Treatment Of Advanced HCC Research Articles

RECIST 1.1, mRECIST, and Choi criteria for evaluating treatment response and survival outcomes in hepatocellular carcinoma patients treated with atezolizumab plus bevacizumab.

We aimed to compare the early responder rates, defined as complete or partial responders, using response evaluation criteria in solid tumors (RECIST) 1.1, modified RECIST (mRECIST), and Choi criteria in advanced HCC patients treated with atezolizumab-bevacizumab (atezo-bev), and to correlate them with progression-free survival (PFS) and overall survival (OS). This retrospective study included advanced HCC patients treated with ≥ 3 cycles of atezo-bev. Two reviewers assessed responses using RECIST 1.1, mRECIST, and Choi criteria at 1st follow-up imaging. Kaplan-Meier curves with log-rank tests evaluated and compared PFS and OS. Cox proportional hazard models identified survival outcome predictors. Kappa statistics assessed inter-reader agreement. We evaluated 77 patients (65 men; mean age, 62.8 ± 12.3 years). Choi's criteria revealed the highest early responders rate (53.2%), exceeding mRECIST (32.5-33.8%) and RECIST 1.1 (24.7-26.0%), with an excellent agreement in all criteria (κ, 0.85-0.95). Across criteria, a consistent number of patients progressed (23-26) and was associated with significantly poor OS (ps ≤ 0.049). Responders by any criteria showed longer PFS (ps ≤ 0.009), and 1-year OS (ps ≤ 0.01). Choi criteria linked to significantly better OS without landmark (p = 0.003), with 1-year OS rates at 76.9% for responders vs 38.1% for non-responders. Cox analysis identified responders by Choi criteria as a significant OS predictor. Choi criteria identified more early responders than RECIST 1.1 and mRECIST, significantly correlating with improved OS. Choi criteria could be considered as a formal response assessment criterion for the emerging atezo-bev systemic treatment. For atezo-bev treatment of advanced HCC, more comprehensive response criteria, such as Choi criteria, could be effective in identifying early responders and predicting survival outcomes along with RECIST 1.1 and mRECIST. Choi criteria identified a higher rate of early responders compared to mRECIST and RECIST1.1 following atezo-bev treatment. Responders by all criteria had longer PFS and 1-year OS, and only those by Choi criteria experienced longer OS without landmark time. Choi criteria, with RECIST 1.1 and mRECIST, is an effective response assessment tool for atezo-bev treatment.

The activity and safety of icaritin for patients with unresectable HCC: A real world, retrospective study.

e16181 Background: Primary liver cancer is a major health burden globally, ranking sixth in incidence and third in mortality among all cancers[1]. Over the past 5 years, immune checkpoint inhibitors (ICIs) and multi-targeted tyrosine-kinase inhibitors have emerged as new treatment options for advanced hepatocellular carcinoma[2–4]. Nevertheless, only a small subset of patients with hepatocellular carcinoma derive a response to ICI monotherapy. Icaritin, a target tumor micro-environment(TME) modulating compound, which interacts with MyD88/IkB kinase-a (IKK)[5], inhibiting the TNF-a-induced IKK and nuclear factor-κB (NF-kB) signaling pathways and blocking PD-L1 expression in HBV-related HCC[6-9] and has been approved in China for the treatment of first-line advanced HCC. Icaritin phase III study previously reported at 2021 ASCO, we therefore investigated the efficacy of icaritin in patients with unresectable stage IIA-IIIB (CNLC stage) HCC in a real-world setting. Methods: This multi-center, retrospective study, conducted between May 2022 and Nov 2023. We retrospectively collected medical records of patients (pts) with unresectable IIA-IIIB (CNLC stage) HCC who received icaritin monotherapy (mono-group) or icaritin combined with PD-1/L1 and/or anti-VEGF therapy (combination group) as first line therapy. The primary endpoints were progression free survival (PFS); Secondary endpoints included overall survival (OS) rate, objective response rate (ORR) by RECIST v1.1, and safety. Results: Patients characteristics: 49 pts were eligible for inclusion with median age of 60.7 years old (range 18.0-89.0), 91.8% were ECOG PS 0-1, 86.5% had HBV infection, 79.6% were stage III and 48.9% were AFP>400 ng/ml. 33 pts administrated with combination therapy, other 16 pts’ regimen was icaritin monotherapy. Efficacy: As of the data cutoff for the preliminary analysis of progression free survival (Nov 30, 2023), the median follow-up was 11.17 months (95%CI 6.74–12.12). The ORR for the combination group was 6.06%, and 12.50% for the mono-group, the mPFS was 8.94(95%CI 6.90~9.76) and 5.52 (2.92~NE) for each group. The mOS was not reached for both group, the 6 and 12-months OS rates were 91.00% and 73.67% respectively. Safety: For the safety information, most of TRAEs were grade 1 or 2. No serious AEs were observed. Conclusions: This real-world retrospective study revealed that icaritin monotherapy and icaritin-based combination therapy are promising therapeutic options for unresectable HCC in China. Clinical trial information: ChiCTR2300074565.

