Transarterial chemoembolizaton combined with sorafenib for intermediate-stage hepatocellular carcinoma: a window of tumor burden for survival benefit

Hepatocellular carcinoma (HCC) causes a significant health burden globally and its impact is expected to increase in the coming years. Intermediate stage HCC, as defined by the Barcelona Clinic Liver Cancer (BCLC) system stage B, represents up to 30% of patients at diagnosis and encompasses a broad spectrum of tumor burden. Several attempts have been made to further subclassify this heterogenous group. The current standard of care recommended by BCLC for intermediate stage HCC patients is transarterial chemoembolization (TACE), with modest outcomes reported. While refinements have been made to TACE technique and patient selection, it remains non-curative. In the real-world setting, only 60% of patients with intermediate stage HCC receive TACE, with the remainder deviating to a range of other therapies that have shown promise in select patient subgroups. These include curative treatments (resection, ablation, and liver transplantation), radiotherapy (stereotactic and radioembolization), systemic therapies, and their combination. In this review, we summarize the classifications and current management for patients with intermediate stage HCC as well as highlight recent key developments in this space.

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A New Treatment Option for Intermediate-Stage Hepatocellular Carcinoma with High Tumor Burden: Initial Lenvatinib Therapy with Subsequent Selective TACE

Liver Cancer ◽

10.1159/000502905 ◽

2019 ◽

Vol 8 (5) ◽

pp. 299-311 ◽

Cited By ~ 9

Author(s):

Masatoshi Kudo

Keyword(s):

Hepatocellular Carcinoma ◽

Treatment Option ◽

Intermediate Stage ◽

Tumor Burden ◽

High Tumor Burden ◽

New Treatment

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Hepatic Resection Provides Survival Benefit for Selected Intermediate-Stage (BCLC-B) Hepatocellular Carcinoma Patients

Cancer Research and Treatment ◽

10.4143/crt.2018.038 ◽

2019 ◽

Vol 51 (1) ◽

pp. 65-72 ◽

Cited By ~ 5

Author(s):

Zhang Zhaohui ◽

Shen Shunli ◽

Chen Bin ◽

Li Shaoqiang ◽

Hua Yunpeng ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Hepatic Resection ◽

Survival Benefit ◽

Intermediate Stage

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Analyses of Intermediate-Stage Hepatocellular Carcinoma Patients Receiving Transarterial Chemoembolization prior to Designing Clinical Trials

Liver Cancer ◽

10.1159/000508809 ◽

2020 ◽

Vol 9 (5) ◽

pp. 596-612

Author(s):

Keisuke Koroki ◽

Sadahisa Ogasawara ◽

Yoshihiko Ooka ◽

Hiroaki Kanzaki ◽

Kengo Kanayama ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Clinical Trials ◽

Transarterial Chemoembolization ◽

Checkpoint Inhibitors ◽

Intermediate Stage ◽

Tumor Burden ◽

Durable Response ◽

High Burden ◽

High Tumor Burden ◽

Stage Disease

Background: Intermediate-stage hepatocellular carcinoma (HCC) has a high frequency of recurrence and progression to advanced stage after transarterial chemoembolization (TACE), particularly in patients with high tumor burden. Promising new results from immune checkpoint inhibitors (ICIs) and ICI-based therapies are expected to replace TACE, especially in HCC patients with high tumor burden. Aims: The present study aimed to evaluate the effectiveness of TACE with a view to design clinical trials comparing TACE and ICIs. Methods: We retrospectively identified intermediate-stage HCC patients undergoing TACE from our database and subdivided patients into low- and high-burden groups based on three subclassification models using the diameter of the maximum tumor and the number of tumors. Clinical outcomes were compared between low- and high-burden intermediate-stage HCC. Results: Of 1,161 newly diagnosed HCC patients, 316 were diagnosed with intermediate-stage disease and underwent TACE. The median overall survival from high-burden intermediate-stage disease was not significantly different by clinical course, reaching high tumor burden in all subclassification models. The prognosis of high-burden patients after initial TACE was poor compared with low-burden patients for two models (except for the up-to-seven criteria). In all three models, high-burden patients showed a poor durable response rate (DRR) both ≥3 months and ≥6 months and poor prognosis after TACE. Moreover, patients with confirmed durable response ≥3 months and ≥6 months showed better survival outcomes for high-burden intermediate-stage HCC. Conclusions: Our results demonstrate the basis for selecting a population that would not benefit from TACE and setting DRR ≥3 months or ≥6 months as alternative endpoints when designing clinical trials comparing TACE and ICIs.

