Editorial

3 pages, 160 KiB

Open AccessEditorial

Novel Therapies for Hepatocellular Carcinoma

by Lorenza Rimassa

Cancers 2020, 12(10), 3049; https://doi.org/10.3390/cancers12103049 - 20 Oct 2020

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Since 2007, for patients with advanced- or intermediate-stage hepatocellular carcinoma (HCC) unsuitable for locoregional treatments and with preserved liver function, the multikinase inhibitor (MKI) sorafenib has been the worldwide standard of care [...] Full article

(This article belongs to the Special Issue Novel Therapies for Hepatocellular Carcinoma)

Research

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15 pages, 2509 KiB

Open AccessArticle

Tumor Treating Fields (TTFields) Concomitant with Sorafenib Inhibit Hepatocellular Carcinoma In Vitro and In Vivo

by Shiri Davidi, Sara Jacobovitch, Anna Shteingauz, Antonia Martinez-Conde, Ori Braten, Catherine Tempel-Brami, Einav Zeevi, Roni Frechtel-Gerzi, Hila Ene, Eyal Dor-On, Tali Voloshin, Itai Tzchori, Adi Haber, Moshe Giladi, Adrian Kinzel, Uri Weinberg and Yoram Palti

Cancers 2022, 14(12), 2959; https://doi.org/10.3390/cancers14122959 - 15 Jun 2022

Cited by 9 | Viewed by 2547 | Correction

Abstract

Hepatocellular carcinoma (HCC), a highly aggressive liver cancer, is a leading cause of cancer-related death. Tumor Treating Fields (TTFields) are electric fields that exert antimitotic effects on cancerous cells. The aims of the current research were to test the efficacy of TTFields in [...] Read more.

Hepatocellular carcinoma (HCC), a highly aggressive liver cancer, is a leading cause of cancer-related death. Tumor Treating Fields (TTFields) are electric fields that exert antimitotic effects on cancerous cells. The aims of the current research were to test the efficacy of TTFields in HCC, explore the underlying mechanisms, and investigate the possible combination of TTFields with sorafenib, one of the few front-line treatments for patients with advanced HCC. HepG2 and Huh-7D12 human HCC cell lines were treated with TTFields at various frequencies to determine the optimal frequency eliciting maximal cell count reduction. Clonogenic, apoptotic effects, and autophagy induction were measured. The efficacy of TTFields alone and with concomitant sorafenib was tested in cell cultures and in an orthotopic N1S1 rat model. Tumor volume was examined at the beginning and following 5 days of treatment. At study cessation, tumors were weighed and examined by immunohistochemistry to assess autophagy and apoptosis. TTFields were found in vitro to exert maximal effect at 150 kHz, reducing cell count and colony formation, increasing apoptosis and autophagy, and augmenting the effects of sorafenib. In animals, TTFields concomitant with sorafenib reduced tumor weight and volume fold change, and increased cases of stable disease following treatment versus TTFields or sorafenib alone. While each treatment alone elevated levels of autophagy relative to control, TTFields concomitant with sorafenib induced a significant increase versus control in tumor ER stress and apoptosis levels, demonstrating increased stress under the multimodal treatment. Overall, TTFields treatment demonstrated efficacy and enhanced the effects of sorafenib for the treatment of HCC in vitro and in vivo, via a mechanism involving induction of autophagy. Full article

(This article belongs to the Special Issue Novel Therapies for Hepatocellular Carcinoma)

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23 pages, 10357 KiB

Open AccessArticle

MBP-11901 Inhibits Tumor Growth of Hepatocellular Carcinoma through Multitargeted Inhibition of Receptor Tyrosine Kinases

by Hyun Jin Park, Garam Choi, Seongmin Ha, Yesl Kim, Min-Jin Choi, Minsup Kim, Md. Kamrul Islam, Yongmin Chang, Tae-Jun Kwon, Dongkyu Kim, Eunbee Jang, Tae Hwan Kim, Sha Joung Chang and Yeoun-Hee Kim

Cancers 2022, 14(8), 1994; https://doi.org/10.3390/cancers14081994 - 14 Apr 2022

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Abstract

Hepatocellular carcinomas (HCCs) are aggressive tumors with a poor prognosis. Approved first-line treatments include sorafenib, lenvatinib, and a combination of atezolizumab and bevacizumab; however, they do not cure HCC. We investigated MBP-11901 as a drug candidate for HCC. Cell proliferation and cytotoxicity were [...] Read more.

Hepatocellular carcinomas (HCCs) are aggressive tumors with a poor prognosis. Approved first-line treatments include sorafenib, lenvatinib, and a combination of atezolizumab and bevacizumab; however, they do not cure HCC. We investigated MBP-11901 as a drug candidate for HCC. Cell proliferation and cytotoxicity were evaluated using normal and cancer human liver cell lines, while Western blotting and flow cytometry evaluated apoptosis. The anticancer effect of MBP-11901 was verified in vitro through migration, invasion, colony formation, and JC-1 MMP assays. In mouse models, the tumor volume, tumor weight, and bodyweight were measured, and cancer cell proliferation and apoptosis were analyzed. The toxicity of MBP-11901 was investigated through GOT/GPT and histological analyses in the liver and kidney. The signaling mechanism of MBP-11901 was investigated through kinase assays, phosphorylation analysis, and in silico docking simulations. Results. MBP-11901 was effective against various human HCC cell lines, leading to the disappearance of most tumors when administered orally in animal models. This effect was dose-dependent, with no differences in efficacy according to administration intervals. MBP-11901 induced anticancer effects by targeting the signaling mechanisms of FLT3, VEGFR2, c-KIT, and PDGFRβ. MBP-11901 is suggested as a novel therapeutic agent for the treatment of advanced or unresectable liver cancer. Full article

(This article belongs to the Special Issue Novel Therapies for Hepatocellular Carcinoma)

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15 pages, 1356 KiB

Open AccessArticle

Tumor Treating Fields Concomitant with Sorafenib in Advanced Hepatocellular Cancer: Results of the HEPANOVA Phase II Study

by Eleni Gkika, Anca-Ligia Grosu, Teresa Macarulla Mercade, Antonio Cubillo Gracián, Thomas B. Brunner, Michael Schultheiß, Monika Pazgan-Simon, Thomas Seufferlein and Yann Touchefeu

Cancers 2022, 14(6), 1568; https://doi.org/10.3390/cancers14061568 - 18 Mar 2022

Cited by 12 | Viewed by 3338

Abstract

Advanced hepatocellular carcinoma (HCC) is an aggressive disease associated with poor prognosis. Tumor Treating Fields (TTFields) therapy is a non-invasive, loco-regional treatment approved for glioblastoma and malignant pleural mesothelioma. HCC preclinical and abdominal simulation data, together with clinical results in other solid tumors, [...] Read more.

