Liver Cancer最新文献

Background: Multidisciplinary treatment of hepatocellular carcinoma (HCC) has made notable advancements with the emergence of novel agents for systemic therapies, including receptor tyrosine kinase inhibitors (TKIs) and cancer immuno-oncology (IO) therapy utilizing immune checkpoint inhibitors. Although each of these regimens is effective as monotherapy for advanced HCCs, combining them with locoregional therapy (LRT), such as transarterial chemoembolization (TACE), hepatic arterial infusion chemotherapy (HAIC), and radiotherapy (RT), provides an additional antitumor effect. The emergence of novel systemic therapies has given rise to anticipation for the development of multidisciplinary treatments with a combination of systemic therapy and LRT, which aim to achieve curative-intent resection and improve long-term prognosis after resection.

Summary: Perioperative combination therapy, a combination of multiple treatment modalities including systemic therapy (TKI and/or IO) and LRT (TACE, HAIC, or RT), is attracting attention as a potentially useful approach for multidisciplinary curative-intent surgical resection or ablation. Currently, there is no evidence-based guidance regarding selection criteria and optimal regimens for perioperative combination therapy. The definition of oncological resectability for HCC is being pursued to establish the indication and protocol for perioperative combination therapy, which broadly encompasses conversion as well as neoadjuvant and adjuvant therapy for intermediate-to-advanced HCC.

Key messages: Perioperative combination therapy, which positions curative-intent surgical resection or ablation within the combination of multiple modalities including systemic therapy and LRT, provides perspectives for improving the long-term prognosis of patients with initially unresectable HCC and borderline resectable HCC with a high risk of recurrence.

Introduction: Uncertainty exists regarding whether hepatectomy enhances the prognosis for initially unresectable hepatocellular carcinoma (HCC) that becomes resectable subsequent to conversion therapy. This study conducted a comparative analysis of survival rates between patients who underwent hepatectomy and those who did not, following complete or partial response to conversion therapy.

Methods: This retrospective study examined 300 patients with HCC who underwent hepatectomy following conversion therapy, along with 265 nonsurgical control subjects (215 receiving locoregional/systemic therapy and 50 under active surveillance) across 20 Chinese medical centers from 2019 to 2023. The primary outcomes assessed included overall survival (OS), event-free survival (EFS), recurrence-free survival, and the rate of complete pathological response.

Results: Hepatectomy was associated with significantly better OS than locoregional or systemic therapy or active surveillance (the 3-year OS rates were 79.9% and 58.5%, respectively, p < 0.001) but comparable EFS (median: 40.6 vs 33.4 months, p = 0.403). These results were confirmed after analyzing subgroups matched to each other based on propensity scoring. Among patients who underwent hepatectomy, those who responded completely to conversion therapy showed significantly better OS than those who responded partially (HR: 0.40, 95% CI: 0.21-0.75) as well as significantly better EFS (HR: 0.45, 95% CI: 0.29-0.70). Among patients who did not undergo hepatectomy, OS and EFS were comparable between those who responded partially and those who responded completely to conversion therapy. Additionally, locoregional or systemic therapy showed significantly better results in terms of OS and EFS compared to active surveillance. Of the patients who underwent hepatectomy, 116 (38.7%) showed complete pathological response. In patients underwent hepatectomy, those who experienced complete pathological response showed significantly better OS than those who did not (HR: 0.34, 95% CI: 0.18-0.65) as well as significantly better recurrence-free survival (HR: 0.38, 95% CI: 0.25-0.59).

Conclusions: Hepatectomy can provide a significant OS benefit to patients with initially unresectable HCC that responds partially or completely to conversion therapy.

Introduction: Magnetic resonance imaging (MRI) has been shown to outperform computed tomography (CT) in diagnosing hepatocellular carcinoma (HCC), although inconsistencies exist across studies. We compared the performance of CT and gadoxetic acid-enhanced MRI in diagnosing HCC according to various guidelines, and to assess the incremental value of a second-line examination.

Methods: This retrospective multicenter study included patients at risk of developing HCC with focal liver lesions (FLLs) ≥10 mm. These patients underwent both contrast-enhanced CT and gadoxetic acid-enhanced MRI between January 2015 and June 2018. Four radiologists independently assessed the images using criteria from the Liver Imaging Reporting and Data System (LI-RADS), the Asian Pacific Association for the Study of the Liver (APASL), and the Korean Liver Cancer Association-National Cancer Center (KLCA-NCC) guidelines. The diagnostic performance of CT and MRI was compared across guidelines.

