Systemic therapy for hepatocellular carcinoma: current status and future perspectives

Overall Survival ◽

Systemic Therapy ◽

Immune Checkpoint ◽

Standard Of Care ◽

Current Status ◽

First Line ◽

Sorafenib Treatment ◽

First Choice

Abstract Since sorafenib was established as the standard of care for patients with advanced hepatocellular carcinoma, various tyrosine kinase inhibitors, targeting vascular endothelial growth factor receptor and other molecular growth factors, have been developed. Lenvatinib demonstrated non-inferiority to sorafenib in terms of the overall survival, and it has also become confirmed as another standard of care for patients with advanced hepatocellular carcinoma. Recently, various immune checkpoint inhibitors have been investigated, either as monotherapy or in combination with another agent, and superiority of the combination of atezolizumab plus bevacizumab, in terms of the overall survival and progression-free survival, has been demonstrated over sorafenib, which is recognized as the treatment regimen of first choice for first-line systemic therapy of advanced hepatocellular carcinoma. Regorafenib, cabozantinib and ramucirumab have been demonstrated to show survival benefits as second-line treatment agents for progressive disease after first-line sorafenib treatment. There are still various medical requirements in systemic therapy for hepatocellular carcinoma. To date, no evidence has been established for the selection of sequential treatment after immune checkpoint inhibitor-containing treatments, especially atezolizumab plus bevacizumab. A promising treatment for Child-Pugh class B hepatocellular carcinoma patients is also an urgent medical need that has not yet been met. Although there are some difficulties in establishing the needed evidence, well-designed clinical trials are warranted.

Baseline Interleukin-6 and -8 predict response and survival in patients with advanced hepatocellular carcinoma treated with sorafenib monotherapy: an exploratory post hoc analysis of the SORAMIC trial

Journal of Cancer Research and Clinical Oncology ◽

10.1007/s00432-021-03627-1 ◽

2021 ◽

Author(s):

Osman Öcal ◽

Kerstin Schütte ◽

Juozas Kupčinskas ◽

Egidijus Morkunas ◽

Gabija Jurkeviciute ◽

...

Keyword(s):

Overall Survival ◽

Objective Response ◽

Sorafenib Treatment ◽

Post Hoc Analysis ◽

Y90 Radioembolization ◽

Baseline Values ◽

Post Hoc

Abstract Purpose To explore the potential correlation between baseline interleukin (IL) values and overall survival or objective response in patients with hepatocellular carcinoma (HCC) receiving sorafenib. Methods A subset of patients with HCC undergoing sorafenib monotherapy within a prospective multicenter phase II trial (SORAMIC, sorafenib treatment alone vs. combined with Y90 radioembolization) underwent baseline IL-6 and IL-8 assessment before treatment initiation. In this exploratory post hoc analysis, the best cut-off points for baseline IL-6 and IL-8 values predicting overall survival (OS) were evaluated, as well as correlation with the objective response. Results Forty-seven patients (43 male) with a median OS of 13.8 months were analyzed. Cut-off values of 8.58 and 57.9 pg/mL most effectively predicted overall survival for IL-6 and IL-8, respectively. Patients with high IL-6 (HR, 4.1 [1.9–8.9], p < 0.001) and IL-8 (HR, 2.4 [1.2–4.7], p = 0.009) had significantly shorter overall survival than patients with low IL values. Multivariate analysis confirmed IL-6 (HR, 2.99 [1.22–7.3], p = 0.017) and IL-8 (HR, 2.19 [1.02–4.7], p = 0.044) as independent predictors of OS. Baseline IL-6 and IL-8 with respective cut-off values predicted objective response rates according to mRECIST in a subset of 42 patients with follow-up imaging available (IL-6, 46.6% vs. 19.2%, p = 0.007; IL-8, 50.0% vs. 17.4%, p = 0.011). Conclusion IL-6 and IL-8 baseline values predicted outcomes of sorafenib-treated patients in this well-characterized prospective cohort of the SORAMIC trial. We suggest that the respective cut-off values might serve for validation in larger cohorts, potentially offering guidance for improved patient selection.

OC.04.3 FIRST-LINE IMMUNE CHECKPOINT INHIBITOR-BASED SEQUENTIAL THERAPIES FOR ADVANCED HEPATOCELLULAR CARCINOMA: A RATIONALE FOR FUTURE TRIALS

Digestive and Liver Disease ◽

10.1016/s1590-8658(21)00503-x ◽

2021 ◽

Vol 53 ◽

pp. S107

Author(s):

G. Cabibbo ◽

C. Celsa ◽

S. Battaglia ◽

M. Enea ◽

G.E.M. Rizzo ◽

...