Efficacy and safety of SBRT combined with sintilimab and IBI305 in patients with advanced HCC and previously failed immunotherapy: study protocol of a phase 2 clinical trial

IntroductionHepatocellular carcinoma (HCC) is a leading cause of cancer-related death in China. The combination of immune checkpoint inhibitors (ICIs) and antiangiogenic drugs, such as bevacizumab and tyrosine kinase inhibitors, has...

Low protein expression of LZTR1 in hepatocellular carcinoma triggers tumorigenesis via activating the RAS/RAF/MEK/ERK signaling

LZTR1 is a substrate specific adaptor for E3 ligase involved in the ubiquitination and degradation of RAS GTPases, which inhibits the RAS/RAF/MEK/ERK signaling to suppress the pathogenesis of Noonan syndrome and glioblastoma. However, it's still unknown whether LZTR1 destabilizes RAS GTPases to suppress HCC progression by inhibiting these signaling pathway. Lenvatinib is the first-line drug for the treatment of advanced HCC, however, it has high drug resistance. To explore the roles of LZTR1 in HCC progression and the underlying mechanisms of lenvatinib resistance, techniques such as bioinformatics analysis, immunohistochemical staining, RT-qPCR, Western blot, cell functional experiments, small interfering RNA transfection and cycloheximide chase assay were applied in our study. Among these, bioinformatics analysis and immunohistochemical staining results indicated that LZTR1 protein was aberrantly expressed at low levels in HCC tissues, and low protein expression of LZTR1 was associated with poor prognosis of HCC patients. In vitro functional experiments confirmed that low expression of LZTR1 promoted HCC cell proliferation and migration via the aberrant activation of the RAS/RAF/MEK/ERK signaling due to the dysregulation of LZTR1-induced KRAS ubiquitination and degradation. Transwell assays revealed that blocking of LZTR1-mediated KRAS degradation could induce lenvatinib resistance in HCC cells. In conclusion, our study revealed that LZTR1 knockdown promoted HCC cell proliferation and migration, and induced lenvatinib resistance via activating the RAS/RAF/MEK/ERK signaling, which may provide new ideas for HCC treatment.

Clinical efficacy of lenvatinib, trans-arterial chemoembolization, and PD-1/L1 inhibitors in advanced hepatocellular carcinoma: a systematic review and network meta-analysis.

Currently, the effectiveness of TACE, Lenvatinib, and PD-1/L1 inhibitors used alone or in combination has been thoroughly reported. However, the differences in effectiveness between these treatment protocols require further verification. To this end, this study employs a Bayesian network meta-analysis to compare the efficacy and safety of TACE, Lenvatinib, and PD-1/L1 inhibitors, whether administered by monotherapy or in combination, providing evidence-based medicine for the treatment of unresectable HCC. This study employed a network meta-analysis to evaluate the efficacy and safety of trans-arterial chemoembolization (TACE), Programmed Cell Death Protein/Ligand 1 (PD-1/L1) inhibitors, and Lenvatinib in the treatment of advanced HCC. Literature on the treatment of advanced HCC with TACE, PD-1/L1 inhibitors, and Lenvatinib was searched for in both Chinese and English databases, including PubMed, EMBASE, ClinicalTrials.gov, Cochrane Library, CNKI, and Wanfang. Two researchers conducted independent screening and data extraction, and the meta-analysis was performed using R language with the gemtc package. After retrieval and screening, a total of 21 articles were included, involving 2052 participants and six treatment modalities: Lenvatinib (L), TACE (T), TACE + Lenvatinib (TL), Lenvatinib + PD-1/L1 inhibitors (LP), TACE + Lenvatinib + PD-1/L1 inhibitors (TLP), and TACE + PD-1/L1 inhibitors (TP). In terms of objective response rate (ORR), the TLP regimen provided the optimal effect. In predicting the best ORR, TLP had the highest (75.5%) probability. In terms of disease control rate (DCR), the TLP regimen showed the best effect. In predicting the best DCR, the TLP again offered the highest (76.1%) probability. In terms of overall survival (OS), the best outcome was observed in the TLP protocol. In predicting the best OS, the TLP holds the highest (86.00%) probability. Furthermore, the best outcome in progression-free survival (PFS) was found in the TLP regimen. In predicting the best PFS, the TLP still holds the highest (97.0%) result. The combination of TACE, Lenvatinib, and PD-1/L1 inhibitors appears to provide the maximum benefit for inoperable HCC patients.

