Liver Cancer最新文献

Introduction: Intermediate-stage hepatocellular carcinoma (HCC) presents varying tumor burdens. For patients unsuitable for transcatheter arterial chemoembolization (TACE) due to high tumor burden, recent guidelines recommend systemic therapy. This study evaluates the efficacy and safety of atezolizumab plus bevacizumab for TACE-unsuitable patients with unresectable intermediate-stage HCC beyond up-to-seven criteria.

Methods: This prospective, phase II, single-arm, non-blinded study enrolled TACE-naïve patients with unresectable intermediate-stage HCC beyond up-to-seven criteria, Child-Pugh A, no previous systemic therapy, and ECOG Performance Status score of 0-1 from 35 sites in Japan. Patients received atezolizumab 1,200 mg and bevacizumab 15 mg/kg every 3 weeks. The primary endpoint was the 6-month progression-free survival (PFS) rate by modified RECIST (mRECIST). Key secondary endpoints included the objective response rate (ORR) and safety. Exploratory endpoints examined individual changes in tumor size, comparison by inverse probability weighting (IPW) of data with retrospective historical data of TACE-treated patients, and conversion rate to a curative intent therapy.

Results: In total, 74 patients were enrolled from December 2020 to September 2021 (median follow-up, 15.1 months). The 6-month PFS rate by mRECIST was 66.8% (90% CI: 56.8, 75.0), and the lower limit of the 90% CI exceeded the pre-specified threshold of 55%. ORR by mRECIST was 40.5%. After treatment with atezolizumab plus bevacizumab, 10 patients, including 5 patients who had a tumor burden beyond the up-to-11 criteria at baseline, were able to transition to curative intent therapy. PFS by mRECIST by IPW was 9.2 months with atezolizumab plus bevacizumab versus 5.7 months with TACE (hazard ratio 0.67, p = 0.029). Adverse events (AEs), mostly hypertension, proteinuria, and malaise, were common. AEs requiring corticosteroids occurred in 10 patients (13.5%).

Conclusion: Atezolizumab plus bevacizumab appears beneficial as first-line treatment for TACE-unsuitable patients with unresectable intermediate-stage unresectable HCC beyond up-to-seven criteria. Future strategies utilizing multimodal approaches may further improve outcomes.

Introduction: Liver injury is a treatment-related adverse event (liver-TRAE), one of the most common complications of atezolizumab plus bevacizumab (Atez/Bev) therapy, when treating unresectable hepatocellular carcinoma (uHCC). Fever following immune checkpoint inhibitor (ICI) therapy may predict ICI-induced liver injury in various malignancy types. However, the association between fever and liver-TRAEs in patients with uHCC treated with Atez/Bev has not been investigated. We prospectively evaluated the relationship between the onset of liver-TRAEs and preceding fever and sought to identify circulating biomarkers that predict liver injury in patients with Atez/Bev-treated uHCC.

Methods: The primary outcome of this prospective, multicenter study was the association between liver-TRAEs (grade ≥2) and the presence of ICI-induced fever before the onset of liver injury. We used a multiplex bead-based immunoassay to evaluate 40 circulating proteins in the serum before and at 1, 3, and 6 weeks after initial Atez/Bev treatment.

Results: Among 99 patients receiving Atez/Bev, grade ≥2 liver-TRAEs occurred in 10 (10.1%) during the follow-up period (median, 14.7 months). The incidences of liver-TRAEs associated with fever before liver injury were 27.8% (n = 5/18) and 6.2% (n = 5/81) in the fever and non-fever groups, respectively. Multivariable analysis showed that the presence of fever was a significant risk factor for liver-TRAEs (odds ratio 7.57; 95% confidence interval, 1.83-33.89; p = 0.006). Furthermore, the prognosis was worse in the liver-TRAE (grade ≥2) group (p = 0.065 for progression-free survival and p = 0.074 for overall survival). Among patients with preceding fever, the liver-TRAE group had significantly lower CXCL-5 levels before treatment, higher IL-6 levels at 1 and 3 weeks, and lower CXCL-5, IFN-γ, and IL-10 levels at 6 weeks (p < 0.05).

Conclusion: Fever during Atez/Bev treatment may predict liver-TRAEs, which leads to poor prognosis in patients with uHCC. Altered inflammatory cytokine and chemokine levels may help predict liver-TRAEs in patients with fever after Atez/Bev therapy.