Advanced hepatocellular carcinoma (HCC) is an aggressive disease associated with poor prognosis. Tumor Treating Fields (TTFields) therapy is a non-invasive, loco-regional treatment approved for glioblastoma and malignant pleural mesothelioma. HCC preclinical and abdominal simulation data, together with clinical results in other solid tumors, provide a rationale for investigating TTFields with sorafenib in this patient population. HEPANOVA was a phase II, single arm, historical control study in adults with advanced HCC (NCT03606590). Patients received TTFields (150 kHz) for ≥18 h/day concomitant with sorafenib (400 mg BID). Imaging assessments occurred every 12 weeks until disease progression. The primary endpoint was the overall response rate (ORR). Safety was also evaluated. Patients (n = 27 enrolled; n = 21 evaluable) had a poor prognosis; >50% were Child–Turcotte–Pugh class B and >20% had a baseline Eastern Clinical Oncology Group performance status (ECOG PS) of 2. The ORR was higher, but not statistically significant, for TTFields/sorafenib vs. historical controls: 9.5% vs. 4.5% (p = 0.24), respectively; all responses were partial. Among patients (n = 11) with ≥12 weeks of TTFields/sorafenib, ORR was 18%. Common adverse events (AEs) were diarrhea (n = 15/27, 56%) and asthenia (n = 11/27, 40%). Overall, 19/27 (70%) patients had TTFields-related skin AEs; none were serious. TTFields/sorafenib improved response rates vs. historical controls in patients with advanced HCC, with no new safety concerns or related systemic toxicity. Full article

(This article belongs to the Special Issue Novel Therapies for Hepatocellular Carcinoma)

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19 pages, 4811 KiB

Open AccessArticle

Efficacy of Superselective Conventional Transarterial Chemoembolization Using Guidance Software for Hepatocellular Carcinoma within Three Lesions Smaller Than 3 cm

by Shiro Miyayama, Masashi Yamashiro, Rie Ikeda, Junichi Matsumoto, Kiyotaka Takeuchi, Naoko Sakuragawa, Teruyuki Ueda, Taku Sanada, Kazuo Notsumata and Takuro Terada

Cancers 2021, 13(24), 6370; https://doi.org/10.3390/cancers13246370 - 19 Dec 2021

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Abstract

The indication of transarterial chemoembolization (TACE) has advanced to hepatocellular carcinoma (HCC) of Barcelona Clinic Liver Cancer (BCLC) stage A when surgical resection (SR), thermal ablation, and bridging to transplantation are contraindicated; however, TACE for small HCC is frequently difficult and ineffective because [...] Read more.

The indication of transarterial chemoembolization (TACE) has advanced to hepatocellular carcinoma (HCC) of Barcelona Clinic Liver Cancer (BCLC) stage A when surgical resection (SR), thermal ablation, and bridging to transplantation are contraindicated; however, TACE for small HCC is frequently difficult and ineffective because of less hypervascularity and the presence of tumor portions receiving a dual blood supply. Here, we report outcomes of superselective conventional TACE (cTACE) for 259 patients with HCCs within three lesions smaller than 3 cm using guidance software. Automated tumor feeder detection (AFD) functionality was applied to identify tumor feeders on cone-beam computed tomography during hepatic arteriography (CBCTHA) data. When it failed, the feeder was identified by manual feeder detection functionality and/or selective angiography and CBCTHA. Regarding the technical success in 382 tumors (mean diameter, 17.2 ± 5.9 mm), 310 (81.2%) were completely embolized with a safety margin (5 mm wide for HCC ≤25 mm and 10 mm wide for HCC >25 mm). In 61 (16.0%), the entire tumor was embolized but the safety margin was not uniformly obtained. The entire tumor was not embolized in 11 (2.9%). Regarding the tumor response at 2–3 months after cTACE in 303 tumors excluding those treated with combined radiofrequency ablation (RFA) or SR and lost to follow-up, 287 (94.7%) were classified into complete response, seven (2.3%) into partial response, and nine (3.0%) into stable disease. The mean follow-up period was 44.9 ± 27.6 months (range, 1–109) and the cumulative local tumor progression rates at 1, 3, 5, and 7 years were 17.8, 27.8, 32.0, and 36.0%, respectively. The 1-, 3-, 5-, and 7-year overall and recurrence-free survival rates in 175 patients, excluding those with Child–Pugh C class, who died of other malignancies, or who underwent combined RFA or hepatic resection, were 97.1 and 68.7, 82.8 and 34.9, 64.8 and 20.2, and 45.3 and 17.3%, respectively. Our results indicate the efficacy of superselective cTACE using guidance software for HCC within three lesions smaller than 3 cm. Full article

(This article belongs to the Special Issue Novel Therapies for Hepatocellular Carcinoma)

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11 pages, 268 KiB

Open AccessArticle

Hepatotoxicity in Patients with Hepatocellular Carcinoma on Treatment with Immune Checkpoint Inhibitors

by Nicola Personeni, Tiziana Pressiani, Antonio D’Alessio, Maria Giuseppina Prete, Silvia Bozzarelli, Luigi Terracciano, Arianna Dal Buono, Antonio Capogreco, Alessio Aghemo, Ana Lleo, Romano Fabio Lutman, Massimo Roncalli, Laura Giordano, Armando Santoro, Luca Di Tommaso and Lorenza Rimassa

Cancers 2021, 13(22), 5665; https://doi.org/10.3390/cancers13225665 - 12 Nov 2021

Cited by 6 | Viewed by 1989

Abstract

Risk factors for hepatic immune-related adverse events (HIRAEs) in patients with advanced/unresectable hepatocellular carcinoma (HCC) treated with immune checkpoint inhibitors (ICIs) are unclear. We investigated: (i) clinical and morpho-pathological predictors of HIRAEs in 27 pretreatment tumor specimens, including surrogate biomarkers of the HCC [...] Read more.