Combination of Doxorubicin and Antiangiogenic Agents in Drug-Eluting Beads: In Vitro Loading and Release Dynamics in View of a Novel Therapeutic Approach for Hepatocellular Carcinoma.

Antiangiogenic agents have been used for many years as a first-line systemic treatment for advanced HCC. Embolization with cytostatic drugs on the other hand is the first-line treatment for intermediate HCC. The two types of drugs have not been combined for intraarterial delivery yet. The loading and release dynamics and the in vitro effect of their combination are tested in this experimental study. Drug-eluting beads were loaded with doxorubicin, sunitinib and sunitinib analogue piperazine (SAP) alone and with their combinations. Diameter change, loading, release, and effect in cellular proliferation were assessed. The average microsphere diameter after loading was 473.7µm (μm) for Doxorubicin, 388.4μm for Sunitinib, 515.5μm for SAP, 414.8μm for the combination Doxorubicin/Sunitinib and 468.8μm for the combination Doxorubicin /SAP. Drug release in 0.9%NaCl was 10% for Doxorubicin, 49% for Sunitinib, 25% for SAP, 20%/18% for the combination Doxorubicin/Sunitinib, and 18%/23% for the combination Doxorubicin/SAP whereas in human plasma it was 56%, 27%, 13%, 76%/63% and 62%/15%, respectively. The mean concentration of Doxorubicin that led to inhibition of 50% of cellular proliferation in an HCC Huh7 cell line was 163.1nM (nM), for Sunitinib 10.3 micromolar (μΜ), for SAP 16.7μΜ, for Doxorubicin/Sunitinib 222.4nM and for Doxorubicin/SAP 275nM. Doxorubicin may be combined with antiangiogenic drugs with satisfactory in vitro loading and release outcomes and effect on cellular lines.

Abstract 7597: Therapeutic potential of ketogenic diet as an adjuvant to lenvatinib treatment in hepatocellular carcinoma

Abstract Hepatocellular carcinoma (HCC) has been a major public health concern worldwide for decades because of its high mortality rates and poor prognosis, which are attributable to frequent tumor relapse and limited treatment regimens. Lenvatinib is one of the tyrosine kinase inhibitors approved for first-line treatment of advanced HCC, but its efficacy remains modest. Growing evidence suggest that the unsatisfactory survival benefits of lenvatinib could be attributed to the acquired drug resistance developed in HCC patients. In this study, we aim to explore the intrinsic metabolic vulnerability which could be exploited to enhance the treatment efficacy of lenvatinib in HCC. Our previous study showed that loss of tyrosine catabolism accompanied with a reduced downstream ketone metabolite beta-hydroxybutyrate (BHB) supports HCC initiation. To explore the therapeutic value of BHB in potentiating lenvatinib treatment in HCC, tyrosine catabolism-suppressing HCC cells were treated with BHB. We found that BHB treatment suppressed cell proliferation, increased cellular reactive oxygen species and potentiated the efficacy of lenvatinib treatment. Similar tumor-suppressive effect was observed when BHB was administered in vivo in mice bearing HCC patient derived xenograft. Combination treatment of lenvatinib and ketogenic diet which induces BHB level could drastically attenuate tumor development in immunocompetent mice bearing hepatic tumors. This study presents a potentially translatable combination treatment regimen to potentiate the therapeutic efficacy of lenvatinib in advanced HCC. Citation Format: Minghe Zhang, Terence Kin-Wah Lee, Stephanie Ma, Man Tong. Therapeutic potential of ketogenic diet as an adjuvant to lenvatinib treatment in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7597.

