Liver Cancer最新文献

Background: Outcomes of patients with unresectable hepatocellular carcinoma (HCC) who achieve clinical complete response (cCR) to PD-1 inhibitor-based combination therapy are unclear. This study aimed to explore whether cCR after combination therapy is an accurate and reliable prognostic indicator and to identify predictors of cCR and pathological complete response that could aid in managing patients with HCC.

Methods: Data were analyzed retrospectively for 1,266 patients with initially unresectable HCC who received combination therapy involving PD-1 inhibitors and interventional therapy at 23 medical centers across China between 2019 and 2023. Survival was compared between patients who showed cCR or not after combination therapy, and subgroup analyses differentiated further between patients who experienced pathological complete response or not after combination therapy and patients who subsequently underwent curative hepatectomy or not.

Results: Among all patients, 200 (15.8%) achieved cCR after combination therapy, and 360 (28.4%) underwent curative hepatectomy following combination therapy. Survival rates at 3 years were significantly higher among those who achieved cCR after combination therapy than those who did not, whether overall survival (82.4 vs. 35.9%; HR 0.15, 95% CI: 0.12-0.19) or progression-free survival (63.4 vs. 26.4%; HR 0.19, 95% CI: 0.16-0.23). Similar results were obtained with subsets of patients matched through propensity scoring based on baseline characteristics. Patients who underwent hepatectomy showed significantly longer overall and progression-free survival than those who did not; and among those who underwent surgery, cCR after combination therapy was associated with significantly better survival. Multivariable analysis identified the following independent predictors of cCR: α-fetoprotein <400 ng/mL, single tumor, absence of macrovascular invasion, absence of extrahepatic metastasis, and combined with anti-angiogenic agents. cCR correlated strongly with pathological complete response (Φ = 0.633) and independently predicted it (OR 17.43, 95% CI: 5.69-53.35).

Conclusions: cCR following PD-1 inhibitor-based combination therapy is associated with excellent survival in patients with unresectable HCC. Such response and the clinical characteristics that predict it may be useful for assessing prognosis after combination therapy.

Introduction: The outcomes and optimal postoperative management of patients with initially unresectable hepatocellular carcinoma (uHCC) who achieve pathological complete response (pCR) after systemic therapy and curative resection remain undefined.

Methods: This multicenter retrospective cohort study included consecutive patients with initially uHCC who received systemic therapy followed by curative resection at three tertiary centers in China between January 2020 and December 2023. The primary outcome was overall survival (OS); secondary endpoints included recurrence-free survival (RFS) and incidence of treatment-related adverse events (AEs).

Results: Of the 2,212 patients who underwent conversion surgery, 1,623 (73.4%) received systemic therapy-based regimens; among them, 257 (15.8%) patients achieved pCR and were included in the analysis. The median tumor diameter was 9.0 cm; 39.7% had multifocal tumors, 55.6% presented with macrovascular invasion, and 70.4% were AFP-positive. Most patients (87.2%) received combination regimens based on immune checkpoint inhibitors. Postoperative adjuvant therapy was administered in 88 (34.2%) patients for a median duration of 6.05 months. After a median follow-up of 32.7 months, the 1-, 3-, and 5-year RFS rates were 81.7%, 60.3%, and 58.3%, and OS rates were 98.0%, 91.1%, and 85.5%, respectively. No significant differences in RFS or OS were observed between the adjuvant and active surveillance groups, though AEs occurred more frequent in the adjuvant group. Subgroup analyses failed to identify any population with clear benefit from adjuvant therapy. On multivariate analysis, postoperative alpha-fetoprotein (AFP) positivity was independently associated with inferior RFS and OS.

Conclusions: Patients with uHCC who achieve pCR after systemic therapy and curative resection exhibit favorable long-term outcomes. Active surveillance yields comparable survival to adjuvant therapy with reduced toxicity. A "Tumor-Free with Drug-Free" strategy may be feasible in patients with normalized postoperative AFP levels, while those with persistent AFP positivity may represent a high-risk subgroup requiring individualized postoperative management.

Introduction: The majority of patients with hepatocellular carcinoma (HCC) are diagnosed at an intermediate stage, and current treatment options are associated with unfavourable overall prognosis. This study aimed to evaluate the efficacy of conversion therapy before resection compared with direct resection or comprehensive therapy alone in patients with intermediate-stage HCC, with a focus on pathological responses and long-term outcomes.

Methods: In this multicentre study, 248 patients diagnosed with intermediate-stage HCC between January 2020 and December 2023 were enrolled. Of these, 56 patients received preoperative conversion therapy followed by resection (conversion resection group), 162 underwent direct resection (direct resection group), and 30 received comprehensive therapy alone and did not undergo surgical resection (comprehensive therapy group). Propensity score matching was performed to balance the baseline characteristics, and pathological responses were systematically evaluated.