Risk factors for hepatic immune-related adverse events (HIRAEs) in patients with advanced/unresectable hepatocellular carcinoma (HCC) treated with immune checkpoint inhibitors (ICIs) are unclear. We investigated: (i) clinical and morpho-pathological predictors of HIRAEs in 27 pretreatment tumor specimens, including surrogate biomarkers of the HCC immune class (based on intratumoral tertiary lymphoid structures, and glutamine synthase, CD3, and CD79 expression); and (ii) the relationship between HIRAE onset and subsequent treatment outcomes. Fifty-eight patients were included—20 (34%) received ICIs alone, and 38 (66%) received ICIs plus targeted agents as first- or further-line treatment. After a median time of 0.9 months (range, 0.4–2.7), nine patients (15.5%) developed grade ≥ 3 hepatitis, which was significantly associated with higher baseline ALT levels (p = 0.037), and an infectious HCC etiology (p = 0.023). ICIs were safely resumed in six out of nine patients. Time to treatment failure (TTF) was not significantly different in patients developing grade ≥ 3 hepatitis vs. lower grades (3.25 vs. 3.91 months, respectively; p = 0.81). Biomarker surrogates for the HCC immune class were not detected in patients developing grade ≥ 3 hepatitis. Grade ≥ 3 hepatitis has a benign course that does not preclude safe ICI reintroduction, without any detrimental effect on TTF. Full article

(This article belongs to the Special Issue Novel Therapies for Hepatocellular Carcinoma)

15 pages, 1478 KiB

Open AccessArticle

Clinical Importance of Regimens in Hepatic Arterial Infusion Chemotherapy for Advanced Hepatocellular Carcinoma with Macrovascular Invasion

by Takashi Niizeki, Hideki Iwamoto, Tomotake Shirono, Shigeo Shimose, Masahito Nakano, Shusuke Okamura, Yu Noda, Naoki Kamachi, Suzuki Hiroyuki, Miwa Sakai, Ryoko Kuromatsu, Hironori Koga and Takuji Torimura

Cancers 2021, 13(17), 4450; https://doi.org/10.3390/cancers13174450 - 03 Sep 2021

Cited by 10 | Viewed by 2198

Abstract

Macroscopic vascular invasion (MVI) is a poor prognostic factor in hepatocellular carcinoma (HCC). Hepatic arterial infusion chemotherapy (HAIC) is a promising treatment in MVI-HCC. However, it is not clear which regimens are suitable for HAIC. In this study, we aimed to compare the [...] Read more.

Macroscopic vascular invasion (MVI) is a poor prognostic factor in hepatocellular carcinoma (HCC). Hepatic arterial infusion chemotherapy (HAIC) is a promising treatment in MVI-HCC. However, it is not clear which regimens are suitable for HAIC. In this study, we aimed to compare the therapeutic effects between New FP (a fine-powder cisplatin suspended with lipiodol plus 5-fluorouracil) and low dose FP (LFP/cisplatin plus 5-fluorouracil) in the treatment of MVI-HCC patients with Child–Pugh class A. New FP is a regimen that consists of a fine-powder cisplatin suspended with lipiodol and 5-fluorouracil. Fifty-one patients were treated with LFP, and 99 patients were New FP. We compared the therapeutic effects of LFP and New FP and assessed factors that associated with the therapeutic effects. The median survival and progression-free survival times of LFP and New FP were 16.1/24.7 and 5.4/8.8 months, respectively (p < 0.05, p < 0.05). The complete response (29%) and objective response rate (76%) of New FP were significantly higher than those of LFP (p < 0.001, p < 0.01). Factors associated with better therapeutic response were better ALBI-grade and New FP treatment choice. New FP is a more powerful regimen than LFP in HAIC for MVI-HCC. New FP represents a recommended HAIC regimen for the treatment of patients with MVI-HCC. Full article

(This article belongs to the Special Issue Novel Therapies for Hepatocellular Carcinoma)

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10 pages, 1285 KiB

Open AccessArticle

ALBI Score Is a Strong Predictor of Toxicity Following SIRT for Hepatocellular Carcinoma

by Céline Lescure, Florian Estrade, Maud Pedrono, Boris Campillo-Gimenez, Samuel Le Sourd, Marc Pracht, Xavier Palard, Héloïse Bourien, Léa Muzellec, Thomas Uguen, Yan Rolland, Etienne Garin and Julien Edeline

Cancers 2021, 13(15), 3794; https://doi.org/10.3390/cancers13153794 - 28 Jul 2021

Cited by 15 | Viewed by 2408

Abstract

Background: Selective internal radiation therapy (SIRT) is an innovative treatment of hepatocellular carcinoma (HCC). The albumin-bilirubin (ALBI) score was designed to better evaluate liver functions in HCC. Methods: We studied, retrospectively, data from patients treated with SIRT for HCC. The primary endpoint was [...] Read more.