PP33 The Cost-effectiveness Of Regorafenib In The Treatment Of Advanced Hepatocellular Carcinoma From A Canadian Perspective

IntroductionHepatocellular carcinoma (HCC) is the most common form of liver cancer and the fourth leading cause of cancer-related death globally. There are unmet needs for effective systematic therapy. The findings of the RESORCE trial highlighted the improvement in overall survival with regorafenib in advanced HCC patients progressing on sorafenib treatment. This study aimed to assess the cost-effectiveness of regorafenib compared with best supportive care (BSC) for advanced HCC from the Canadian healthcare system perspective.MethodsWe developed a Markov model based on four health states: live with adverse events, live without adverse events, progression, and dead. Health outcomes were measured using life-years (LYs), and quality-adjusted life-years (QALYs), and costs were presented in Canadian dollars (CAD). Clinical inputs were derived from the RESORCE trial. A 1.5 percent discount rate was applied to costs and outcomes. One-way and probabilistic sensitivity analyses were performed to assess the uncertainty in findings due to variability in parameters. TreeAge Pro software was used for model implementation.ResultsThe use of regorafenib results in a gain of 0.38 LYs and 0.25 QALYs as compared to BSC with a high incremental cost of CAD26,954 (USD22,313). The ICER for regorafenib compared with BSC was CAD105,850/QALY (USD87,624/QALY) in the base-case analysis. Further, probabilistic sensitivity analyses revealed regorafenib not to be cost-effective at a willingness-to-pay threshold of CAD50,000/QALY.ConclusionsRegorafenib was not found to be cost-effective in the treatment of advanced HCC because of the lower health benefits and higher incremental costs. Lowering the official price of regorafenib or use for only selected patients who can achieve maximum benefits would enhance its cost-effectiveness and treatment preference value.

Current Evidence for Immune Checkpoint Inhibition in Advanced Hepatocellular Carcinoma.

The treatment of advanced unresectable HCC (aHCC) remains a clinical challenge, with limited therapeutic options and poor prognosis. The results of IMbrave150 and HIMALAYA have changed the treatment paradigm for HCC and established immune checkpoint inhibition (ICI), either combined with anti-angiogenic therapy or dual ICI, as preferred first-line therapy for eligible patients with aHCC. Numerous other combination regimens involving ICI are under investigation with the aim of improving the tumour response and survival of patients with all stages of HCC. This review will explore the current evidence for ICI in patients with advanced HCC and discuss future directions, including the unmet clinical need for predictive biomarkers to facilitate patient selection, the effects of cirrhosis aetiology on response to ICI, and the safety of its use in patients with impaired liver function.

Evolution of systemic therapy for advanced HCC patients: Did we make progress in 2022?

Evolution of systemic therapy for advanced HCC patients: Did we make progress in 2022?

OS analysis of patients with different short-term response and progression patterns of donafenib versus sorafenib as first-line therapy for advanced hepatocellular carcinoma: An exploratory subgroup analysis of ZGDH3.

