Liver Cancer最新文献

Background and aims: Treatment options for steatotic liver disease (SLD) are limited compared to those for viral hepatitis, which may affect the prognosis of patients with hepatocellular carcinoma (HCC).

Methods: This retrospective cohort study included 255 and 125 patients with SLD-related HCC and viral-controlled HCC (80 hepatitis C and 45 hepatitis B) who underwent curative radiofrequency ablation (RFA) for primary HCC (maximum tumor diameter ≤3 cm and ≤3 lesions). Viral control was defined as a sustained virological response to hepatitis C and undetectable hepatitis B viruses on a nucleos(t)ide analog before HCC diagnosis. Overall survival, recurrence rates, and hepatic decompensation rates were evaluated using the Kaplan-Meier method and Cox proportional hazard models between the two groups. Validation was performed in a surgical cohort of 120 patients (70 with SLD and 50 controls).

Results: The 1-, 3-, and 5-year survival rates were 97%, 81%, and 62% for patients with SLD-related HCC, and 100%, 94%, and 89% for viral-controlled patients in the RFA cohort, respectively (p < 0.001, log-rank test). Multivariate analysis showed no significant difference in recurrence between the two groups (adjusted hazard ratio [aHR] 1.06, p = 0.75); however, a higher risk of hepatic decompensation was observed in patients with SLD-related HCC (aHR 6.17; p < 0.001) and a worse overall survival (aHR 2.04; p = 0.003). Similar results were observed in the surgical cohort.

Conclusion: Patients with SLD-related HCC have a higher risk of decompensation than viral-controlled patients with HCC, which leads to a worse overall survival.

Background: The clinical complexity of patients with hepatocellular carcinoma (HCC), the availability of multiple therapeutic options, and clinical therapeutic intents could make it challenging to identify an unequivocal limit between conversion, downstaging/downsizing, and neoadjuvant therapies and curative or palliative intent treatments and to dimension the most proper sequential therapeutic strategy for each patient.

Summary: The concept of converse therapeutic hierarchy could rationally embrace all the different sequential treatment options (e.g., from surgery to systemic therapy) and the different therapeutic clinical intents (e.g., curative, neoadjuvant, downstaging/downsizing, conversion, and palliative), sharing the common goal of converting the patient with HCC from a less to a more favourable condition to improve the chance (higher applicability - conversion or downstaging intent) or the effectiveness (better postoperative outcome - neoadjuvant intent) of "intent-to-cure treatments." This narrative review aims to introduce and explain the umbrella concept of the converse therapeutic hierarchy as a valuable framework for everyday clinical practice, enabling clinicians to better define ideal candidates and good responders for each sequential strategy. Furthermore, the converse therapeutic hierarchy concept represents a flexible container that should be continuously filled with new scientific evidence to build different sequential treatment strategies in the multidisciplinary and multi-step management of patients with HCC. An operative and pragmatic definition of the various sequential treatment strategies, based on the initial probability of intent to cure therapy for patients with HCC, has also been proposed. This probability varies from very high to low. It is related to the initial treatment choice and the multiparametric patient evaluation (e.g., patient's fitness, tumour features, liver function, and technical aspects) done by an expert multidisciplinary tumour board.

Key messages: The converse therapeutic hierarchy concept represents a valuable and pragmatic framework for everyday clinical practice. It also serves as a flexible container that must be filled with new high-quality evidence and expert consensus to better define the clinical boundaries between the different HCC sequential treatment strategies (e.g., neoadjuvant, downstaging/downsizing, and conversion).

Introduction: Lenvatinib effectively manages unresectable hepatocellular carcinoma (HCC). Current prognostic models do not integrate tumor burden with liver function. By combining the Up-to-7 criteria and the albumin-bilirubin (ALBI) grade, we developed the Up7-ALBI score, a novel scoring system for predicting survival outcomes in patients with unresectable HCC receiving lenvatinib.

Methods: This multicenter, retrospective study analyzed 205 patients with unresectable HCC. Tumor burden and liver function were assessed using the up-to-7 criteria and the ALBI grade, respectively. Cox proportional-hazards models evaluated their impact on survival. The Up7-ALBI score was developed to categorize patients into distinct prognostic groups. Its prognostic value was validated in a cohort of HCC patients receiving immunotherapy.

Results: The overall response rate (assessed as per the Response Evaluation Criteria in Solid Tumors [RECIST] 1.1 criteria) was 13.2%. This rate was significantly higher for patients without metastases (18.6%) and those with a radiologic tumor burden within the up-to-7 criteria (22.7%). The median progression-free survival and overall survival (OS) were 7.3 and 12.2 months, respectively. Exceeding the up-to-7 criteria (hazard ratio [HR]: 1.61; 95% confidence interval [CI]: 1.00-2.57) and an ALBI grade of 2 or 3 (HR: 1.62; 95% CI: 1.06-2.47) emerged as independent risk factors of OS. A novel Up7-ALBI score stratified patients into low-, intermediate-, and high-risk groups for survival (30.8 vs. 14.2 vs. 9.3 months; p < 0.01). A validation cohort of 58 HCC patients with immunotherapy showed the consistent prognostic value of Up7-ALBI score. The Akaike information criterion value of the Cox proportional-hazards model for BCLC stage, ALBI grade, and Up7-ALBI score was 1,203, 1,174, and 1,170, respectively.

Conclusion: The Up7-ALBI score, incorporating tumor burden and liver function, effectively stratified survival outcomes in HCC patients treated with lenvatinib. Further validation in larger cohorts and across different systemic therapies is required to confirm its broad clinical applicability.

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.