Background: Selective internal radiation therapy (SIRT) is an innovative treatment of hepatocellular carcinoma (HCC). The albumin-bilirubin (ALBI) score was designed to better evaluate liver functions in HCC. Methods: We studied, retrospectively, data from patients treated with SIRT for HCC. The primary endpoint was the occurrence of radioembolization-induced liver disease (REILD). The secondary endpoint was overall survival (OS). Results: 222 patients were studied. The ALBI grade 1 patients had significantly less REILD (3.4%) after the first SIRT than ALBI grade 2 or 3 patients (16.8%, p = 0.002). Of the 207 patients with data, 77 (37.2%) had a worsening of ALBI grade after one SIRT. The baseline ALBI grade was significantly associated with OS (p = 0.001), also in the multivariable analysis. The ALBI grade after the first SIRT was significantly associated with OS (p ≤ 0.001), with median OS of 26.4 months (CI 95% 18.2–34.7) for ALBI grade 1 patients (n = 48) versus 17.3 months (CI 95% 12.9–21.8) for ALBI grade 2 patients (n = 123) and 8.1 months (CI 95% 4.1–12.1) for ALBI grade 3 patients (n = 36). Conclusions: The baseline ALBI grade is a strong predictor of REILD. The baseline ALBI score and variations of ALBI are prognostic after SIRT. Full article

(This article belongs to the Special Issue Novel Therapies for Hepatocellular Carcinoma)

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12 pages, 422 KiB

Open AccessFeature PaperArticle

Multicenter Propensity Score-Based Study of Laparoscopic Repeat Liver Resection for Hepatocellular Carcinoma: A Subgroup Analysis of Cases with Tumors Far from Major Vessels

by Arimasa Miyama, Zenichi Morise, Luca Aldrighetti, Giulio Belli, Francesca Ratti, Tan-To Cheung, Chung-Mau Lo, Shogo Tanaka, Shoji Kubo, Yukiyasu Okamura, Katsuhiko Uesaka, Kazuteru Monden, Hiroshi Sadamori, Kazuki Hashida, Kazuyuki Kawamoto, Naoto Gotohda, KuoHsin Chen, Akishige Kanazawa, Yutaka Takeda, Yoshiaki Ohmura, Masaki Ueno, Toshiro Ogura, Kyung-Suk Suh, Yutaro Kato, Atsushi Sugioka, Andrea Belli, Hiroyuki Nitta, Masafumi Yasunaga, Daniel Cherqui, Nasser Abdul Halim, Alexis Laurent, Hironori Kaneko, Yuichiro Otsuka, Ki-Hun Kim, Hwui-Dong Cho, Charles Chung-Wei Lin, Yusuke Ome, Yasuji Seyama, Roberto I. Troisi, Giammauro Berardi, Fernando Rotellar, Gregory C. Wilson, David A. Geller, Olivier Soubrane, Tomoaki Yoh, Takashi Kaizu, Yusuke Kumamoto, Ho-Seong Han, Ela Ekmekcigil, Ibrahim Dagher, David Fuks, Brice Gayet, Joseph F. Buell, Ruben Ciria, Javier Briceno, Nicholas O’Rourke, Joel Lewin, Bjorn Edwin, Masahiro Shinoda, Yuta Abe, Mohammed Abu Hilal, Mohammad Alzoubi, Minoru Tanabe and Go Wakabayashi Show full author list Hide full author list

Cancers 2021, 13(13), 3187; https://doi.org/10.3390/cancers13133187 - 25 Jun 2021

Cited by 9 | Viewed by 2984

Abstract

Less morbidity is considered among the advantages of laparoscopic liver resection (LLR) for HCC patients. However, our previous international, multi-institutional, propensity score-based study of emerging laparoscopic repeat liver resection (LRLR) failed to prove this advantage. We hypothesize that these results may be since [...] Read more.

Less morbidity is considered among the advantages of laparoscopic liver resection (LLR) for HCC patients. However, our previous international, multi-institutional, propensity score-based study of emerging laparoscopic repeat liver resection (LRLR) failed to prove this advantage. We hypothesize that these results may be since the study included complex LRLR cases performed during the procedure’s developing stage. To examine it, subgroup analysis based on propensity score were performed, defining the proximity of the tumors to major vessels as the indicator of complex cases. Among 1582 LRLR cases from 42 international high-volume liver surgery centers, 620 cases without the proximity to major vessels (more than 1 cm far from both first–second branches of Glissonian pedicles and major hepatic veins) were selected for this subgroup analysis. A propensity score matching (PSM) analysis was performed based on their patient characteristics, preoperative liver function, tumor characteristics and surgical procedures. One hundred and fifteen of each patient groups of LRLR and open repeat liver resection (ORLR) were earned, and the outcomes were compared. Backgrounds were well-balanced between LRLR and ORLR groups after matching. With comparable operation time and long-term outcome, less blood loss (283.3±823.0 vs. 603.5±664.9 mL, p = 0.001) and less morbidity (8.7 vs. 18.3 %, p = 0.034) were shown in LRLR group than ORLR. Even in its worldwide developing stage, LRLR for HCC patients could be beneficial in blood loss and morbidity for the patients with less complexity in surgery. Full article

(This article belongs to the Special Issue Novel Therapies for Hepatocellular Carcinoma)

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11 pages, 1740 KiB

Open AccessArticle

Neutrophil-to-Lymphocyte Ratio as a Biomarker Predicting Overall Survival after Chemoembolization for Intermediate-Stage Hepatocellular Carcinoma

by Hee Ho Chu, Jin Hyoung Kim, Ju Hyun Shim, Dong Il Gwon, Heung-Kyu Ko, Ji Hoon Shin, Gi-Young Ko, Hyun-Ki Yoon and Nayoung Kim

Cancers 2021, 13(11), 2830; https://doi.org/10.3390/cancers13112830 - 06 Jun 2021

Cited by 17 | Viewed by 2777

Abstract

The clinical impact of neutrophil-to-lymphocyte ratio (NLR) in predicting outcomes in hepatocellular carcinoma (HCC) patients treated with transarterial chemoembolization (TACE) remain unclear, and additional large-scale studies are required. This retrospective study evaluated outcomes in treatment-naïve patients who received TACE as first-line treatment for [...] Read more.