Results: Among conversion resection group, 13 patients (23.2%) achieved a pathological complete response, and 29 (51.8%) achieved a major pathological response. The conversion resection group exhibited significantly lower microvascular invasion rates (17.9% vs. 58.6%, p < 0.001) and higher tumour differentiation grades (p < 0.001). The median recurrence-free survival (RFS) was markedly improved in the conversion resection group (not reached vs. 12.3 months, p < 0.001), with 3-year overall survival (OS) rates of 94.7% vs. 77.6% vs. 43.9% being observed in the conversion resection group, direct resection group and comprehensive therapy group, respectively (p < 0.001). Multivariate analysis identified conversion therapy as an independent prognostic factor for both RFS (HR: 0.241, p < 0.001) and OS (HR: 0.179, p = 0.006).

Conclusions: Preoperative conversion therapy could significantly improve pathological responses and long-term survival outcomes in intermediate-stage HCC patients.

Introduction: The development of targeted therapies and immune checkpoint inhibitors for advanced hepatocellular carcinoma (HCC) reinforces the need for individualized treatment. However, precision medicine is hindered by the lack of mandatory tissue biopsy for genomic profiling in HCC. Liquid biopsy enables genomic profiling of circulating tumor DNA (ctDNA), which could compensate for the lack of tissue-based analysis. This study evaluated the concordance between ctDNA and tumor tissue genomic profiling and its feasibility in advanced HCC treated with atezolizumab plus bevacizumab (atezo/bev).

Methods: This cohort study prospectively collected pretreatment plasma samples from 130 patients with advanced HCC who underwent tissue-based sequencing before systemic therapy from June 2020 to October 2022. Tumor tissue sequencing was performed using the Oncomine Comprehensive Assay, and ctDNA sequencing was conducted using Guardant360.

Results: ctDNA variants revealed 72.6% (69/95; 95% CI, 62.9-80.6%) sensitivity and 75.0% (69/92; 95% CI, 65.3-82.7%) positive predictive value compared to tumor tissue. With an interval of ≤30 days between ctDNA and tumor tissue sampling, the sensitivity increased to 96.3% (26/27; 95% CI, 81.7-99.3%). In patients treated with first-line atezo/bev, maximum variant allele frequency (maxVAF) of ctDNA was significantly correlated with poor survival outcomes even after adjustment for clinicogenomic variables.

Conclusion: In advanced HCC, ctDNA-based genotyping demonstrated clinically acceptable concordance with tissue-based profiling, providing a reliable alternative when tissue samples are limited. Additionally, ctDNA maxVAF demonstrated independent prognostic value in patients treated with first-line atezo/bev. Liquid biopsy using ctDNA can help address challenges associated with limited tissue-based genomic profiling in advanced HCC.

Background: Cabozantinib is recommended after sorafenib failure in systemic therapy of hepatocellular carcinoma (HCC), based on the results of CELESTIAL. Herein, CLERANCE was designed to evaluate the safety and efficacy of cabozantinib after prior sorafenib failure in real-life setting.

Methods: This prospective French multicenter phase-4 trial (NCT03963206) recruited 110 patients with unresectable HCC when a decision of cabozantinib was made in tumor board. The primary endpoint was incidence of grade-3/4 treatment-related adverse events (TRAEs). Secondary endpoints included overall survival, objective response rate, progression-free survival, time to progression, and profiles of cabozantinib tolerance and management.

Results: Final analysis focused on the 99 patients who started cabozantinib. Patients were mainly males, Child-Pugh A, and modified-ALBI grade-1/2a/2b. Sorafenib had been discontinued after 4.2 months median administration. Grade-3/4 TRAEs were reported in 61.3% of patients. The objective response rate was 7% with 58% of disease control rate, and median progression-free survival 6.2 months, time to progression 8.2 months, overall survival 11.5 months since the start of cabozantinib and 23.2 months since the start of the first systemic line. Baseline modified-ALBI grade-1+2a and alpha-fetoprotein <400 ng/mL were independent markers of better outcome in multivariate analysis. The median duration of cabozantinib administration was 5.2 months, median daily dose 40 mg, 66% patients needing dose reductions.

Conclusions: In CLERANCE, tolerability and efficacy of cabozantinib were similar to those observed in CELESTIAL. We obtained more details in the management of cabozantinib doses, identified surrogate markers of better outcome, and underlined prolonged overall survival for patients able to undergo subsequent lines.

Background: Our previous epidemiological study revealed a significantly higher incidence of liver angiosarcoma in Asian patients than that in their European counterparts. Elucidating the etiology and hallmarks of this aggressive malignancy may offer insights into the development of novel therapeutic strategies.

Methods: We analyzed samples from liver and non-liver angiosarcoma patients treated at the National Taiwan University Hospital, as well as data from the angiosarcoma cohort of the Count Me In Project. Hepatocellular carcinoma (HCC) samples were used as controls for liver tumors. Whole-exome sequencing and de novo extraction of single-base substitution mutation signatures were performed. Transcriptomic profiling was used to assess oncogenic pathways and the tumor microenvironment. Telomere lengths were estimated using TelSeq and telomeric repeat-containing RNA levels were quantified using TERRA-QUANT.

