Published online May 21, 2021. doi: 10.3748/wjg.v27.i19.2415
Peer-review started: January 26, 2021
First decision: February 27, 2021
Revised: March 10, 2021
Accepted: April 21, 2021
Article in press: April 21, 2021
Published online: May 21, 2021
The recent expansion of first-line systemic therapy options for patients with advanced hepatocellular carcinoma represents a significant advance in the treatment of this disease. However, the majority of clinical trials in first-line hepatocellular carcinoma management used placebo or sorafenib as comparators, and there are limited data providing a cross comparison of the efficacy and safety of treatments in this setting, especially for newly-approved immune checkpoint inhibitor and vascular endothelial growth factor inhibitor combination treatments.
Clinical trials of recently-approved therapies for hepatocellular carcinoma have revealed differing profiles of efficacy and safety, and comparative data to inform selection of first-line treatments for individual patients are limited. Furthermore, although lenvatinib is widely seen as a standard of care in real clinical practice, and is a recommended first-line therapy in most international treatment guidelines, there are limited head-to-head data comparing lenvatinib with other systemic therapies.
The objectives of this network meta-analysis were to systematically review and compare the response rates, survival outcomes, and safety of first-line systemic therapies for advanced hepatocellular carcinoma, and to provide a comparison between lenvatinib and other systemic therapies in this setting. The study also included a sub-group analysis of patients with hepatitis B virus infection, which is an important population in the Asia-Pacific region and has not been covered by other current meta-analyses.
We searched PubMed, Science Direct, the Cochrane Database, Excerpta Medica Database, and abstracts from the American Society of Clinical Oncology 2020 annual congress. Eligible studies were randomized controlled trials of systemic therapy enrolling adults with advanced/unresectable hepatocellular carcinoma. A network meta-analysis was used to synthesize data and perform direct and indirect comparisons between treatments for endpoints including (where available) overall response rate, overall survival, progression-free survival, time-to-progression, incidence of Grade ≥ 3 adverse events, incidence of treatment interruptions due to adverse events, and incidence of dose reductions due to adverse events. P value, a frequentist analog to the surface under the cumulative ranking curve, was used to rank treatments.
Treatments included in the analysis were atezolizumab plus bevacizumab, brivanib, donafenib, dovitinib, FOLFOX4, lenvatinib, linifanib, nintedanib, nivolumab, sorafenib, sunitinib, vandetanib, 11 sorafenib combination therapies, and three other combination therapies. Atezolizumab plus bevacizumab was ranked first for progression-free survival and overall survival but also had the highest rate of discontinuations due to adverse events. Lenvatinib ranked first for overall response rate and second for progression-free survival. Our findings show that first-line systemic treatment should be selected based on individualized treatment goals and provide valuable comparative data that can help to inform treatment decisions.
Our findings suggest that there is no one single first-line treatment for advanced hepatocellular carcinoma associated with superior outcomes across all outcome measurements. Therefore, first-line systemic treatment should be selected based on individualized treatment goals.
Future research should continue to evaluate new therapeutic strategies for hepatocellular carcinoma in the context of existing treatments, and provide further information to support treatment selection for individual patients.