Results: In total, 1,590 FLLs (median size, 22.6 mm) were analyzed in 1,455 patients (median age, 59 years; male, 1,101). Sensitivity was higher with MRI than with CT for APASL (89.3% [95% CI: 87.7%, 90.8%] vs. 78.9% [95% CI: 77.0%, 80.8%], respectively) and KLCA-NCC (78.7% [95% CI: 76.7%, 85.0%] vs. 73.7% [95% CI: 71.6%, 75.7%], respectively) (p = 0.002 for both). However, LI-RADS showed lower sensitivity with MRI than with CT (70.6% [95% CI: 68.4%, 72.6%] vs. 74.7% [95% CI: 72.6%, 76.7%], p = 0.002), due to fewer nonperipheral washout. MRI re-categorized 22.4%, 32.2%, and 53.5% of non-HCC observations on CT as HCC with LI-RADS, KLCA-NCC, and APASL, respectively. CT re-classified 30.2%, 29.0%, and 25.8% of non-HCC observations on MRI as HCC with LI-RADS, KLCA-NCC, and APASL, respectively.

Conclusion: The added value of gadoxetic acid-enhanced MRI after CT depends on the diagnostic criteria used. Restricting washout timing to the portal venous phase in LI-RADS reduces the sensitivity of gadoxetic acid-enhanced MRI relative to CT.

Introduction: A previous phase 3 FOHAIC-1 study demonstrated that hepatic arterial infusion chemotherapy (HAIC) of FOLFOX regimen displayed favorable outcomes in advanced hepatocellular carcinoma (HCC) patients, including those with high-risk features (main portal tumor invasion and >50% liver infiltration). This study aimed to compare the treatment efficacy of HAIC-FOLFOX versus atezolizumab-bevacizumab in HCC patients.

Methods: Individual patient data from the Chinese FOHAIC-1 study and aggregate data from the global IMbrave150 study were used to conduct an anchored matching-adjusted indirect comparison. Hazard ratios (HR) and restricted mean survival times (RMST) were calculated to assess survival differences. Landmark analysis was performed to evaluate time-sensitive treatment effects, and simulated treatment comparison (STC) was conducted as a sensitivity analysis. Rates of treatment-related adverse events (TRAEs) and TRAE-related discontinuations were also compared.

Results: After matching baseline characteristics, HAIC showed a numerical OS benefit (HR 0.57, 95% CI, 0.30-1.08) and similar PFS benefit (HR 0.79, 95% CI, 0.43-1.47) compared to atezolizumab-bevacizumab in the overall population. In high-risk patients, HAIC demonstrated significantly improved OS (HR 0.30, 95% CI, 0.12-0.72) and 2.89-month longer RMST compared to atezolizumab-bevacizumab (95% CI, 0.15-5.64 months). Additionally, HAIC showed superior PFS (HR 0.25, 95% CI, 0.10-0.64) and 2.88-month longer RMST over atezolizumab-bevacizumab (95% CI, 0.90-4.86). Landmark analysis in the high-risk group revealed that HAIC was associated with significant improvements in both OS (HR 0.32, 95% CI, 0.13-0.79) and PFS (HR 0.24, 95% CI, 0.09-0.63) during the 0-12 months following treatment initiation. Sensitivity analysis using the anchored STC analysis yielded consistent results. HAIC was associated with lower rates of grade 3-4 TRAEs and TRAE-related discontinuation in both the overall population and the high-risk group.

Conclusion: HAIC treatment provided superior survival benefits and a favorable safety profile compared to atezolizumab-bevacizumab in high-risk HCC patients.

Introduction: Mutations in circulating nucleic acids can be used as biomarkers for the early detection and management of hepatocellular carcinoma (HCC). However, while circulating tumor DNA and microRNA have been extensively explored, circulating tumor mRNA and circulating mRNA mutants (ctmutRNA), which may provide advantages over other analytes, remain less well described. We previously reported the identification of 288 HCC selective ctmutRNA variants, called "candidates," from a small cohort of HCC patients using total RNAseq. The objective of the current study was to use targeted RNAseq to validate the specificity and sensitivity of these HCC selective variants in an independent cohort of patients with liver cirrhosis (LC).

Methods: Several methods to isolate small extracellular vesicles and amplify mRNA from the circulation were compared. RNA was isolated, and the primers and probes selective for the 288 regions of interest were used with RNA from HCC (N = 50) and LC and no HCC (N = 35) patients. HCC tumor tissues (N = 11), a normal liver tissue and 3 cell lines were also studied. cDNA synthesis was followed by library construction using QIAseq RNA Fusion XP panel. QC analysis was carried out with an Agilent Bioanalyzer before sequencing on a NextSeq 550 instrument. A GATK HaplotypeCaller was used for variant calling and annotation carried out using snpEff.