The clinical impact of neutrophil-to-lymphocyte ratio (NLR) in predicting outcomes in hepatocellular carcinoma (HCC) patients treated with transarterial chemoembolization (TACE) remain unclear, and additional large-scale studies are required. This retrospective study evaluated outcomes in treatment-naïve patients who received TACE as first-line treatment for intermediate-stage HCC between 2008 and 2017. Patients who underwent TACE before and after 2013 were assigned to the development (n = 495) and validation (n = 436) cohorts, respectively. Multivariable Cox analysis identified six factors predictive of outcome, including NLR, which were used to create models predictive of overall survival (OS) in the development cohort. Risk scores of 0–3, 4–7, and 8–12 were defined as low, intermediate, and high risk, respectively. Median OS times in the low-, medium-, and high-risk groups in the validation cohort were 48.1, 24.3, and 9.7 months, respectively (p < 0.001). Application to the validation cohort of time-dependent ROC curves for models predictive of OS showed AUC values of 0.72 and 0.70 at 3 and 5 years, respectively. Multivariable logistic regression analysis found that NLR ≥ 3 was a significant predictor (odds ratio, 3.4; p < 0.001) of disease progression 6 months after TACE. Higher baseline NLR was predictive of poor prognosis in patients who underwent TACE for intermediate-stage HCC. Full article

(This article belongs to the Special Issue Novel Therapies for Hepatocellular Carcinoma)

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12 pages, 2062 KiB

Open AccessFeature PaperArticle

Initial Experience of Atezolizumab Plus Bevacizumab for Unresectable Hepatocellular Carcinoma in Real-World Clinical Practice

by Hideki Iwamoto, Shigeo Shimose, Yu Noda, Tomotake Shirono, Takashi Niizeki, Masahito Nakano, Shusuke Okamura, Naoki Kamachi, Hiroyuki Suzuki, Miwa Sakai, Akira Kajiwara, Satoshi Itano, Masatoshi Tanaka, Taizo Yamaguchi, Ryoko Kuromatsu, Hironori Koga, Takuji Torimura and on behalf of The Kurume Liver Cancer Study Group of Japan

Cancers 2021, 13(11), 2786; https://doi.org/10.3390/cancers13112786 - 03 Jun 2021

Cited by 47 | Viewed by 5118

Abstract

Background: Atezolizumab plus bevacizumab was approved for patients with hepatocellular carcinoma (HCC). Although clinical trials have revealed its efficacy, the outcomes in the real-world clinical practice are unclear. We retrospectively evaluated the efficacy and safety of atezolizumab plus bevacizumab for HCC. Materials and [...] Read more.

Background: Atezolizumab plus bevacizumab was approved for patients with hepatocellular carcinoma (HCC). Although clinical trials have revealed its efficacy, the outcomes in the real-world clinical practice are unclear. We retrospectively evaluated the efficacy and safety of atezolizumab plus bevacizumab for HCC. Materials and Methods: This is a multicenter study conducted between November 2020 and March 2021. Among the 61 patients, 51 were assessed for progression-free survival (PFS), therapeutic response, and adverse events (AEs). Results: The median PFS was 5.4 months. The objective response rate (ORR) was 35.3%. The disease control rate (DCR) was 86.3%. The incidence rates of AEs at any grade and grade >3 were 98.0% and 29.4%, respectively. The most frequent AE at any grade and grade >3 was hepatic disorder. In patients with a previous history of molecular targeted agent (MTA) or the degree of albumin-bilirubin (ALBI) grade, there were no significant differences in the PFS, ORR, DCR, and incidence rates of AEs. Conclusion: The study demonstrated that atezolizumab plus bevacizumab was effective and safe for patients with HCC even in the real-world setting including patients with a previous MTA history or other than ALBI grade 1. Full article

(This article belongs to the Special Issue Novel Therapies for Hepatocellular Carcinoma)

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12 pages, 1266 KiB

Open AccessArticle

Phenotypic Characteristics of the Tumour Microenvironment in Primary and Secondary Hepatocellular Carcinoma

by Petros Fessas, Paolo Spina, Renzo L. Boldorini, Mario Pirisi, Rosalba Minisini, Francesco A. Mauri, Fraser Simpson, Paola Olivieri, Alessandra Gennari, Ching Ngar Wong, Abdul Siddique, Robert D. Goldin, Ayse U. Akarca, Teresa Marafioti and David J. Pinato

Cancers 2021, 13(9), 2137; https://doi.org/10.3390/cancers13092137 - 29 Apr 2021

Cited by 11 | Viewed by 2785

Abstract

(1) Background: The intra-tumoural heterogeneity (ITH) of hepatocellular carcinoma (HCC) and its microenvironment (TME) across primary and secondary disease is poorly characterised. (2) Methods: Intra-tumoural (IT) and peri-tumoural (PT) staining of matched primary and secondary samples was conducted to evaluate the distribution of [...] Read more.

(1) Background: The intra-tumoural heterogeneity (ITH) of hepatocellular carcinoma (HCC) and its microenvironment (TME) across primary and secondary disease is poorly characterised. (2) Methods: Intra-tumoural (IT) and peri-tumoural (PT) staining of matched primary and secondary samples was conducted to evaluate the distribution of CD4+/FOXP3+ and CD8+/PD1+ T-cells. Samples underwent PD-L1/2 immunostaining, tumour mutational burden (TMB) evaluation, and high-resolution T-cell receptor (TCR) sequencing to derive T-cell clonality and targeted transcriptomics. (3) Results: We analysed 24 samples from matched primary (n = 11) and secondary (n = 13; 5 synchronous, 6 metachronous) deposits, 11 being extrahepatic (84.6%). IT CD8+ density was lower than PT in both primary (p = 0.005) and secondary deposits (p = 0.01), consistent with immune exclusion. PD-L1+ tumours displayed higher IT and PT CD8+/PD1+ cell density compared to PD-L1- (p < 0.05), and primary IT infiltrate was enriched in CD4+/FOXP3+ cells, compared to PT regions (p = 0.004). TCR-sequencing demonstrated enrichment of the top T-cell clonotype in secondary versus primary HCC (p = 0.02), without differences in overall productive clonality (p = 0.35). TMB was similar across primary versus secondary HCC (p = 0.95). While directed gene set analysis demonstrated the uniformity of transcriptional signatures of individual immune cell types, secondary deposits demonstrated higher COLEC12 (p = 0.004), CCL26 (p = 0.02), CD1E (p = 0.02) and CD36 (p = 0.03) expression with downregulation of CXCL1 (p = 0.03), suggesting differential regulation of innate immunity. (4) Conclusion: Immune exclusion is a defining feature of the HCC TME. Despite evidence of homogeneity in somatic TMB, secondary HCC is characterised by the expansion of a distinct T-cell clonotype and differential regulation of innate immune pathways. Full article

