 60 patients per group) to account for a 20% dropout rate (PASS, version 16, NCSS statistical software). Data will be analysed on an intention-to-treat basis according to patients’ originally assigned group.
Recruitment {15}
Patients with beyond-the-Milan criteria HCC will be considered as candidates for trial enrolment in concordance with the inclusion and exclusion criteria. Written informed consent will be obtained from each patient. A total of 120 patients will be enrolled from the three hospitals by competitive recruitment.
Assignment of interventions: allocation
Sequence Generation {16a}
An independent statistician will generate random numbers using STATA (ver. 16, StataCorp LLC) using a 1:2 to 1:6 random block stratified by three strata (i.e., hospitals). Data will be stored in a secure online database (i.e., REDCap) using electronic case report forms (e-CRFs).
Concealment Mechanism {16b}
Informed consent will be obtained at the hepatology outpatient clinic. After agreeing to participate in the trial, patients will be admitted to the hospital based on its interventional radiology schedule. Random allocation will be performed on the day of second TACE. An outpatient hepatology clinic nurse who is independent from this trial will access the secure, password-protected, online database (i.e., REDCap) to perform patient allocation and notify the hepatologist only. All researchers and patients will be blinded to allocation status except for the hepatologist. Patient allocation will be released after the completion of second TACE.
Implementation {16c}
An independent statistician (YJY) will generate a stratified computer-generated block randomization list using STATA. A hepatologist will screen patients on an outpatient basis. If a patient agrees to participate in the trial, then the hepatologist will register the patient in the online database. Patients will be admitted to the hospital the day before second TACE. Second TACE will be performed by a dedicated interventional radiologist. After second TACE, patient allocation will be opened. According to their allocation, patients will be subsequently treated with RFA or discharged from the hospital.
Assignment of interventions: Blinding
Who Will Be Blinded {17a}
The interventional radiologist and patients will be blinded to patient allocation before second TACE and unblinded after second TACE. The independent outcome assessors will be blinded to patient allocation. The primary outcome (i.e., CR) will be assessed by comparing initial and follow-up MRIs.
Procedure For Unblinding If Needed {17b}
After allocation, patients and the interventional radiologist performing second TACE will be blinded. After second TACE, the hepatologist will reveal patient allocation.
Data collection and management
Plans For Assessment And Collection Of Outcomes {18a}
Consistent with the usual treatment course for HCC, initial laboratory tests and MRI will be performed. Tumour marker assessment (i.e., alpha-fetoprotein and protein induced by vitamin K absence-II) and MRI will also be performed 1 month after treatment. Blood laboratory tests and CTs will be performed depending on patients’ medical conditions as decided by the physician.
Plans To Promote Participant Retention And Complete Follow-up {18b}
Patients will receive a recommendation to continue follow-up care at their treating hospital. There are no plans to promote participation retention.
Data Management {19}
All data will be stored securely in an online database (i.e., REDCap). The investigators will be responsible for data registration and management. Data will be checked by at least two investigators.
Confidentiality {27}
Data from each patient will be assigned a code number, which will be the only link to patients’ identities during the trial period to maintain anonymity. Signed informed consent will be secured in a locked cabinet in a secure place in each hospital. Data will be stored for 3 years after trial completion according to the Enforcement Decree of the Bioethics and Safety Act of Korea. Data will be destroyed after 3 years; however, data storage may be extended with institutional review board (IRB) permission.
Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}
Baseline and follow-up procedural laboratory test results and MRI images will be stored. There is no future research plan.
Statistical methods
Statistical Methods For Primary And Secondary Outcomes {20a}
Parametric data will be reported as mean and standard deviation. Non-parametric data will be reported as median and range. Independent sample t-tests or Mann–Whitney U tests for continuous variables and Chi-square or Fisher’s exact tests for categorical variables will be used to compare treatment groups. For the primary endpoint, rate of CR will be compared using a Chi-square test. For secondary endpoints, Kaplan–Meier survival analysis and log-rank tests will be performed. A p-value < 0.05 will be considered statistically significant.
Methods For Additional Analyses (E.g., Subgroup Analyses) {20b}
Patient subgroups will be analysed according to treating hospital and liver function (i.e., Child-Pugh score).
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
Data produced following protocol non-adherence will not be included in the trial and will be disclosed. All researchers will make an effort to reduce missing data to a minimum. We will handle missing data with multiple imputation (MICE Package, R ver. 4.0.3, The R Foundation for Statistical Computing, Vienna, Austria). Missing values will be handled appropriately following established guidelines [11].
Plans To Give Access To The Full Protocol, Participant Level-data, And Statistical Code {31c}
The full protocol will be available on the registry website and is published here.
Oversight and monitoring
Composition Of The Coordinating Centre And Trial Steering Committee {5d}
JHK and DJS will take full responsibility for scientific validity, study quality, study conduct, procedures, patient management after AEs, and the quality of the final trial results and reports. All investigators will share information through periodic meetings and will discuss appropriate trial management when problems occur.
Composition Of The Data Monitoring Committee, Its Role, And Reporting Structure {21a}
A data monitoring committee (DMC) will be constituted by three independent medical researchers (Yun-Jung Yang; Institute of Biomedical Science, Catholic Kwandong University International St. Mary’s Hospital, Incheon, Korea, Jaesin Lee; Department of Internal Medicine, Incheon St. Mary's Hospital, The Catholic University of Korea, Incheon, Korea, Il Jung Kim; Department of Radiology, Bucheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea). The DMC will check the appropriateness of source documents, patient compliance, protocol violations, the process of consent acquisition and storage, review of e-CRFs and investigators’ binders, collection of information on AEs, and follow-up procedures. The committee will be responsible for protecting participant safety, evaluating trial effectiveness, making decisions on trial conduct or cessation, and advising on protocol improvement.
Any procedure-associated AEs will be checked during the follow-up period and recorded in the e-CRFs. In the case of serious AEs (grade ≥ 3), AEs will be reported to the principal investigator (DJS) within 24 hours. Each DMC member will judge whether the AE is associated with the investigated therapy, and any related serious AEs will immediately be reported to the IRB and principal investigator. Each researcher should report any serious AEs or other unexpected problems to the IRB within 15 working days. The DMC can recommend cessation of the trial if one treatment group has significantly more AEs than the other treatment group, the occurrence of serious AEs including procedure-related death, or complete enrolment of participants earlier than expected.
Adverse Event Reporting And Harms {22}
AEs will be classified according to CTCAE [12]. Any serious AE (i.e., grade ≥ 3) will be reported to the IRB. Daily checks for each patient will be conducted by the research team at each hospital and communicated with the other research teams.
Frequency And Plans For Auditing Trial Conduct {23}
Patient monitoring by an independent monitor will take place until data from 40 participants are collected or every 12 months if 40 participants are not enrolled. The inspection centre of each hospital will designate inspectors to conduct systematic inspections of trial-related activities and documents. Evaluation of patients and data will be completely independent from the investigators at each hospital and the trial sponsors.
Interim Analyses {21b}
No interim analyses are planned.
Plans For Communicating Important Protocol Amendments To Relevant Parties (E.g., Trial Participants, Ethical Committees) {25}
Any change to this trial protocol will be reported to the IRB of each hospital and trial registry.
Dissemination plans {31a}
The results of this trial will be published in a peer-reviewed medical journal.