e16143 Background: Donafenib, a deuterated derivative of sorafenib, significantly prolonged overall survival (OS) in patients with advanced hepatocellular carcinoma in an open, randomized, parallel-controlled phase II/III trial (ZGDH3) compared with sorafenib. The purpose of this study was to explore and analyse the OS benefits of donafenib and sorafenib treatment in patients with different short-term response and progression patterns. Methods: This analysis was based on the ITT population of ZGDH3 study (defined as all randomized patients). The median OS of donafenib and sorafenib was assessed by the Kaplan-Meier method and was compared according to different short-term response (SD, others) and progression patterns (intrahepatic lesion growth, intrahepatic new lesion, extrahepatic lesion growth, extrahepatic new lesion). The stratified Cox proportional hazard model was used to calculate the hazard ratio and its 95% confidence interval. Results: 668 patients were included in the analysis (334 in each group). Donafenib was associated with a trend of improved OS benefit when compared with sorafenib in most subgroups (HR < 1), including best short-term response of SD or others, confirmed short-term response of SD or others, intrahepatic lesion growth or not, intrahepatic new lesion or not, extrahepatic new lesion or not, no extrahepatic lesion growth. The benefit was statistically significant in the following subgroups: in patients with response of SD, the mOS of donafenib and sorafenib were 19.3 and 15.5 months, respectively (HR 0.714, 95%CI 0.550-0.928). Among patients with confirmed response of SD, the mOS was 29.0 and 22.8 months, respectively (HR 0.641, 95% CI 0.418-0.983). Among patients without extrahepatic lesion growth (defined as lesion growth ≥20% from baseline), the mOS was 12.6 months and 10.0 months, respectively (HR 0.783, 95% CI 0.648-0.945). Among patients without new extrahepatic lesions, the mOS was 13.1 months and 11.0 months (HR 0.816, 95% CI 0.677-0.998), respectively. Conclusions: Donafenib exhibited better survival benefit than sorafenib in most subgroups, especially in patients with the best response and confirmed best response of SD, which further confirmed the excellent efficacy of donafenib in first-line treatment of advanced HCC. Clinical trial information: NCT02645981 . [Table: see text]

Abstract 1074: The potential of 18β-glycyrrhetinic acid benefit lenvatinib induced cytotoxicity on hepatocellular carcinoma

Abstract Hepatocellular carcinoma (HCC) is usually caused by long-term inflammation such as infected by hepatitis B and C viruses. The current standard treatment methods of HCC has included with general surgery, radiation, etc. However, the recurrence rate remain high even after standard treatment, it is necessary to find a better treatment option to control the progression of HCC. Lenvatinib is a multi-endothelial angiogenesis factor inhibitor which is a first-line target drug for the treatment of advanced HCC. Some studies indicated that activation of the PI3K/AKT pathway could lead to the resistance effect of lenvatinib in HCC. 18β-glycyrrhetinic acid (18β-GA) is a hydrolyzed product of glycyrrhizic acid in the intestine. Studies reported that 18β-GA can effectively treat inflammatory diseases and may have antitumor potential. Some studies also indicated that 18β-GA can down-regulate the signaling transduction of PI3K/AKT pathway in various type of cancers. Therefore, in this study, we focused on exploring whether 18β-GA can be used as an adjuvant to downregulate PI3K/AKT signaling and thus enhance the efficacy of lenvatinib on HCC cells and animal model. Here, we used the MTT assay to investigate the cytotoxicity of HCC cells (Huh7 and Hep3B) after various dose of lenvatinib and (or) 18β-GA treatment. We also used combination index (CI) to evaluate the suitable combination condition. In our results, the CI value of lenvatinib 30 μM combined with 18β-GA 100 μM is smaller than 1, which indicated the synergistic effect of combination. We confirmed the superior extrinsic/intrinsic apoptosis induction ability was found in lenvatinib combined with 18β-GA as compared to single treatment. The activation of Fas/FasL pathway, Annexin V, cleaved caspase-3, -8 and -9 were used to confirm the apoptosis induction by lenvatinib combined with 18β-GA. Transwell invasion and wound healing assays results also indicated the invasion/migration suppression ability of lenvatinib combined with 18β-GA on HCC cells. The phosphorylation of AKT were markedly decreased by lenvatinib combined with 18β-GA in HCC cells. Hep3B bearing animal data proved the superior tumor control of lenvatinib combined with 18β-GA. Additionally, the liver function and normal tissue pathology may not affect by combination of lenvatinib and 18β-GA. To conclude, our result demonstrated that 18β-GA may sensitize HCC to lenvatinib via inactivation of PI3K/AKT signaling pathway and induction of extrinsic/intrinsic apoptosis signaling. Citation Format: Yeh Pei-Wen, Yu-Chiang Liu, Yuan Chang, Jiann-Hwa Chen. The potential of 18β-glycyrrhetinic acid benefit lenvatinib induced cytotoxicity on hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1074.