(This article belongs to the Special Issue Novel Therapies for Hepatocellular Carcinoma)

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11 pages, 428 KiB

Open AccessArticle

The Use of Cabozantinib in Advanced Hepatocellular Carcinoma in Hong Kong—A Territory-Wide Cohort Study

by Jeffrey Sum-Lung Wong, Yawen Dong, Vikki Tang, Thomas Leung, Cynthia S. Y. Yeung, Anna Tai, Ada Law, Tracy Shum, Gerry Gin-Wai Kwok, Bryan Cho-Wing Li, Roland Leung, Joanne Chiu, Ka-Wing Ma, Wong-Hoi She, Josephine Tsang, Tan-To Cheung and Thomas Yau

Cancers 2021, 13(9), 2002; https://doi.org/10.3390/cancers13092002 - 21 Apr 2021

Cited by 7 | Viewed by 2883

Abstract

(1) Background: Cabozantinib is approved in sorafenib-exposed advanced hepatocellular carcinoma (aHCC). We evaluated the real-life pattern of use, efficacy, and tolerability of cabozantinib in aHCC. (2) Methods: This territory-wide study included consecutive aHCC patients who received cabozantinib between February 2018 and September 2020 [...] Read more.

(1) Background: Cabozantinib is approved in sorafenib-exposed advanced hepatocellular carcinoma (aHCC). We evaluated the real-life pattern of use, efficacy, and tolerability of cabozantinib in aHCC. (2) Methods: This territory-wide study included consecutive aHCC patients who received cabozantinib between February 2018 and September 2020 in Hong Kong. The objective response rate (ORR), disease control rate (DCR), overall survival (OS), and adverse events (AE) were assessed. (3) Results: Overall, 42 patients were included. Approximately 83.3% had Child-Pugh A cirrhosis. About 64.3% received cabozantinib as a single agent, and the remaining 35.7% received cabozantinib as an add-on to immune checkpoint inhibitors (ICIs). For single-agent patients, the median follow-up was 6.7 months. The ORR was 3.7%, DCR was 44.4%, and the median OS was 8.28 months. About 74.1% of patients experienced any AEs with 7.4% having grade ≥3 AEs. Among patients who received prior ICIs (n = 16), the ORR was 6.3%, and the median OS was 8.28 months. An exploratory analysis of patients who received cabozantinib as an add-on to ICIs showed an ORR of 6.7% and a median OS of 15.1 months, with 73.3% having any AE and 13.3% having grade ≥3 AEs. (4) Conclusions: Cabozantinib had good anti-tumor activity, survival benefits, and acceptable tolerability in real-life aHCC patients. Full article

(This article belongs to the Special Issue Novel Therapies for Hepatocellular Carcinoma)

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Review

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15 pages, 617 KiB

Open AccessReview

Advances in Promoting the Efficacy of Chimeric Antigen Receptor T Cells in the Treatment of Hepatocellular Carcinoma

by Jie Shen, Dashuai Yang and Youming Ding

Cancers 2022, 14(20), 5018; https://doi.org/10.3390/cancers14205018 - 13 Oct 2022

Cited by 3 | Viewed by 2229

Abstract

HCC, one of the most common and deadly cancers worldwide, develops from hepatocytes and accounts for more than 90% of primary liver cancers. The current widely used treatment modalities are far from meeting the needs of liver cancer patients. CAR-T cell therapy, which [...] Read more.

HCC, one of the most common and deadly cancers worldwide, develops from hepatocytes and accounts for more than 90% of primary liver cancers. The current widely used treatment modalities are far from meeting the needs of liver cancer patients. CAR-T cell therapy, which has recently emerged, has shown promising efficacy in lymphoma and hematologic cancers, but there are still many challenges to overcome in its application to the clinical treatment of HCC, including osmotic barriers, the inhibition of hepatocellular carcinoma microenvironment activity, the limited survival and killing ability of CAR-T cells, and inevitable side effects, among others. As a result, a number of studies have begun to address the suboptimal efficacy of CAR-T cells in HCC, and many of these schemes hold good promise. This review focuses on advances in the past five years aimed at promoting the efficacy of CAR-T cell therapy for treatment of HCC. Full article

(This article belongs to the Special Issue Novel Therapies for Hepatocellular Carcinoma)

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14 pages, 985 KiB

Open AccessReview

How Far beyond Diabetes Can the Benefits of Glucagon-like Peptide-1 Receptor Agonists Go? A Review of the Evidence on Their Effects on Hepatocellular Carcinoma

by Konstantinos Arvanitakis, Theocharis Koufakis, Kalliopi Kotsa and Georgios Germanidis

Cancers 2022, 14(19), 4651; https://doi.org/10.3390/cancers14194651 - 24 Sep 2022

Cited by 14 | Viewed by 4139

Abstract

Hepatocellular carcinoma (HCC) is characterized by poor survival rate and quality of life, while available treatments remain generally limited. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) originally emerged as drugs for the management of diabetes, but have also been shown to alleviate cardiorenal risk. [...] Read more.