Results: Among the test panel of 288 ctmutRNA candidates in the original cohort, 75 were detected in the new cohort of plasma samples. Moreover, 388 other variants in proximity to the original lesions were also found in multiple HCC but not LC plasma samples. A subset of 36 HCC selective variants was able to identify all HCC patients. The most common tumor specific variants were Indels and SNPs. Novel mRNA fusion variants, corresponding to SENP7, HYI, SAR1A, RASA2, TUBA transcripts, etc., were identified in HCC and LC patients.

Conclusion: Circulating RNA could be a robust analyte for noninvasive early detection of HCC and circulating RNA panels could be powerful tools in the entire spectrum of clinical management.

Introduction: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths. Current international guidelines recommend 6-monthly ultrasound surveillance in all patients with cirrhosis and those with hepatitis B virus-related risk factors to detect early-stage HCC. However, it is unknown whether the benefits of surveillance are comparable across patient groups and underlying disease-related factors. We aimed to evaluate patient- and disease-related factors associated with HCC stage at diagnosis and survival in an ethnically diverse UK population.

Methods: This was a multicentre retrospective observational study including patients with newly diagnosed HCC between 2007 and 2020 from six UK centres. Cox proportional-hazards regression and multivariate logistic regression models were used.

Results: Overall, 1,780 HCC patients comprising 20.9% with ArLD, 29.7% with NAFLD, and 31.0% with viral hepatitis were analysed. Surveillance was associated with improved survival in patients with viral hepatitis but not in patients with ArLD and NAFLD. Surveillance was also associated with early-stage disease (BCLC stage 0 or A) at presentation in viral hepatitis but not in patients with ArLD. Females with ArLD were 2.5-fold more likely to present with early-stage HCC than males. Patients with NAFLD were more likely to develop HCC in the absence of cirrhosis. Type 2 diabetes was not associated with mortality, but metformin use did show survival benefit. Patients of white ethnicity had improved survival and were less likely to present with late-stage HCC compared to other ethnicities.

Conclusions: HCC surveillance as currently delivered was less effective for detecting early-stage HCC in patients with non-viral and non-cirrhotic liver disease. Gender and ethnicity influences stage at presentation and outcomes. HCC surveillance strategies are needed to refine risk stratification particularly in patients with NAFLD or without cirrhosis.

Introduction: In addition to radical resection, liver transplantation (LTx) is an effective treatment for hepatocellular carcinoma (HCC). However, tumor recurrence limits the efficacy of LTx in some patients. This study investigated the role of ¹⁸F-fludeoxyglucose (¹⁸F-FDG) positron emission tomography/computed tomography (PET/CT) in predicting the prognosis of patients with HCC after LTx.

Methods: A total of 278 consecutive patients with HCC who underwent pre-LTx PET/CT were divided into derivation (n = 178) and temporal validation (n = 100) cohorts and evaluated for PET/CT values, immunohistochemical (IHC) findings, and DNA sequencing of tumor tissues.

Results: Patients with post-LTx recurrence exhibited significantly higher tumor maximum standardized uptake values (SUVmax) in pre-LTx PET/CT scans. Receiver operating characteristic curve analyses identified the tumor SUVmax to liver SUVmax ratio (T_SUVmax/L_SUVmax) as the strongest predictor of post-LTx recurrence, with an optimal cutoff value of 1.43. Kaplan-Meier analyses demonstrated that a T_SUVmax/L_SUVmax >1.43 was associated with a shorter time to recurrence (TTR) and overall survival (OS) in both cohorts (p < 0.001 for both). Multivariate Cox regression analyses confirmed that T_SUVmax/L_SUVmax >1.43 was an independent risk factor for tumor recurrence in both cohorts. IHC revealed that T_SUVmax/L_SUVmax >1.43 correlated with higher Ki-67 and CK19 expression. DNA sequencing indicated that tumors with T_SUVmax/L_SUVmax >1.43 had more mutations and a higher TMB. Furthermore, T_SUVmax/L_SUVmax >1.43 was significantly associated with mutations in TP53, EPPK1, MDM4, SLAMF7, SDHC, B4GALT3, RXRG, and FCGR family genes, as well as TP53 and PI3K signaling-related alterations.

Conclusions: The preoperative T_SUVmax/L_SUVmax is a potential predictor of tumor recurrence in patients with HCC following LTx. Its use improves candidate selection and post-LTx management.