The emerging therapies are reshaping the first-line treatment for advanced hepatocellular carcinoma: a systematic review and network meta-analysis.

Background: Given the superior performance of various therapies over sorafenib in advanced hepatocellular carcinoma (HCC) and the absence of direct comparisons, it is crucial to explore the efficacy of these treatments in phase III randomized clinical trials. Objectives: The goal is to identify which patients are most likely to benefit significantly from these emerging therapies, contributing to more personalized and informed clinical decision-making. Design: Systematic review and network meta-analysis. Data sources and methods: PubMed, Embase, ClinicalTrials.gov, and international conference databases have been searched from 1 January 2010 to 1 December 2023. Results: After screening, 17 phase III trials encompassing 18 treatments were included. In the whole-population network meta-analysis, the newly first-line tremelimumab plus durvalumab (Tre + Du) was found to be comparable with atezolizumab plus bevacizumab (Atezo + Beva) in providing the best overall survival (OS) benefit [hazard ratio (HR) 1.35, 95% confidence interval (CI): 0.93-1.92]. Concerning OS benefits, sintilimab plus bevacizumab biosimilar (Sint + Beva), camrelizumab plus rivoceranib (Camre + Rivo), and lenvatinib plus pembrolizumab (Lenva + Pemb) appear to exhibit similar effects to Tre + Du and Atezo + Beva. In the context of progression-free survival, Atezo + Beva seemed to outperform Tre + Du (HR: 0.66 CI: 0.49-0.87), while the effects are comparable to Sint + Beva, Camre + Rivo, and Lenva + Pemb. Upon comparison between Asia-Pacific and non-Asia-Pacific cohorts, as well as between hepatitis B virus (HBV)-infected and non-HBV-infected populations, immune checkpoint inhibitor (ICI)-based treatments seemed to exhibit heightened efficacy in the Asia-Pacific group and among individuals with HBV infection. However, combined ICI-based therapies did not show more effectiveness than molecular-targeted drugs in patients without macrovascular invasion and/or extrahepatic spread. As for grades 3-5 adverse events, combined therapies showed comparable safety to sorafenib and lenvatinib. Conclusion: Compared with sorafenib and lenvatinib, combination therapies based on ICIs significantly improved the prognosis of advanced HCC and demonstrated similar safety. At the same time, the optimal treatment approach should be tailored to individual patient characteristics, such as etiology, tumor staging, and serum alpha-fetoprotein levels. With lower incidence rates of treatment-related adverse events and non-inferior efficacy compared to sorafenib, ICI monotherapies should be prioritized as a first-line treatment approach for patients who are not suitable candidates for ICI-combined therapies. Trial registration: PROSPERO, CRD42022288172.

Lay summary/Key points The efficiency of various systemic therapies in advanced HCC patients with specific characteristics remains to be explored. This study revealed that the efficacy of ICI combined therapies is influenced by factors such as tumor staging, etiology, patient demographics, and more. Additionally, ICI monotherapies should be prioritized as a first-line treatment approach for patients who are not suitable candidates for ICI combined therapies. Complementing to recent guidelines, this study indicated that several critical factors needed to be took into consideration for patients with advanced HCC.

Comparable Clinical Outcomes Between Transarterial Chemoembolization or Hepatic Arterial Infusion Chemotherapy Combined with Tyrosine Kinase Inhibitors and PD-1 Inhibitors in Unresectable Hepatocellular Carcinoma.