Keyword(s):

Immune Checkpoint ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitor ◽

First Line

Update on Systemic Therapy for Advanced Soft-Tissue Sarcoma

Current Oncology ◽

10.3747/co.27.5475 ◽

2020 ◽

Vol 27 (11) ◽

pp. 25-33 ◽

Cited By ~ 5

Author(s):

A. Smrke ◽

Y. Wang ◽

C. Simmons

Keyword(s):

Overall Survival ◽

Clinical Trials ◽

Soft Tissue ◽

Soft Tissue Sarcoma ◽

Systemic Therapy ◽

English Language ◽

Standard Of Care ◽

Current Evidence ◽

First Line ◽

First Line Therapy

Background: Soft-tissue sarcoma (sts) represents a rare group of mesenchymal neoplasms comprising more than 50 heterogeneous subtypes. Great efforts have been made to increase the understanding of the treatment of advanced sts (unresectable or metastatic disease). We set out to determine whether outcomes for patients with advanced sts have improved over time and to assess the current evidence for systemic therapy. Methods: In a scoping review, we evaluated the contemporary evidence for systemic treatment of advanced sts in adults (>18 years of age). Phase i, ii, and iii studies of systemic therapy for advanced sts published in the English language were included. After abstract and full-text review of seventy-seven studies, sixty-two trials met the inclusion criteria. Results: The number of clinical trials conducted and published in advanced sts has increased over the last 30 years. Although median overall survival has increased, attempts at improving first-line therapy through dose intensification, doublet chemotherapy, or alternative backbones have not been successful. The optimal therapy beyond anthracyclines remains a challenge, especially given the heterogeneity that grouping multiple sts subtypes within clinical trials creates. However, increasing numbers of agents are being studied, and several studies had shown isolated benefit in progression-free or overall survival. Summary: First-line systemic therapy with an anthracycline remains the standard of care for advanced sts. However, choice of subsequent therapy beyond anthracyclines remains challenging. Novel systemic therapies, use of molecular diagnostics to direct therapy, subtype-specific trials, and learnings from real-world retrospective data are all important for improving outcomes in patients with advanced sts.

First-line Immune Checkpoint Inhibitor-based Sequential Therapies for Advanced Hepatocellular Carcinoma: Rationale for Future Trials

Qeios ◽

10.32388/qdwami ◽

2022 ◽

Author(s):

Ciro Celsa

Keyword(s):

Immune Checkpoint ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitor ◽

First Line

Systemic Therapy in Hepatocellular Carcinoma

10.5772/intechopen.100257 ◽

2021 ◽

Author(s):

Chanchai Charonpongsuntorn

Keyword(s):

Systemic Therapy ◽

Immune Checkpoint ◽

Checkpoint Inhibitors ◽

Immune Checkpoint Blockade ◽

Advanced Stage ◽

First Line ◽

Standard Guideline ◽

Novel Drugs ◽

First Time

Systemic therapy of advanced stage hepatocellular carcinoma (HCC) was limited to the sorafenib in the past decade since 2007. Novel agents including multiple targeting agents, immune checkpoint inhibitors and anti-angiogenesis reported efficacy in treatment. This is the first time, the combination of atezolizumab and bevacizumab as first-line treatment is superior to sorafenib. Standard guideline in advanced HCC was changing. New novel drugs increase in available including multiple targeting agents and immune checkpoint blockade such as Lenvatinib, regorafenib, cabozantinib, ramucirumab and immunotherapy as first line or second line therapy will benefit in term of survival benefit and quality of life in advanced stage or unresectable hepatocellular carcinoma

Role of immunotherapy in the management of hepatocellular carcinoma: current standards and future directions

Current Oncology ◽

10.3747/co.27.7315 ◽

2020 ◽

Vol 27 (S3) ◽

Author(s):

A. Weinmann ◽

P.R. Galle

Keyword(s):