Introduction: Transarterial chemoembolization (TACE) is the primary treatment for intermediate-stage hepatocellular carcinoma (HCC). Synergistic effects are expected by adding recently developed systemic therapies onto TACE. We investigated patient and physician preferences for this treatment approach.

Methods: Preferences of patients with HCC who underwent TACE and physicians treating HCC were assessed using a discrete choice experiment. Eighteen hypothetical treatment profiles were set based on seven attributes, including survival outcomes, treatment burden, and side effects, with two or three levels. A mixed-logit model estimated the preference weights for each attribute level.

Results: The 85 HCC patients surveyed had a median age of 69 (interquartile range 59-75) years. Most were male (84.7% [72/85]). Most physicians (70.4% [69/98]) were ≥40 years old, and 93.9% (92/98) were male. Both patients and physicians showed the largest positive preferences for 5-year overall survival (OS) {preference weight (95% confidence interval [CI]) 3.41 (2.85, 3.97) and 4.84 (3.90, 5.79), p < 0.001, respectively}, relative to 2-year OS. Following this, patients preferred minimizing the risk of fatigue with negative preferences (95% CI) for a 50% risk relative to a 10% risk (-0.84 [-1.24, -0.43], p < 0.001), and physicians preferred extended time to progression (TTP) from 6 months to 2 years (1.39 [0.82, 1.95], p < 0.001). Physicians, but not patients, exhibited a significant negative preference (95% CI) for a 40% increase in the risk of immune-related side effects (-1.03 [-1.67, -0.39], p = 0.002, and -0.41 [-0.84, 0.02], p = 0.063, respectively). Preferences varied depending on patient and physician characteristics.

Conclusion: OS was the most important factor for both patients and physicians in TACE-based treatment for HCC, with fatigue the second largest preference factor for patients and TTP for physicians. Understandings of immune-related side effects seemed to vary among participants. These findings enhance patient-physician communication and shared decision-making.

Background: Hepatocellular carcinoma (HCC), which represents the most common type of primary liver cancer, is increasingly perceived as a complex ecosystem with marked spatial and temporal heterogeneity as well as varied sensitivities to treatment. Recent revolutions in the management of HCC, particularly the introduction of several immune checkpoint inhibitor-based regimens, are placing pressing needs on more tailored imaging-aided prognostic decision-making for individualized treatment selection beyond the current "one-size-fits-all" tumor burden measurement.

Summary: With an accumulating number of advanced imaging and artificial intelligence techniques bridging the gap between preclinical and clinical applications, the role of imaging in HCC is rapidly expanding from conventional surveillance, diagnosis, staging, and treatment-response evaluation to personalized pathomolecular profiling, prognostication, and therapeutic decision-making. Ultimately, imaging may direct the selection of treatment modalities precisely tailored to individual patients and tumors.

Key messages: In this review, we describe the evolving role of imaging in the noninvasive assessment of key pathomolecular drivers of outcomes in HCC, outline the applications of imaging in prognostication, risk stratification, and selection of major treatment approaches, as well as discuss unmet needs and potential future directions.

Background and aims: We conducted an updated network meta-analysis to evaluate and identify the optimal first-line treatment for advanced hepatocellular carcinoma (HCC) among all relevant interventional and targeted therapies.

Methods: We analyzed 16 phase 2 or 3 randomized controlled trials involving 9,482 patients with metastatic or unresectable HCC published between 2018 and 2024. The trials evaluated 11 systemic agents and 5 interventional treatments in combination with systemic therapy, using either sorafenib or lenvatinib as the control. The primary outcome was overall survival (OS), and secondary outcomes included progression-free survival (PFS) and grade 3-4 adverse events. Subgroup analyses were conducted to assess individual treatment efficacies in specific clinical settings.

Results: Transarterial chemoembolization (TACE) combined with lenvatinib provided the greatest improvement in OS over sorafenib, with a hazard ratio of 0.41 (95% confidence interval, 0.30-0.58), followed by sintilimab + IBI305 (0.57; 0.43-0.75), camrelizumab + rivoceranib (0.62; 0.48-0.80), atezolizumab + bevacizumab (0.66; 0.51-0.85), lenvatinib + pembrolizumab (0.77; 0.62-0.97), and tremelimumab + durvalumab (0.78; 0.64-0.95). These combinations, except for tremelimumab + durvalumab, also showed significantly superior PFS to sorafenib. TACE + lenvatinib was ranked first in OS analyses with the other current standard-of-care regimens (lenvatinib, atezolizumab + bevacizumab, and tremelimumab + durvalumab) as controls. TACE + lenvatinib, sintilimab + IBI305, and atezolizumab + bevacizumab demonstrated consistently significant extension of OS over sorafenib in subsets with portal invasion, extrahepatic metastasis, and hepatitis B. All immunotherapy-based combinations were significantly associated with a higher risk of adverse events than sorafenib.