T cells in the heterogeneous tumour immune microenvironment of hepatocellular carcinoma: Implications for immune checkpoint inhibitor therapy

AbstractHepatocellular carcinoma (HCC) is a leading cause of cancer‐related death worldwide. Recently, patient care was revolutionized by the introduction of immunotherapy combining anti‐programmed death‐ligand 1 (PD‐L1) checkpoint inhibition with anti‐vascular endothelial growth factor (VEGF) therapy as first‐line treatment for advanced unresectable HCC. Additional promising studies with mono‐ or combination immunotherapy are in advanced phases of clinical testing. Currently, however, our understanding of which patients profit from immunotherapy and how therapy response may be related to the composition of the tumour immune microenvironment remains incomplete. Inhibitory receptors as targets of immune checkpoint inhibitor (ICI) therapies are strongly expressed by T cells in the tumour microenvironment (TME). However, the HCC microenvironment is highly heterogeneous as illustrated by distinct molecular subtypes and subclassifications with an immune‐rich microenvironment representing only a small proportion of HCCs. A better understanding of the tumour immune microenvironment is expected to provide insights for clinically applicable biomarkers to optimize immunotherapies. Recent studies identified subtypes of PD‐1 expressing CD8+ T cells with divergent function in the HCC TME associated with different outcomes, suggesting that specific PD‐1 expressing CD8+ tissue‐resident memory T cells (TRM), but not exhausted CD8+ T cells (TEX), govern positive therapy outcomes. This review discusses the T‐cell response in the HCC TME in the context of its heterogeneity, molecular and immune classifications and implications for ICI therapy and biomarker discovery.

Response to: "Comment on Hepatectomy Versus Sorafenib in Advanced Nonmetastatic Hepatocellular Carcinoma".

We thank Quian et al for their interest about our article entitled “Hepatectomy Versus Sorafenib in Advanced Nonmetastatic Hepatocellular Carcinoma.”1 Their comments indeed give us the opportunity to point out some relevant concepts. The latest Barcelona Clinic Liver Cancer update enlarges the number of drugs available for the treatment of advanced stage HCC, with Sorafenib not being anymore, the first-line treatment.2 However, sorafenib and the subsequent systemic therapies for HCC have been introduced just for unresectable patients.3 Nevertheless, despite the resectability of a certain part of patients with advanced HCC was well established,4,5 the systemic therapy has been superimposed as the front-line and, in some way, the only therapeutic choice. Despite the robust evidence reporting a significant survival advantage of liver resection for advanced stages (whenever possible),6,7 the surgical option has remained ignored by the guidelines for these cases. Our article aimed to investigate what that has meant by comparing the previous first-line treatment (sorafenib) versus the surgical curative approach, in a very large national cohort, weighting all the anamnestic and oncologic differences between the 2 groups. About the potential confounding factors represented by adjuvant therapies after surgery as claimed by Quian et al, it is worth to mention that patients who underwent liver resection did not receive further treatment unless tumor recurrence occurred and, even in the case of recurrence, surgery remained the first option, if suitable. Conversely, patients undergoing systemic therapy prosecuted sorafenib or were shifted to the best supportive care in the event of progression. We agree with Quian et al that neo- and adjuvant approaches will progressively play an increasing role in the management of these patients that, in the case of neoadjuvant therapy, might subsequently be also operated.8,9 However, while waiting for the read out of ongoing trials testing combinations of different therapies, especially in the neoadjuvant setting, there is no reason to postpone surgery in resectable patients. The optimal survival observed after liver resection could also be explained as the consequence of a peculiar conceptual approach to those patients: in fact, when patients are managed with a curative intent, in the case of relapse other curative approaches are considered (and feasible) more often than in patients treated with palliative therapies. Otherwise, when patients are considered at the time of HCC diagnosis as not curable, uncommonly they are switched to other treatments in the case of, for example, a favorable response. This conceptual approach is supported by the treatment allocation proposed by the Barcelona Clinic Liver Cancer which is quite rigid, considering the different treatments available as alternatives rather than part of an sequential pathway to reach the cure or, at least, the stabilization of the tumor. From this point of view, a therapeutic hierarchy strategy,10 may ensure to tailor the clinical decision to the patient characteristics, without restricting the treatment to a particular stage, but offering the most suitable approach as the sum of the survival advantage and the feasibility. Quian et al emphasized the differences between the 2 groups (sorafenib vs resection) as a major drawback of our paper. Objectively, these differences exist. However, this is not surprising but somehow obvious, because the definition of advanced HCC covers a wide variety of disease presentations and liver resection could be a solution applicable just in a part of them. However, when that happens results are providing not negligible chances of cure,4–7 and of established safety since decades.11 Anyway, despite the retrospective nature of our analysis, the methodology we used reduced the risk of selection bias and the effect of confounding factors, by the matching or the weighting of all the differently distributed variables between groups. Indeed, large numbers and advanced statistical method, as per inverse probability weighting (IPW), are able to provide evidence comparable to that of randomized clinical trials.12 As pointed out in the discussion, we do not presume that our methodology is perfect, but the results we reported deserve consideration, strengthening more than an impression that surgery, when feasible, should be hierarchically considered a priority. Finally, Quian et al suggested evaluating the results according to different types of macrovascular invasion aimed at providing a therapeutic indication between surgery and systemic therapy. However, patients with invasion of the main portal trunk were excluded from our study. In the other cases, the invaded portal branch was resected together with the pertinent vascular area of the parenchyma. Because of this, we cannot provide a comparison among different management strategy.