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Redefining Tumor Burden in Patients with Intermediate-Stage Hepatocellular Carcinoma: The Seven-Eleven Criteria

Liver Cancer ◽

10.1159/000517393 ◽

2021 ◽

pp. 1-12

Author(s):

Ya-Wen Hung ◽

I-Cheng Lee ◽

Chen-Ta Chi ◽

Rheun-Chuan Lee ◽

Chien-An Liu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Odds Ratio ◽

Characteristic Curve ◽

Intermediate Stage ◽

Complete Response ◽

Tumor Burden ◽

Hazard Ratio ◽

Information Criteria ◽

High Burden ◽

High Tumor Burden

Background and Aims: For patients with intermediate-stage hepatocellular carcinoma (HCC), the definition of high tumor burden remains controversial. This study aimed to compare the prognostic value of different criteria of tumor burden in patients with intermediate-stage HCC undergoing transarterial chemoembolization (TACE). Methods: From 2007 to 2019, 632 treatment-naive patients with intermediate-stage HCC undergoing TACE were retrospectively enrolled. We compared different criteria of tumor burden in discriminating radiologic response and survival, including up-to-7, up-to-11, 5–7, 7 lesions criteria, and newly proposed 7–11 criteria. Results: The proportions of patients classified as high tumor burden were varied by different criteria. Among the 5 criteria, 7–11 criteria have the best performance to discriminate complete response (CR) and overall survival (OS) after TACE. In patients with low, intermediate, and high tumor burden classified by 7–11 criteria, the CR rate was 21, 12, and 2.5%, respectively (p < 0.001), and the median OS was 33.1, 22.3, and 11.9 months, respectively (p < 0.001). By multivariate analysis, 7–11 criteria were significantly associated with CR (intermediate vs. high burden, odds ratio = 4.617, p = 0.002; low vs. high burden, odds ratio = 8.675, p < 0.001) and OS (intermediate vs. high burden, hazard ratio = 0.650, p < 0.001; low vs. high burden, hazard ratio = 0.520, p < 0.001). Seven to 11 criteria also had the lowest corrected Akaike information criteria, highest homogeneity value, and highest area under the receiver operating characteristic curve in predicting 1-, 2-, and 3-year mortality among all criteria. Conclusion: Conventional definitions of tumor burden were not optimal for patients with intermediate HCC. The new 7–11 criteria had the best discriminative power in predicting radiologic response and survival in patients with intermediate-stage HCC undergoing TACE.

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Intermediate Stage Hepatocellular Carcinoma Classifications: the Review

Journal of oncology: diagnostic radiology and radiotherapy ◽

10.37174/2587-7593-2021-4-1-53-64 ◽

2021 ◽

Vol 4 (1) ◽

pp. 53-64

Author(s):

D. M. Khaitsman ◽

I. V. Pogrebnyakov ◽

E. R. Virshke ◽

I. A. Trofimov ◽

D. Yu. Frantsev ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Transarterial Chemoembolization ◽

Prognostic Value ◽

Survival Rates ◽

Intermediate Stage ◽

Tumor Burden ◽

Patient Cohort ◽

Common Cancer

Hepatocellular carcinoma is the fifth most common cancer worldwide and the approaches to treatmentdiffer due to the stage of the disease. According to BCLC classification, B stage patients are recommendedto be underwent transarterial chemoembolization. However, BCLC B integrates patients with differentintrahepatic tumor burden and with different liver deterioration. There are many staging classifications thatdetermine the treatment and survival rates due to heterogeneity of this patient cohort. The aim of this studyis to review the existing ones and to describe their prognostic value.