Conclusions: For advanced HCC, our first-line analysis consistently scored TACE + lenvatinib the best for survival outcomes, followed by various immunotherapy-based combinations. However, the superior efficacy of TACE + lenvatinib should be interpreted with consideration of its derivation from a region with high hepatitis B virus prevalence.

Introduction: Oncological resectability criteria for hepatocellular carcinoma have been defined (resectable [R]/borderline resectable 1 [BR1]/borderline resectable 2 [BR2]); however, their validation is necessary.

Methods: A total of 1,469 patients who underwent hepatectomy and 525 patients who received systemic chemotherapy, including lenvatinib, atezolizumab plus bevacizumab, and durvalumab plus tremelimumab, as first-line treatment were analyzed.

Results: In the BR1 group, the median survival times (MSTs) of patients who underwent hepatectomy and systemic chemotherapy were 52.7 and 34.6 months, respectively, without a significant difference (p = 0.075). In the propensity score matching (PSM) analysis of the BR1 group, the MSTs of hepatectomy and systemic chemotherapy were 42.4 and 35.1 months, respectively, without a significant difference (p = 0.772). Hepatitis virus infection, modified albumin-bilirubin (mALBI) grade 2b + 3, and the presence of extrahepatic metastasis were identified as poor prognostic factors for hepatectomy, whereas mALBI grade 2b + 3 was the only poor prognostic factor for systemic chemotherapy. In the BR2 group, the MSTs of hepatectomy and systemic chemotherapy were 20.1 and 19.5 months, respectively, with significantly better survival for hepatectomy than for systemic chemotherapy (p = 0.017). In the PSM analysis of the BR2 group, the MSTs of hepatectomy and systemic chemotherapy were 20.1 and 21.0 months, respectively, without a significant difference (p = 0.375). Serum alpha-fetoprotein levels≥100, intrahepatic tumor number ≥6, and the presence of extrahepatic metastasis were identified as poor prognostic factors for hepatectomy, whereas female, serum alpha-fetoprotein levels ≥100, mALBI grade 2b + 3, intrahepatic maximal tumor size >5 cm, and the presence of extrahepatic metastasis were identified as poor prognostic factors for systemic chemotherapy.

Conclusion: In the PSM analysis, no significant differences were observed between the BR1 and BR2 groups for hepatectomy and systemic chemotherapy. The intrahepatic tumor number for hepatectomy and the intrahepatic maximal tumor size for systemic chemotherapy are significant risk factors for BR2 patients, highlighting the characteristics of each treatment and the potential for selecting the optimal modality.

Background: Preclinical models have shown that metabolic dysfunction-associated steatotic liver disease (MASLD)-related hepatocellular carcinoma (HCC) may exhibit reduced responsiveness to immunotherapy, especially for intrahepatic lesions due to liver tumor microenvironment. Radiological pattern of progression has been validated in clinical studies as a useful tool for predicting outcomes in HCC undergoing systemic treatments.

Aims: The aim of this study was to determine whether MASLD influences the pattern of progression in patients treated with atezolizumab-bevacizumab.

Methods: This multicenter, prospective study included patients with unresectable HCC receiving atezolizumab-bevacizumab. Progression patterns were defined as previously proposed. Patients were categorized as either MASLD or controls based on a recent multisocietal Delphi consensus statement. Multivariable models analyzed the risk of specific progression patterns and their impacts on post-progression survival (PPS) and overall survival (OS). A historical cohort treated with sorafenib was also analyzed to determine whether observed patterns were specific for atezolizumab-bevacizumab.

Results: Four-hundred twenty patients were included (MASLD: n = 88, 21.0%). Time to progression (TTP) was shorter in MASLD compared to controls, due to an increased risk of intrahepatic growth (IHG - hazard ratio [HR] 1.739, 95% confidence interval [CI] 1.206-2.507, p = 0.003]). Neither etiology nor IHG predicted a different PPS. No differences between etiologies were found in OS. Etiology did not influence the pattern of progression under sorafenib in the historical cohort.