Results: De novo extraction identified four mutation signatures (A-D). Signature A exhibited high similarity to SBS22 (cosine similarity = 0.93), which was associated with aristolochic acid exposure. This signature showed a significantly greater contribution to liver angiosarcoma and HCCs but not to non-liver angiosarcomas. According to the mSigAct analysis, 80% (8/10) of liver angiosarcoma cases displayed a significant SBS22 signature. Moreover, liver angiosarcomas demonstrated a significantly higher tumor mutation burden, increased frequencies of TP53 and ATRX mutations, and greater T-cell infiltration than non-liver angiosarcomas. Telomere length was significantly longer in liver angiosarcomas than in matched normal tissues, a pattern that was not observed in Taiwanese non-liver angiosarcomas or HCCs. Notably, liver angiosarcomas exhibited markedly lower telomerase activity than their non-liver counterparts and HCCs, suggesting a reliance on the alternative lengthening of telomere (ALT) pathway.

Conclusion: Our study provides compelling evidence that aristolochic acid exposure is associated with liver angiosarcoma, and elaboration of ALT activation in liver angiosarcomas offers new insights into their underlying biology and may guide the development of targeted therapeutic approaches.

Background: Rechallenge with immune checkpoint inhibitors (ICIs) has recently emerged as a potential therapeutic strategy for patients with hepatocellular carcinoma (HCC) who discontinue initial immunotherapy due to disease progression, immune-related adverse events (irAEs), or treatment completion. However, there are no standardized rechallenge regimen, patient indications, and few studies on its mechanism.

Summary: This review provided a comprehensive, up-to-date summary on the clinical evidence, treatment regimens, patient characteristics, and biological rationale underlying ICI rechallenge for HCC patients. Current studies have identified four main rechallenge strategies according to the combinations of agents used in the initial and rechallenge treatments, most of which involve targeted therapy combined with anti-PD-L1 or dual ICIs. Across published studies, ICI rechallenge has shown variable but notable antitumor activity with an acceptable safety profile. Clinical benefits appear to be more frequently observed in HCC patients with preserved liver function, age <60 years, and lower tumor burden, although these findings require cautious interpretation due to interstudy heterogeneity and potential selection bias. Mechanistic investigations suggest that renewed immune activation may result from immunogenic cell death, tumor microenvironment remodeling, and reexpression of inhibitory checkpoints such as PD-L1 or CTLA-4, thereby restoring antitumor immunity.

Key messages: ICI rechallenge represents a rational and feasible therapeutic option for selected HCC patients, providing an opportunity to achieve additional clinical benefit after initial ICI resistance or discontinuation. Although the frequency of irAEs may increase, most events remain manageable with vigilant monitoring and timely intervention. Future research should focus on optimizing regimen selection, refining predictive biomarkers, and elucidating the molecular basis of immune reactivation to guide individualized ICI rechallenge strategies and expand their clinical applicability.

[This corrects the article DOI: 10.1159/000535943.].

Background: Systemic therapy containing immune checkpoint inhibitors (ICIs) has become the standard of care for patients with advanced hepatocellular carcinoma (HCC). A prior analysis from the pre-ICI era demonstrated a moderate correlation between progression-free survival (PFS) and overall survival (OS). We performed a literature-based meta-analysis to include randomized phase III trials (RCTs) of ICIs to evaluate surrogate endpoints for OS in advanced HCC.

Methods: RCTs evaluating systemic therapies in advanced HCC published/presented between 2007 and 2024 were identified through a systemic literature search. Hazard ratios (HRs) for OS and PFS were extracted. The change in the overall response rates (ΔORR) was calculated as the difference between experimental and control arms. Pearson correlation and mixed-effects meta-regression analyses were performed. Strength of correlation was determined using the criteria from the Institute for Quality and Efficiency in Health Care (IQWIG). Surrogate threshold effect (STE) was determined for each comparison when possible. Subgroup analysis was performed. A p < 0.05 was considered to be statistically significant.

Results: In total, 21 1st-line and 12 2nd-line RCTs were included. Of 1st-line RCTs, 48% evaluated ICIs either alone or in combination. There was a weak correlation between HR-PFS and HR-OS (n = 18, r = 0.64, 95% confidence interval (CI): 0.25-0.85, p = 0.004) and no correlation between ΔORR and HR-OS (n = 21, r = 0.42, 95% CI: -0.01 - 0.72, p = 0.06). The STE for HR-PFS was 0.68. Subgroup analyses revealed a moderate correlation between HR-PFS and HR-OS in 1st-line RCTs enrolling fewer patients with nonviral etiology (n = 9, r = 0.75, 95% CI: 0.17-0.94, p = 0.02). There was, however, a strong correlation between HR-PFS and HR-OS in 2nd-line RCTs (n = 10, r = 0.90, 95% CI: 0.61-0.98, p < 0.001). The STE for HR-PFS in 2nd-line RCTs was 0.87.

Conclusion: The correlation between HR-PFS and HR-OS is weak in 1st-line RCTs in advanced HCC where OS remains the most appropriate endpoint. There is a strong association between HR-PFS and HR-OS for 2nd-line RCTs, suggesting that PFS is a suitable surrogate endpoint in that setting.