Hepatocellular carcinoma (HCC) is characterized by poor survival rate and quality of life, while available treatments remain generally limited. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) originally emerged as drugs for the management of diabetes, but have also been shown to alleviate cardiorenal risk. Furthermore, they have demonstrated a wide range of extraglycemic effects that led to their evaluation as potential therapies for a variety of diseases beyond diabetes, such as obesity, neurogenerative disorders and nonalcoholic fatty liver disease. Given the presence of the GLP-1 receptor in hepatocytes, animal data suggest that GLP-1 RAs could regulate molecular pathways that are deeply involved in the genesis and progression of HCC, including inflammatory responses, tumor cell proliferation and oxidative stress, through direct and indirect effects on liver cells. However, future studies must assess several aspects of the benefit-to-risk ratio of the use of GLP-1 RAs in patients with HCC, including co-administration with approved systemic therapies, the incidence of gastrointestinal side effects in a high-risk population, and weight loss management in individuals with poor nutritional status and high rates of cancer cachexia. In this narrative review, we discuss the potential role of GLP-1 analogs in the treatment of HCC, focusing on the molecular mechanisms that could justify a possible benefit, but also referring to the potential clinical implications and areas for future research. Full article

(This article belongs to the Special Issue Novel Therapies for Hepatocellular Carcinoma)

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24 pages, 2004 KiB

Open AccessEditor’s ChoiceReview

Novel Cellular Therapies for Hepatocellular Carcinoma

by Harriet Roddy, Tim Meyer and Claire Roddie

Cancers 2022, 14(3), 504; https://doi.org/10.3390/cancers14030504 - 20 Jan 2022

Cited by 16 | Viewed by 4461

Abstract

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer related death worldwide. Most patients present with advanced disease, and current gold-standard management using tyrosine kinase inhibitors or immune checkpoint inhibitors (ICIs) offers modest clinical benefit. Cellular immune therapies targeting HCC are [...] Read more.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer related death worldwide. Most patients present with advanced disease, and current gold-standard management using tyrosine kinase inhibitors or immune checkpoint inhibitors (ICIs) offers modest clinical benefit. Cellular immune therapies targeting HCC are currently being tested in the laboratory and in clinical trials. Here, we review the landscape of cellular immunotherapy for HCC, defining antigenic targets, outlining the range of cell therapy products being applied in HCC (such as CAR-T and TCR-T), and exploring how advanced engineering solutions may further enhance this therapeutic approach. Full article

(This article belongs to the Special Issue Novel Therapies for Hepatocellular Carcinoma)

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14 pages, 1064 KiB

Open AccessReview

How Immunotherapy Has Changed the Continuum of Care in Hepatocellular Carcinoma

by Giulia Martini, Davide Ciardiello, Fernando Paragliola, Valeria Nacca, Walter Santaniello, Fabrizio Urraro, Maria Stanzione, Marco Niosi, Marcello Dallio, Alessandro Federico, Francesco Selvaggi, Carminia Maria Della Corte, Stefania Napolitano, Fortunato Ciardiello and Erika Martinelli

Cancers 2021, 13(18), 4719; https://doi.org/10.3390/cancers13184719 - 21 Sep 2021

Cited by 8 | Viewed by 3343

Abstract

Hepatocellular carcinoma (HCC) is one of the leading causes of death worldwide. The use of local treatment, such as surgical resection, liver transplant, and local ablation, has improved the survival of patients with HCC detected at an early stage. Until recently, the treatment [...] Read more.

Hepatocellular carcinoma (HCC) is one of the leading causes of death worldwide. The use of local treatment, such as surgical resection, liver transplant, and local ablation, has improved the survival of patients with HCC detected at an early stage. Until recently, the treatment of patients with metastatic disease was limited to the use of the multikinase inhibitor (MKI) sorafenib with a marginal effect on survival outcome. New target approaches, such as the oral MKI lenvatinib in first-line treatment and regorafenib, ramucirumab, and cabozantinib in later lines of therapy, have demonstrated efficacy in patients with preserved liver function (Child–Pugh class A) and good performance status. On the other hand, the implementation of immune checkpoint inhibitors directed against PD-1 (nivolumab and pembrolizumab), PD-L1 (atezolizumab), and anti-CTLA4 (ipilimumab) in the management of advanced HCC has strongly changed the continuum of care of HCC. Future research should include the evaluation of molecular biomarkers that can help patient selection and provide new insight on potential combined approaches. In this review, we provide an overview of the clinical evidence of the use of immune checkpoint inhibitors in HCC, and discuss how immunotherapy has been implemented into the continuum of HCC care. Full article

(This article belongs to the Special Issue Novel Therapies for Hepatocellular Carcinoma)

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17 pages, 331 KiB

Open AccessReview

Immunotherapy Updates in Advanced Hepatocellular Carcinoma

by Amisha Singh, Ryan J. Beechinor, Jasmine C. Huynh, Daneng Li, Farshid Dayyani, Jennifer B. Valerin, Andrew Hendifar, Jun Gong and May Cho

Cancers 2021, 13(9), 2164; https://doi.org/10.3390/cancers13092164 - 30 Apr 2021

Cited by 12 | Viewed by 4052

Abstract

Hepatocellular carcinoma (HCC) is the second most common cause of cancer death worldwide. HCC tumor development and treatment resistance are impacted by changes in the microenvironment of the hepatic immune system. Immunotherapy has the potential to improve response rates by overcoming immune tolerance [...] Read more.

Hepatocellular carcinoma (HCC) is the second most common cause of cancer death worldwide. HCC tumor development and treatment resistance are impacted by changes in the microenvironment of the hepatic immune system. Immunotherapy has the potential to improve response rates by overcoming immune tolerance mechanisms and strengthening anti-tumor activity in the tumor microenvironment. In this review, we characterize the impact of immunotherapy on outcomes of advanced HCC, as well as the active clinical trials evaluating novel combination immunotherapy strategies. In particular, we discuss the efficacy of atezolizumab and bevacizumab as demonstrated in the IMbrave150 study, which created a new standard of care for the front-line treatment of advanced HCC. However, there are multiple ongoing trials that may present additional front-line treatment options depending on their efficacy/toxicity results. Furthermore, the preliminary data on the application of chimeric antigen receptor (CAR-T) cell therapy for treatment of HCC suggests this may be a promising option for the future of advanced HCC treatment. Full article

(This article belongs to the Special Issue Novel Therapies for Hepatocellular Carcinoma)

12 pages, 465 KiB

Open AccessReview

The Current Landscape of Clinical Trials for Systemic Treatment of HCC

by Friedrich Foerster and Peter Robert Galle

Cancers 2021, 13(8), 1962; https://doi.org/10.3390/cancers13081962 - 19 Apr 2021

Cited by 39 | Viewed by 4530

Abstract

The clinical development of systemic treatments for hepatocellular carcinoma (HCC) has gained significant momentum in recent years. After the unexpected failure of the phase 3 trials testing the PD1-inhibitors nivolumab and pembrolizumab as monotherapy in advanced HCC, a multitude of trials employing different [...] Read more.