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Effect of Transarterial Chemoembolization on ALBI Grade in Intermediate-Stage Hepatocellular Carcinoma: Criteria for Unsuitable Cases Selection

Cancers ◽

10.3390/cancers13174325 ◽

2021 ◽

Vol 13 (17) ◽

pp. 4325

Author(s):

Chen-Ta Chi ◽

I-Cheng Lee ◽

Rheun-Chuan Lee ◽

Ya-Wen Hung ◽

Chien-Wei Su ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

At Risk ◽

Transarterial Chemoembolization ◽

Standard Of Care ◽

Intermediate Stage ◽

Tumor Burden ◽

Factors Associated ◽

Tumor Number ◽

Tumor Involvement ◽

Grade 3

Transarterial chemoembolization (TACE) is the standard of care for intermediate stage hepatocellular carcinoma (HCC). We aimed to identify unsuitable cases who were at risk of ALBI-grade migration by TACE. Consecutive 531 BCLC-B HCC patients undergoing TACE were reviewed, and factors associated with ALBI-grade migration were analyzed. There were 129 (24.3%) patients experienced acute ALBI-grade migration after TACE, and 85 (65.9%) out of the 129 patients had chronic ALBI-grade migration. Incidences of acute ALBI-grade migration were 13.9%, 29.0% for patients within or beyond up-to-7 criteria (p < 0.001) and 20.0%, 36.2% for patients within or beyond up-to-11 criteria (p < 0.001), respectively. HBV infection, tumor size plus tumor number criteria were risk factors associated with acute ALBI-grade migration. Bilobar tumor involvement was the risk factor of chronic ALBI-grade migration in patients with acute ALBI-grade migration. Up-to-eleven (p = 0.007) performed better than up-to-seven (p = 0.146) to differentiate risk of dynamic ALBI score changes. Moreover, ALBI-grade migration to grade 3 has adverse effect on survival. In conclusion, tumor burden beyond up-to-eleven was associated with ALBI-grade migration after TACE, indicating that up-to-eleven can select TACE-unsuitable HCC patients who are at risk of liver function deterioration.

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Lenvatinib for Hepatocellular Carcinoma: A Literature Review

Pharmaceuticals ◽

10.3390/ph14010036 ◽

2021 ◽

Vol 14 (1) ◽

pp. 36

Author(s):

Takeshi Hatanaka ◽

Atsushi Naganuma ◽

Satoru Kakizaki

Keyword(s):

Hepatocellular Carcinoma ◽

Overall Survival ◽

Liver Cancer ◽

Liver Function ◽

Adverse Events ◽

Therapeutic Response ◽

Objective Response ◽

Intermediate Stage ◽

Tumor Burden ◽

Asia Pacific

Lenvatinib, which is an oral multikinase inhibitor, showed non-inferiority to the sorafenib in terms of overall survival (OS) and a higher objective response rate (ORR) and better progression-free survival (PFS) in patients with hepatocellular carcinoma (HCC). A good liver function and Barcelona Clinic Liver Cancer (BCLC) intermediate stage were the key factors in achieving therapeutic efficacy. The management of adverse events plays an important role in continuing lenvatinib treatment. While sequential therapies contributed to prolonging overall survival, effective molecular targeted agents for the administration after lenvatinib have not been established. Repeated transcatheter arterial chemoembolization (TACE) was associated with a decline in the liver function and poor therapeutic response in BCLC intermediate patients. Recently, the Asia-Pacific Primary Liver Cancer Expert (APPLE) Consensus Statement proposed the criteria for TACE unsuitability. Upfront systemic therapy may be better for the BCLC intermediate stage HCC patients with a high tumor burden, while selective TACE will be recommended for obtaining a curative response in patients with a low tumor burden. This article reviews the therapeutic response, management of adverse events, post-progression treatment after Lenvatinib, and treatment strategy for BCLC intermediate stage HCC.

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