Purpose: To compare the treatment efficacy and safety of transarterial chemoembolization (TACE) or hepatic arterial infusion chemotherapy (HAIC) combined with tyrosine kinase inhibitors (TKIs) and programmed cell death protein-1 (PD-1) inhibitors for patients with unresectable hepatocellular carcinoma (HCC). Patients and Methods: 81 unresectable HCC patients were retrospectively analyzed, including 30 or 51 patients treated with either TKIs and PD-1 inhibitors combined with TACE (TTP) or HAIC (HTP), respectively. Tumor response and survival outcomes were compared. Results: The median overall survival (mOS) was 21.0 months in the TTP group and 15.0 months in the HTP group (P = 0.525; HR = 1.23; 95% CI 0.66-2.29). The median progression-free survival (mPFS) was 6.7 months in the TTP group and 9.9 months in the HTP group (P = 0.160; HR = 0.70; 95% CI 0.42-1.16). After Propensity Score Matching (PSM), the mOS was 21.0 months in the TTP group and 18.0 months in the HTP group (P = 0.644; HR = 1.20; 95% CI 0.56-2.58). The mPFS was 6.4 months in the TTP group and 15.0 months in the HTP group (P = 0.028; HR = 0.49; 95% CI 0.26-0.93). The disease control rate in overall response (90.2% vs 76.7%, P = 0.116, before PSM; 91.7% vs 75.0%, P = 0.121, after PSM) and intrahepatic response (94.1% vs 80.0%, P = 0.070, before PSM; 91.7% vs 79.2%, P = 0.220, after PSM) were higher in the HTP group than in the TTP group. Conclusion: Though including more advanced tumors, the clinical outcomes of HAIC combined with TKIs and PD-1 inhibitors are comparable to TACE-based combination therapy for unresectable HCC. Nevertheless, HTP significantly improved the PFS benefits in HCC patients with with large tumor burden or vascular invasion.

An integrated strategy for deciding open versus laparoscopic hepatectomy for resectable primary liver cancer.

BACKGROUND: Laparoscopic liver resection (LLR) is now widely performed in treating primary liver cancer (PLC) and yields equal long-term and superior short-term outcomes to those of open liver resection (OLR). The optimal surgical approach for resectable PLC (rPLC) remains controversial. Herein, we aimed to develop a nomogram to determine the most appropriate resection approach for the individual patient. METHODS: Patients with rPLC who underwent hepatectomy from January 2013 to December 2018 were reviewed. Prediction model for risky surgery during LLR was constructed. RESULTS: A total of 900 patients in the LLR cohort and 423 patients in the OLR cohort were included. A history of previous antitumor treatment, tumor diameter, tumor location and resection extent were independently associated with risky surgery of LLR. The nomogram which was constructed based on these risk factors demonstrated good accuracy in predicting risky surgery with a C index of 0.83 in the development cohort and of 0.76 in the validation cohort. Patients were stratified into high-, medium- or low-risk levels for receiving LLR if the calculated score was more than 0.8, between 0.2 and 0.8 or less than 0.2, respectively. High-risk patients who underwent LLR had more blood loss (441 ml to 417 ml) and a longer surgery time (183 min to 150 min) than those who received OLR. CONCLUSIONS: Patients classified into the high-risk level for LLR instead undergo OLR to reduce surgical risks and complications and patients classified into the low-risk level undergo LLR to maximize the advantages of minimally invasive surgery. TRIAL REGISTRATION: This study was registered in the Chinese Clinical Trial Registry (registration number: ChiCTR2100049446).

Cholesterol and C-reactive protein prognostic score predicted prognosis of immune checkpoint inhibitors based interventional therapies for intermediate-to-advanced hepatocellular carcinoma patients.

Serum cholesterol (CHO) and C-reactive protein (CRP) have been successfully used as prognostic predictors for several malignancies, respectively. However, the clinicopathological significance of CHO and CRP levels in hepatocellular carcinoma (HCC) patients treated with ICIs-based hepatic artery infusion chemotherapy (HAIC) remains unclear. Serum CHO and CRP levels were measured for a total of 152 HCC patients that had been treated with ICIs-based HAIC from February 2019 to April 2020. Efficacy was evaluated according to tumor response and survival. The median OS was not reached in the CHO-low subgroup and 17.7 months in the CHO-high subgroup (P = 0.015). The median OS was not reached in the CRP-low subgroup and 20.0 months in the CRP-high subgroup (P = 0.010). Univariate and multivariate Cox regression analysis demonstrated that both serum CHO and CRP levels were independent risk factors for the OS of HCC patients treated with ICIs-based HAIC (P < 0.05). Moreover, Cox regression analysis after Propensity Score Matching showed the similar results. CHO and CRP prognostic score (CCPS) combining CHO and CRP levels could significantly stratify HCC patients receiving ICIs-based HAIC into low-, intermediate-, and high-risk subgroups (P < 0.001). Patients in the risk subgroups reported similar disease control rates (P = 0.121) and significantly different overall response rates (low- vs intermediate- vs high-risk groups: 70.6 % vs 46.6 % vs 44.1 %, respectively, P = 0.038) according to modified Response Evaluation Criteria in Solid Tumors (mRECIST). The results of this study support the association between CCPS high risk with the response and OS for HCC patients receiving ICIs-based HAIC.

