Meta-Analysis
Copyright ©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Aug 27, 2025; 17(8): 108533
Published online Aug 27, 2025. doi: 10.4254/wjh.v17.i8.108533
Response rates, survival status and adverse events of placebo in randomized control trials for hepatocellular carcinoma: A meta-analysis
Wei-Yu Chen, Qing Chen, Chen-Chen Wang, Chen-Yue Zhang, Si-Kun Chen, Zhi-Qiang Meng, Ping Han, Shu Dong, Qi-Wen Chen
Wei-Yu Chen, Department of Integrative Oncology, Fudan University Shanghai Cancer Center Xiamen Hospital, Xiamen 361000, Fujian Province, China
Wei-Yu Chen, Qing Chen, Chen-Chen Wang, Chen-Yue Zhang, Zhi-Qiang Meng, Shu Dong, Qi-Wen Chen, Department of Oncology, Shanghai Medical College, Shanghai 200032, China
Qing Chen, Zhi-Qiang Meng, Shu Dong, Qi-Wen Chen, Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
Chen-Chen Wang, Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
Chen-Yue Zhang, Department of Integrated Therapy, Fudan University Shanghai Cancer Center, Shanghai 200032, China
Si-Kun Chen, School of Public Health, Fudan University, Shanghai 200032, China
Ping Han, Breast Cancer Center, Baylor College of Medicine, Houston, TX 77030, United States
Co-first authors: Wei-Yu Chen and Qing Chen.
Co-corresponding authors: Shu Dong and Qi-Wen Chen.
Author contributions: Chen Q and Chen WY contributed to conception or design of the work; Chen WY, Chen Q, Wang CC, and Dong S contributed to data collection and quality assessment; Chen WY and Chen SK contributed to analysis and interpretation of data; Chen WY, Chen Q, and Wang CC contributed to drafted the review; Zhang CY, Meng ZQ, Dong S, Han P, and Chen QW contributed to critical review and final approval; All authors have read and approved the final version of the manuscript.
Conflict-of-interest statement: All authors declare that they have no conflict-of-interest.
PRISMA 2009 Checklist statement: The authors have read the PRISMA 2020 Checklist, and the manuscript was prepared and revised according to the PRISMA 2020 Checklist.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Qi-Wen Chen, MD, Department of Integrative Oncology, Fudan University Shanghai Cancer Center, No. 270 Dongan Road, Shanghai 200032, China. cqwly@hotmail.com
Received: April 17, 2025
Revised: June 16, 2025
Accepted: July 24, 2025
Published online: August 27, 2025
Processing time: 132 Days and 20.2 Hours
Abstract
BACKGROUND

In randomized controlled trials (RCTs), the placebo arm has often been ignored as the attention tends to be focused on the treatment arm. We undertook a meta-analysis based on the data from the placebo arm in RCTs of hepatocellular carcinoma (HCC), the response rates and survival status, and adverse events (AEs) were summarized and evaluated.

AIM

To systematically evaluate the response rates, survival status and AEs in the placebo arms of RCTs for HCC.

METHODS

A systematic search was performed on PubMed, Ovid MEDLINE, Embase and Cochrane Library to identify relevant trials evaluating the efficacy of drugs for the treatment of HCC, published until December 31, 2023. Statistical analysis was performed using R statistical software (version 4.3.2).

RESULTS

A total of 18 RCTs, involving 2390 patients, met the criteria for inclusion in the meta-analysis. The pooled overall disease control rate and objective response rate in the placebo group were 38% [95% confidence interval (CI): 33%-42%] and 1% (95%CI: 1%-2%), respectively. Overall survival and progression-free survival in the placebo group were 7.9 months (95%CI: 7.6-8.31 months) and 1.9 months (95%CI: 1.6-2.1 months), respectively. The incidence of grade 3 or 4 AEs was 37% (95%CI: 30%-43%). Additionally, the incidence of interruptions or dose reductions due to AEs was 20% (95%CI: 13%-27%), while the incidence of treatment discontinuation due to AEs was 9% (95%CI: 6%-12%).

CONCLUSION

Over one-third of advanced HCC patients exhibit therapy-free disease control, with placebo-arm AEs observed. These findings guide single-arm trials design and enhance patient acceptance of anticancer therapies.

Keywords: Hepatocellular carcinoma; Placebo; Randomized controlled trials; Response rates; Survival status; Adverse events

Core Tip: While the therapeutic arm dominates hepatocellular carcinoma clinical trials, the placebo comparator serves as a critical but underutilized window into tumor biology. The natural course of hepatocellular carcinoma under placebo conditions remains poorly quantified, masking potential spontaneous stabilization mechanisms. Furthermore, placebo-associated adverse events in randomized controlled trials remain poorly characterized. Our meta-analysis addresses these gaps through systematically evaluated response rates, survival status and adverse events across placebo arms of hepatocellular carcinoma randomized controlled trials.