Conclusion: IHG was more frequently associated with MASLD-HCC compared to controls, confirming preclinical data and suggesting biological differences between tumors, with potential implications for future research. MASLD should not be seen as a contraindication to immunotherapy.

Introduction: Combining systemic agents with hepatic arterial infusion chemotherapy (HAIC) has produced promising outcomes in advanced hepatocellular carcinoma (HCC). Raltitrexed, an antimetabolite recognized for its extended plasma half-life, enables shorter infusion schedules. This study aimed to assess the efficacy, safety, and potential predictive biomarkers of a therapeutic approach incorporating camrelizumab, lenvatinib, and a HAIC protocol using raltitrexed plus oxaliplatin (RALOX) in patients with intermediate-to-advanced HCC.

Methods: Participants in this single-arm phase II study (NCT05003700) had Barcelona Clinic Liver Cancer (BCLC) stage B or C HCC. They received RALOX-HAIC in tandem with camrelizumab and lenvatinib for a maximum of 6 cycles, continuing until either disease progression or unacceptable toxicity. The primary outcome measure was the objective response rate (ORR).

Results: Thirty-nine individuals underwent at least one tumor review after baseline. The confirmed ORR was 66.7% (95% CI, 49.8-80.9). The median progression-free survival was 13.8 months (95% CI, 10.5-20.5), and the median overall survival was 21.2 months (95% CI, 14.3-21.2). Grade 3-4 treatment-related adverse events occurred in 79.5% of the subjects, with the most common being decreased neutrophil count (41%), decreased platelet count (30.8%), and increased aspartate aminotransferase (23.1%). All side effects were, as anticipated, controllable, and no treatment-related deaths were reported. Serum IL-2, CXCL13, and CCL19 levels significantly differed between stable disease and partial response patients (p < 0.05 and |fold change| >1.5). Furthermore, risk stratification based on these three biomarkers revealed shorter progression-free survival and overall survival in high-risk versus low-risk subgroups (p < 0.05). These results suggested that the serum concentrations of IL-2, CXCL13, and CCL19 emerged as potential predictors of clinical benefits under this triple-combination protocol.

Conclusion: The triple regimen of camrelizumab, lenvatinib, and RALOX-HAIC exhibited notable antitumor capabilities and acceptable tolerability in patients with advanced HCC. Moreover, baseline levels of IL-2, CXCL13, and CCL19 may function as predictive indicators of the response to this first-line therapeutic strategy.

Introduction: Patients with advanced hepatocellular carcinoma (HCC) face an extremely poor prognosis. Sorafenib, a multikinase inhibitor, remains an essential treatment for advanced HCC in certain clinical settings where immunotherapy is either contraindicated or unavailable. However, the survival benefit of transarterial chemoembolization (TACE) plus sorafenib remains under investigation.

Methods: The SELECT trial was a multicenter, randomized, controlled study conducted across twelve centers in China. From September 7, 2013, to December 4, 2019, 199 patients with advanced-stage HCC were randomly assigned in a 1:1 ratio to receive either TACE plus sorafenib or sorafenib monotherapy.

Results: The median age of the study population was 55 years (IQR 46-63), with hepatic virus infection being the predominant cause of HCC. In the intention-to-treat (ITT) population, the overall survival (OS) analysis did not show a statistically significant difference between the combination and sorafenib monotherapy groups (14.9 months [95% CI: 10.5-19.3] vs. 11.9 months [95% CI: 9.0-14.8], HR 0.862, p = 0.312). However, the combination therapy group demonstrated significantly improved time to progression (TTP) (10.0 months [95% CI: 6.4-13.6] vs. 5.9 months [95% CI: 3.1-8.7]; p = 0.016) and post hoc progression-free survival (PFS) (8.5 months [95% CI: 6.7-10.3] vs. 5.6 months [95% CI: 4.1-7.1]; p = 0.034). In predefined per-protocol analysis, the combination therapy group showed a significantly longer median OS compared to the monotherapy group (14.6 months [11.3-17.9] vs. 7.4 months [95% CI: 4.3-10.5], HR 0.539, p = 0.001).

Conclusion: Although the combination of TACE and sorafenib did not demonstrate a significant improvement in OS in the ITT analysis, it met the secondary endpoints, including TTP and post hoc PFS. These findings provide valuable insights for the design of future trials and highlight the importance of integrating locoregional interventions with systemic therapies in the management of advanced-stage HCC.