Combining HAIC and Sorafenib as a Salvage Treatment for Patients with Treatment-Failed or Advanced Hepatocellular Carcinoma: A Single-Center Experience

Hepatic arterial infusion chemotherapy (HAIC) has been proven to be an effective treatment for advanced HCC. In this study, we present our single-center experience of implementing combined sorafenib and HAIC treatment for these patients and compare the treatment benefit with that of sorafenib alone. This was a retrospective single-center study. Our study included 71 patients who started taking sorafenib between 2019 and 2020 at Changhua Christian Hospital in order to treat advanced HCC or as a salvage treatment after the failure of a previous treatment for HCC. Of these patients, 40 received combined HAIC and sorafenib treatment. The efficacy of sorafenib alone or in combination with HAIC was measured in regard to overall survival and progression-free survival. Multivariate regression analysis was performed to identify factors associated with overall survival and progression-free survival. HAIC combined with sorafenib treatment and sorafenib alone resulted in different outcomes. The combination treatment resulted in a better image response and objective response rate. Moreover, among the patients aged under 65 years old and male patients, the combination therapy resulted in a better progression-free survival than sorafenib alone. A tumor size ≥ 3 cm, AFP > 400, and ascites were associated with a poor progression-free survival among young patients. However, the overall survival of these two groups showed no significant difference. Combined HAIC and sorafenib treatment showed a treatment effect equivalent to that of sorafenib alone as a salvage treatment modality used to treat patients with advanced HCC or with experience of a previously failed treatment.

Drug-related adverse events potentially predict the efficacy of apatinib on advanced hepatocellular carcinoma

BackgroundHepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related deaths worldwide every year, and most HCC patients are diagnosed with advanced disease and can only receive systemic treatment. TKIs are the most important components of the systemic treatment of HCC and have both good efficacy and adverse events (AEs). MethodsThis analysis included 207 patients with locally advanced unresectable or metastatic HCC who received oral treatment with apatinib. We analyzed the overall survival (OS) and progression-free survival (PFS) of patients with or without corresponding AEs to evaluate which AEs can predict the efficacy of apatinib.ResultsPatients with hand-foot syndrome (HFS; p = 0.005), proteinuria (p = 0.006) and diarrhea (p < 0.001) had significantly better OS than those without corresponding AEs, and the appearance of HFS (p = 0.006) and proteinuria (p = 0.004) was associated with longer PFS.ConclusionAmong all the AEs induced by apatinib in the treatment of advanced HCC, proteinuria could potentially predict PFS, and diarrhea was a potential predictor of OS.

Balloon-Occluded Radiofrequency Ablation as Bridge to TACE in the Treatment of Advanced HCC with Arterioportal Shunt.