The clinical development of systemic treatments for hepatocellular carcinoma (HCC) has gained significant momentum in recent years. After the unexpected failure of the phase 3 trials testing the PD1-inhibitors nivolumab and pembrolizumab as monotherapy in advanced HCC, a multitude of trials employing different agents in various combinations and at different disease stages have been initiated. The first positive results reported for the combination of atezolizumab and bevacizumab, as the first line treatment of advanced HCC, will bring lasting change to the management of HCC and has increased the odds of success for alternative combination therapies. This review article seeks to provide clarity on the complex and evolving landscape of clinical trials on systemic treatments of HCC. It covers current trials which test various systemic treatments (i) in the first and second line in advanced HCC, (ii) in intermediate HCC, (iii) as adjuvant as well as (iv) neoadjuvant strategies, and (v) including immune interventions other than immune checkpoint inhibition. Full article

(This article belongs to the Special Issue Novel Therapies for Hepatocellular Carcinoma)

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20 pages, 2936 KiB

Open AccessReview

Recent Advances and Future Prospects in Immune Checkpoint (ICI)-Based Combination Therapy for Advanced HCC

by Yawen Dong, Jeffrey Sum Lung Wong, Ryohichi Sugimura, Ka-On Lam, Bryan Li, Gerry Gin Wai Kwok, Roland Leung, Joanne Wing Yan Chiu, Tan To Cheung and Thomas Yau

Cancers 2021, 13(8), 1949; https://doi.org/10.3390/cancers13081949 - 18 Apr 2021

Cited by 27 | Viewed by 5257

Abstract

Advanced, unresectable hepatocellular carcinoma has a dismal outcome. Multiple immune checkpoint inhibitors (ICIs) targeting the programmed-cell death 1 pathway (PD-1/L1) have been approved for the treatment of advanced HCC. However, outcomes remain undesirable and unpredictable on a patient-to-patient basis. The combination of anti-PD-1/L1 [...] Read more.

Advanced, unresectable hepatocellular carcinoma has a dismal outcome. Multiple immune checkpoint inhibitors (ICIs) targeting the programmed-cell death 1 pathway (PD-1/L1) have been approved for the treatment of advanced HCC. However, outcomes remain undesirable and unpredictable on a patient-to-patient basis. The combination of anti-PD-1/L1 with alternative agents, chiefly cytotoxic T-lymphocyte antigen-4 (CTLA-4) ICIs or agents targeting other oncogenic pathways such as the vascular endothelial growth factor (VEGF) pathway and the c-MET pathway, has, in addition to the benefit of directly targeting alterative oncogenic pathways, in vitro evidence of synergism through altering the genomic and function signatures of T cells and expression of immune checkpoints. Several trials have been completed or are underway evaluating such combinations. Finally, studies utilizing transcriptomics and organoids are underway to establish biomarkers to predict ICI response. This review aims to discuss the biological rationale and clinical advances in ICI-based combinations in HCCs, as well as the progress and prospects of the search for the aforementioned biomarkers in ICI treatment of HCC. Full article

(This article belongs to the Special Issue Novel Therapies for Hepatocellular Carcinoma)

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16 pages, 8752 KiB

Open AccessSystematic Review

Conventional Transarterial Chemoembolization Versus Drug-Eluting Beads in Patients with Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis

by Khalid I. Bzeizi, Mohammad Arabi, Negar Jamshidi, Ali Albenmousa, Faisal M. Sanai, Waleed Al-Hamoudi, Saad Alghamdi, Dieter Broering and Saleh A. Alqahtani

Cancers 2021, 13(24), 6172; https://doi.org/10.3390/cancers13246172 - 07 Dec 2021

Cited by 28 | Viewed by 3203

Abstract

Hepatocellular carcinoma (HCC) occurs in nearly three-quarters of all primary liver cancers, with the majority not amenable to curative therapies. We therefore aimed to re-evaluate the safety, efficacy, and survival benefits of treating patients with drug-eluting beads transcatheter arterial chemoembolization (DEB-TACE) compared to [...] Read more.

Hepatocellular carcinoma (HCC) occurs in nearly three-quarters of all primary liver cancers, with the majority not amenable to curative therapies. We therefore aimed to re-evaluate the safety, efficacy, and survival benefits of treating patients with drug-eluting beads transcatheter arterial chemoembolization (DEB-TACE) compared to the conventional transcatheter arterial chemoembolization (C-TACE). Several databases were searched with a strict eligibility criterion for studies reporting on adult patients with unresectable or recurrent HCC. The pooled analysis included 34 studies involving 4841 HCC patients with a median follow-up of 1.5 to 18 months. There were no significant differences between DEB-TACE and C-TACE with regard to complete response, partial response and disease stability. However, disease control (OR: 1.42 (95% CI (1.03,1.96) and objective response (OR: 1.33 (95% CI (0.99, 1.79) were significantly more effective for DEB-TACE treatment with fewer severe complications and all-cause mortality. The pooled-analysis did not find superiority of DEB-TACE in complete or partial response, disease stability, controlling disease progression, and 30 day or end-mortality. However, results showed that DEB-TACE is associated with a better objective response, disease control, and lower all-cause mortality with severe complications compared to C-TACE treatment. Given that the safety outcomes are based on limited studies with a potential for bias, there was no clear improvement of DEB-TACE over C-TACE treatment. Full article

(This article belongs to the Special Issue Novel Therapies for Hepatocellular Carcinoma)

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