Overall Survival ◽

Clinical Trials ◽

Statistical Significance ◽

Phase Iii ◽

Line Treatment ◽

Second Line ◽

First Line ◽

Promising Therapeutic Approach

The multikinase inhibitor sorafenib was the only approved systemic therapy in advanced hepatocellular carcinoma (hcc) for about a decade. In recent years, the number of approved agents has increased significantly as a result of a number of positive phase iii clinical trials. Lenvatinib as a first-line treatment, and regorafenib, cabozantinib, and ramucirumab in the second-line setting are now approved by the U.S. Food and Drug Administration (fda) and the European Medicines Agency. In phase ii studies, immunotherapy with nivolumab and monotherapy using pembrolizumab yielded impressive results for overall survival in therapy-naïve and pretreated patients, leading to the accelerated approval by the fda of nivolumab and pembrolizumab for second-line treatment. However, phase iii trials of nivolumab in the first line and pembrolizumab in the second line as single agents failed to reach statistical significance, although clinical benefit for a subset of patients with long durations of response could be demonstrated. Despite that setback, immunotherapy for hcc is a promising therapeutic approach, and the combination of immunotherapy with other treatment modalities such as monoclonal antibodies, tyrosine kinase inhibitors, or local therapies has the potential to increase the overall response rate and survival. Recently, the results of a phase iii trial of combination atezolizumab–bevacizumab compared with sorafenib showed a highly significant survival benefit and median overall survival that was not reached in the immunotherapy arm, making the combination the preferred standard of care in first-line therapy. Despite the impressive results and generally good toxicity profile of immunotherapy, patients who respond to therapy constitute only a subset of the overall population, and response rates are still limited. This review focuses on the currently reported results and ongoing clinical trials of checkpoint inhibitor–based immunotherapy in hcc.

Novel Pretreatment Scoring Incorporating C-reactive Protein to Predict Overall Survival in Advanced Hepatocellular Carcinoma with Sorafenib Treatment

Liver Cancer ◽

10.1159/000449337 ◽

2016 ◽

Vol 5 (4) ◽

pp. 257-268 ◽

Cited By ~ 6

Author(s):

Hiroyuki Nakanishi ◽

Masayuki Kurosaki ◽

Kaoru Tsuchiya ◽

Yutaka Yasui ◽

Mayu Higuchi ◽

...

Keyword(s):

Overall Survival ◽

C Reactive Protein ◽

Sorafenib Treatment ◽

Reactive Protein

A population-based analysis of prognostic factors in patients with advanced hepatocellular carcinoma treated with sorafenib.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.4_suppl.163 ◽

2012 ◽

Vol 30 (4_suppl) ◽

pp. 163-163

Author(s):

Alan D. Smith ◽

Winson Y. Cheung

Keyword(s):

Overall Survival ◽

Prognostic Factors ◽

Elevated Serum ◽

Clinical Factors ◽

Conventional Chemotherapy ◽

Sorafenib Treatment ◽

Advanced Hcc ◽

Staging Systems

163 Background: Available clinical prognostic scoring systems for advanced hepatocellular carcinoma (HCC) were developed in the era of conventional chemotherapy. In 2008, the molecularly targeted agent sorafenib became the new standard of care for advanced HCC due to its survival benefit. The utility of these prognostic models in the setting of sorafenib is unclear. Our aims were to assess for new prognostic factors in patients treated with sorafenib and compare these with known prognostic systems. Methods: All patients diagnosed with advanced HCC from 2008 to 2010 in British Columbia, Canada and treated with sorafenib at any 1 of 5 regional cancer centers were eligible. Based on the established Okuda, CLIP, Barcelona, and French staging systems, we collected baseline demographic and disease characteristics of patients prior to receipt of sorafenib. Multivariate logistic regression models were constructed to examine for associations between these clinical factors and overall survival. Results: Of 183 patients identified, 152 were evaluable: median age was 63 years, 78% were men, average number of sorafenib treatment was 5.3 cycles, and median overall survival was 9.6 months. The prevalence of hepatitis B, hepatitis C, and alcohol-related liver disease were 32%, 15%, and 11%, respectively. Univariate analyses showed that poor performance status, presence of clinical ascites, as well as elevated serum AST, GGT, ALP, bilirubin and platelet levels were each associated with worse overall survival (all p<0.05). In multivariate analyses, however, none of these clinical factors continued to be independently predictive of outcome (all p>0.05). Conclusions: Traditional clinical prognostic factors developed in the era of conventional chemotherapy do not appear to have the same prognostic utility in this contemporary Western cohort of advanced HCC patients treated with sorafenib. This observation underscores the need to identify molecular biomarkers that provide better prognostic information.