Transarterial chemoembolization is the most widely used palliative treatment for unresectable hepatocellular carcinoma; however, arterioportal shunt represents a contraindication to this treatment. The study aims to assess the feasibility of balloon-occluded radiofrequency ablation in the transitory resolution of an extensive arterioportal shunt in patients with advanced hepatocellular carcinoma as a bridge to safe and effective transarterial chemoembolization. 12 consecutive patients advanced multinodular unilobar unresectable hepatocellular carcinoma with a target lesion larger than 5 cm (mean diameter 7.7 ± 1.4 cm), not suitable to transarterial chemoembolization due to extensive arterioportal shunt, were recruited. Balloon-occluded radiofrequency ablation of the hepatic area surrounding the shunt during occlusion of the artery supplying the shunt was performed, followed by lobar conventional chemoembolization. Intra/periprocedural complications were evaluated. Technical success was defined by the result of radiofrequency ablation in terms of immediate disappearance, reduction, or persistence of the shunt. Local efficacy of chemoembolization was evaluated at 1-month computed tomography according to m-RECIST criteria. Technical success was achieved in all patients. No major complications were observed. 1- month follow-up showed a mean necrotic diameter of 6.3 cm (range: 3.8-8.7 cm), with an acceptable procedural result and persistence of the shunt. An overall response rate was obtained in all patients, with 25% complete response and 75% partial response. Balloon-occluded radiofrequency ablation of an arterioportal shunt in patients with advanced hepatocellular carcinoma can temporarily reduce shunting, allowing to perform safe and therapeutically useful chemoembolization, with satisfactory control of tumor growth.

65P A single-arm, open-label, phase II study of tislelizumab combined with lenvatinib and Gemox regimen for conversion therapy of potentially resectable locally advanced biliary tract cancers

Surgery remains the only curative treatment for biliary tract cancers, and conversion therapy helps to convert locally unresectable patients to resectable patients to improve overall survival. Tislelizumab, a PD-1 monoclonal antibody, shows promising antitumor activity and safety in the treatment of advanced HCC when combined with lenvatinib. This study aimed to explore the efficacy and safety of tislelizumab combined with lenvatinib and GMOX in potentially resectable advanced BTC.

Targeted Therapy for Hepatocellular Carcinoma: Old and New Opportunities.

Simple SummaryHepatocellular carcinoma (HCC) is the most frequent primitive cancer of the liver, accounting for 90% of all recorded cases. HCC is the third most common cause of cancer-related death, with a 5-year survival rate of just 3%. In terms of the advanced stages, systemic treatments have allowed patients to achieve clinical benefits, although the prognosis remains very poor. In the past few decades, new molecular targeted therapies have been developed and clinically evaluated with interesting results. However, on the basis of the poor prognoses and the meager benefits deriving from the available systemic therapies, research into new treatments is extremely necessary. In this review, we focus on the available systemic therapies for advanced HCC, with a look toward the future.Hepatocellular carcinoma (HCC) is the most frequent primitive cancer of the liver, accounting for 90% of all recorded cases. HCC is the third most common cause of cancer-related death, with a 5-year survival rate of just 3%. In the advanced stages, systemic treatments allow doctors to obtain clinical benefits, although the prognosis remains very poor. In the past few decades, new molecular targeted therapies against receptor tyrosine kinases have been developed and clinically evaluated. Sorafenib was the first oral tyrosine kinase inhibitor (TKI) approved for the treatment of advanced HCC in 2007. Subsequently, other TKIs, including Cabozantinib, Regorafenib, Lenvatinib, and vascular endothelial growth factor receptor (VEGFR) inhibitors such as Ramucirumab and VEGF inhibitors such as Bevacizumab have been approved as first- or second-line treatments. More recently, the combination of immune checkpoint inhibitors and VEGF inhibitors (Atezolizumab plus Bevacizumab) have been analyzed and approved for the treatment of advanced HCC. On the basis of the poor prognoses and the meager benefits deriving from the available systemic therapies, research into new treatments is extremely necessary. In this review, we focus on the available systemic therapies for advanced HCC, with a look toward the future.

ME07 New treatment strategy for hepatobiliary cancer

Liver cancer or hepatocellular carcinoma or HCC has been one of the most challenging cancers to treat. Endless number of attempts to evaluate chemotherapeutic interventions, almost all fell short of any improvement of survival. This is despite a subtle improvement of survival using FOLFOX. Tyrosine kinase inhibitors were the critical driver of novel therapeutics for the treatment of advanced HCC. With the development of sorafenib and lenvatinib in first line treatment, two other tyrosine kinase inhibitors regorafenib and cabozantinib add to anti-VEGF ramucirumab demonstrated improved outcome in the second line setting.