The Significance of Transarterial Chemo(Embolization) Combined With Tyrosine Kinase Inhibitors and Immune Checkpoint Inhibitors for Unresectable Hepatocellular Carcinoma in the Era of Systemic Therapy: A Systematic Review

Abstract

Background and AimsRegardless of great progress in early detection of hepatocellular carcinoma (HCC), unresectable HCC (uHCC) still accounts for the majority of newly diagnosed HCC with poor prognosis. With the promising results of a double combination of transarterial chemo(embolization) and tyrosine kinase inhibitors (TKIs), and TKIs and immune checkpoint inhibitors (ICIs), a more aggressive strategy, a triple combination of transarterial chemo(embolization), TKIs, and ICIs has been tried in the recent years. Hence, we aimed to conduct a systematic review to verify the safety and efficacy of the triple therapy for uHCC.MethodsPubMed, MedLine, Embase, the Cochrane Library, and Web of Knowledge were used to screen the eligible studies evaluating the clinical efficacy and safety of triple therapy for patients with uHCC up to April 25th 2022, as well as Chinese databases. The endpoints were the complete response (CR), objective response rate (ORR), disease control rate (DCR), conversion rate, progression-free survival (PFS) rate, overall survival (OS) rate, and the incidence of adverse events (AEs).ResultsA total of 15 studies were eligible with 741 patients receiving transarterial chemoembolization (TACE) or hepatic arterial infusion chemotherapy (HAIC) combined with TKIs and ICIs. The pooled rate and 95% confidence interval (CI) for CR, ORR, and DCR were 0.124 (0.069–0.190), 0.606 (0.528–0.682), and 0.885 (0.835–0.927). The pooled rates for PFS at 0.5 years and 1 year were 0.781 (0.688–0.862) and 0.387 (0.293–0.486), respectively. The pooled rates for OS at 1, 2, and 3 years were 0.690 (0.585–0.786), 0.212 (0.117–0.324), and 0.056 (0.028–0.091), respectively. In addition, the pooled rate and 95%CI for the conversion surgery was 0.359 (0.153–0.595). The subgroup analysis of control studies showed that triple therapy was superior to TACE+TKIs, TKIs+ICIs, and TKIs in CR, ORR, and DCR, conversion rate; PFS; and OS. No fatal AEs were reported, and the top three most common AEs were elevated ALT, elevated AST, and hypertension, as well as severe AEs (grading ≥3).ConclusionWith the current data, we concluded that the triple therapy of TACE/HAIC, TKIs, and ICIs would provide a clinical benefit for uHCC both in short- and long-term outcomes without increasing severe AEs, but the conclusion needs further validation.Systematic Review Registrationhttp://www.crd.york.ac.uk/PROSPERO/, Review registry: CRD42022321970.

Transcatheter arterial chemoembolization plus apatinib with or without camrelizumab for unresectable hepatocellular carcinoma: a multicenter retrospective cohort study

“…The combination of TACE (or hepatic arterial infusion chemotherapy), TKIs and ICIs has been shown to be effective in unresectable HCC, according to a systematic review that included 15 retrospective studies [14]. However, all of Two groups were compared using log-rank test these studies suffered from small sample size, with only 22-86 patients included.…”

Outcomes and prognostic factors in initially unresectable hepatocellular carcinoma treated using conversion therapy with lenvatinib and TACE plus PD-1 inhibitors

“…The triple-combination LTP is a trend in conversion therapy for patients with iuHCC ( 5 ). However, LTP provides improved treatment outcomes while challenging the prediction of successful conversion surgery and prognosis.…”

“…Conversion therapy aims to provide an improved prognosis by converting unresectable hepatocellular carcinoma for a chance to receive curative surgery. In clinical practice, multidrug combination therapy has been explored in intermediate to advanced HCC (3)(4)(5). Lenvatinib combined with transcatheter arterial chemoembolization (TACE) plus programmed cell death protein-1 (PD-1) inhibitors (LTP) has shown improved prognosis in initially unresectable hepatocellular carcinoma(iuHCC) (5)(6)(7).…”

“…In clinical practice, multidrug combination therapy has been explored in intermediate to advanced HCC (3)(4)(5). Lenvatinib combined with transcatheter arterial chemoembolization (TACE) plus programmed cell death protein-1 (PD-1) inhibitors (LTP) has shown improved prognosis in initially unresectable hepatocellular carcinoma(iuHCC) (5)(6)(7). The objective response rate of LTP are higher than those of TACE alone and TACE combined with lenvatinib (6,7).…”

Adjuvant therapy following curative treatments for hepatocellular carcinoma: current dilemmas and prospects

“…Triple therapy such as TACE or HAIC combined with TKIs and ICIs has also achieved promising results in the treatment of advanced HCC, but AEs is a more important issue to be aware of. A recent meata analysis of triple therapy suggests that triple therapy is more likely to cause liver function abnormalities and that some potential AEs cannot be evaluated ( 101 ). Patients who have undergone surgical trauma have fragile liver function, especially for patients with severe cirrhosis, postoperative adjuvant therapy should not be used blindly as combination therapy or interventional therapy in pursuit of efficacy alone.…”