Efficacy and safety of localized concurrent chemoradiation therapy and sorafenib sequential therapy in advanced hepatocellular carcinoma: A prospective phase II trial.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e15678 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e15678-e15678

Author(s):

Beom Kyung Kim ◽

Do Young Kim ◽

Hye Jin Choi ◽

Seung-Hoon Beom ◽

Hye Won Lee ◽

...

Keyword(s):

Overall Survival ◽

Objective Response Rate ◽

Median Overall Survival ◽

Response Rate ◽

Phase Ii Trial ◽

Objective Response ◽

Efficacy And Safety ◽

Sorafenib Treatment

e15678 Background: Patients with advanced hepatocellular carcinoma (HCC) have a particularly poor prognosis of the median overall survival of less than 12 months. Even though sorafenib has been approved for treating advanced stage HCC, the unsatisfactory objective response rate still remain unresolved. In the current study, we aimed to evaluate the efficacy and safety of localized concurrent chemoradiotherapy (CCRT) followed by sequential sorafenib treatment for advanced hepatocellular carcinoma. Methods: This study is an ongoing, phase II trial. Patients with advanced HCC not amenable for curative treatments were eligible. In the course of radiotherapy for 5 weeks, hepatic arterial infusion of 5-fluorouracil (500mg/day) via implanted port was applied during the first 5 days and the last 5 days of radiotherapy. Four weeks after localized CCRT, sorafenib (400mg bid) was maintained. The primary endpoint was overall survival. Results: A total of 47 patients were enrolled. After the completion of localized CCRT, the objective response rate was 31.9%. During the overall treatment course, the objective response rate was 46.8% respectively. Overall, 7 patients (14.9%) underwent curative resection or transplantation after down-staging. The median overall survival was 18.4 months and the progression-free survival was 6.8 months. Adverse events were predictable and manageable with conservative care. Conclusions: Localized CCRT followed by sequential sorafenib treatment in patients with advanced HCC showed significant activity and good tolerability. Furthermore, such a treatment modality, when compared to the use of sorafenib alone, might provide the additional therapeutic benefit through initial tumor reduction, allowing curative treatment after down-staging in 14.9% of patients, Further randomized trial should be required to make the more robust evidence. Clinical trial information: NCT02425605.

Response Prediction in Immune Checkpoint Inhibitor Immunotherapy for Advanced Hepatocellular Carcinoma

Cancers ◽

10.3390/cancers13071607 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1607

Author(s):

Hao-Chien Hung ◽

Jin-Chiao Lee ◽

Yu-Chao Wang ◽

Chih-Hsien Cheng ◽

Tsung-Han Wu ◽

...

Keyword(s):

Disease Control ◽

Immune Checkpoint ◽

Tumor Response ◽

Objective Response ◽

Unmet Need ◽

Sorafenib Treatment ◽

Small Series ◽

Pre Treatment

Immune checkpoint inhibitors (ICI) have been applied to treat advanced stage hepatocellular carcinoma (HCC) and obtain promising effects. However, tumor response to treatment was unpredictable. A predicting biomarker of objective response or disease-control is an unmet need for patient selection. In this study, 45 advanced HCC patients who failed to sorafenib treatment and received nivolumab, 3 mg/kg bi-weekly, were included. Tumor responses to nivolumab treatment were assessed by the modified response evaluation criteria in solid tumors (mRECIST) criteria. Tumor responses were correlated to clinical characteristics to find out response predictors. In this small series, the prevalence of extrahepatic nodal metastasis, distant metastasis, and portal vein thrombus among the patients were 22.2% (n = 10), 48.9% (n = 22), and 42.2% (n = 19), respectively. The pre-treatment tumor size was 7.2 ± 4.2 cm in maximal diameter, and the calculated total tumor volume was 619.0 ± 831.1 cm3. Among 45 patients, 3 patients had partial response (PR), 11 had stable disease (SD), and the other 31 had progression of disease. By correlating clinical data to the patients with PR and SD, serum neutrophil-to-lymphocyte ratio (NLR) (hazard ratio (HR) = 2.04) and patient-generated subjective global assessment (PG-SGA) score (HR = 2.30) were the independent factors in multivariate analysis. By receiver operating characteristic curve analysis, pre-treatment NLR ≤ 2.5 and PG-SGA score < 4 were the cutoff points to predict tumor response to ICI treatment. In conclusion, biomarkers to predict tumor response for HCC are still lacking in this costly ICI therapy. In this study, NLR ≤ 2.5 and PG-SGA score < 4 indicated disease-control, and can be applied as biomarkers to select the right patients to receive this costly therapy.