Preoperative serum ctDNA predicts early hepatocellular carcinoma recurrence and response to systemic therapies.

BACKGROUND: Circulating tumor DNA (ctDNA) can be useful in tumor diagnosis and surveillance. However, its value in hepatocellular carcinoma (HCC) patients receiving curative resection remains unknown. Here, we aim to determine the prognostic value of ctDNA in HCC patients. METHODS: A prospective cohort enrolled 258 HCC patients who underwent curative liver resection from April 1, 2019, to September 31, 2020. Blood samples were collected before surgery for the detection of ctDNA. RESULTS: The number of total mutant genes in ctDNA was associated with early tumor relapse (HR = 2.2, p < 0.001). We defined a gene set consisting of APC, ARID1A, CDKN2A, FAT1, LRP1B, MAP3K1, PREX2, TERT and TP53 as high-risk genes (HRGs) associated with early recurrence. Patients were classified into low-, median- and high-risk levels based on the number of mutant genes in the HRGs. High-risk patients had worse recurrence free survival, especially single-tumor patients (HR = 13.0, p < 0.001). The risk level and TNM stage were independently associated with tumor recurrence. A preoperative recurrence estimation nomogram based on those two factors was constructed and demonstrated good accuracy with a C index of 0.76 (95% CI 0.70-0.82). Patients preserved FAT1 or LRP1B variants but without TP53 variants had worse progression free survival for receiving lenvatinib combined with immune checkpoint inhibitors after recurrence (HR = 17.1, p < 0.001). Furthermore, RNA sequencing data revealed that ctDNA status was associated with tumor immune infiltration. CONCLUSION: Preoperative serum ctDNA can be a practical noninvasive approach to predict recurrence after surgery and response to systemic therapies. ctDNA-guided HCC management should be recommended.

Baseline HBV Loads Do Not Affect the Prognosis of Patients with Hepatocellular Carcinoma Receiving Anti-Programmed Cell Death-1 Immunotherapy.

BACKGROUND: A high hepatitis B virus (HBV) load is a common exclusion criterion in hepatocellular carcinoma (HCC) clinical trials for anti-programmed cell death (PD)-1 immunotherapy. However, the validity of this criterion is barely verified. This study aimed to evaluate the impact of baseline HBV DNA levels and antiviral therapy on the oncological outcomes and liver functions of patients with HCC receiving anti-PD-1 immunotherapy. METHODS: We reviewed HCC trials related to anti-PD-(L)1 immunotherapy and whether they ruled out patients with increased HBV loads on clinicaltrials.gov. Then, for this retrospective study, we enrolled 253 HCC patients treated with anti-PD-1 blockade in our institution. Baseline information was compared between patients with low and high HBV loads. Overall survival (OS) and progression-free survival (PFS) were compared, and univariate and multivariate analyses were applied to identify potential risk factors for oncological outcomes and hepatic impairment. RESULTS: Among 76 HCC clinical trials including 13,927 patients receiving anti-PD-(L)1 blockade, 41 (53.9%) excluded patients with relatively high baseline HBV loads. The PFS and OS did not differ significantly between patients with baseline HBV loads ≤ 2000 IU/mL and those with viral loads >2000 IU/mL (p=0.615 and 0.982). The incidence of hepatic impairment showed no association with the baseline HBV load (p=0.319). Patients receiving antiviral therapy had a better OS than those without antiviral therapy in the high baseline HBV load group (p= 0.001). CONCLUSION: High HBV loads did not compromise the clinical outcomes of HCC patients receiving anti-PD-1 blockade. Antiviral therapy could improve the OS of HCC patients with high HBV loads.