Hypothyroidism Is a Predictive Factor for Better Clinical Outcomes in Patients with Advanced Hepatocellular Carcinoma Undergoing Lenvatinib Therapy

Patients with advanced hepatocellular carcinoma (HCC) undergoing molecular targeted therapy often experience non-negligible adverse events (AEs). Paradoxically, certain AEs are reportedly associated with a good prognosis. We aimed to identify factors predictive of treatment duration and overall survival (OS) in patients with HCC undergoing lenvatinib therapy. Forty-six consecutive patients with advanced HCC who received lenvatinib therapy from April 2018 to November 2019 were prospectively followed until November 2019. Treatment efficacy was assessed according to the modified Response Evaluation Criteria in Solid Tumors for 2–3 months after therapy initiation. The disease control rate (DCR) was defined as the percentage of patients with a complete response, partial response, or stable disease. The DCR was 65.2%, with a median survival of 10.2 months. Grade 2/3 hypoalbuminemia resulted in shorter treatment duration. Factors predictive of longer OS were a Child-Pugh score of 5 at baseline and the occurrence of Grade 2/3 hypothyroidism. Conversely, Grade 2/3 hypoalbuminemia was associated with a poorer prognosis. An AE of Grade 2/3 hypothyroidism was associated with a better prognosis in patients receiving lenvatinib treatment for advanced HCC. Continuing anticancer therapy with appropriate thyroid hormone replacement may contribute to longer OS.

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Phase II Trial of the Combination of Bevacizumab and Erlotinib in Patients Who Have Advanced Hepatocellular Carcinoma

Journal of Clinical Oncology ◽

10.1200/jco.2008.18.3301 ◽

2009 ◽

Vol 27 (6) ◽

pp. 843-850 ◽

Cited By ~ 231

Author(s):

Melanie B. Thomas ◽

Jeffrey S. Morris ◽

Romil Chadha ◽

Michiko Iwasaki ◽

Harmeet Kaur ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Response Rate ◽

Group Performance ◽

Performance Status ◽

Eastern Cooperative Oncology Group ◽

Evaluation Criteria ◽

Progression Free Survival ◽

Advanced Hepatocellular Carcinoma ◽

Study Objective ◽

Advanced Hcc

Purpose The study objective was to determine the proportion of patients with hepatocellular carcinoma (HCC) treated with the combination of bevacizumab (B) and erlotinib (E) who were alive and progression free at 16 weeks (16-week progression-free survival [PFS16]) of continuous therapy. Secondary objectives included response rate, median PFS, survival, and toxicity. Patients and Methods Patients who had advanced HCC that was not amenable to surgical or regional therapies, up to one prior systemic treatment; Childs-Pugh score A or B liver function; Eastern Cooperative Oncology Group performance status 0, 1, or 2 received B 10 mg/kg every 14 days and E 150 mg orally daily, continuously, for 28-day cycles. Tumor response was evaluated every 2 cycles by using Response Evaluation Criteria in Solid Tumors Group criteria. A total of 40 patients were treated. Results The primary end point of PFS16 was 62.5%. Ten patients achieved a partial response for a confirmed overall response rate (intent-to-treat) of 25%. The median PFSevent was 39 weeks (95% CI, 26 to 45 weeks; 9.0 months), and the median overall survival was 68 weeks (95% CI, 48 to 78 weeks; 15.65 months). Grades 3 to 4 drug-related toxicity included fatigue (n = 8; 20%), hypertension (n = 6; 15%), diarrhea (n = 4; 10%) elevated transaminases (n = 4; 10%), gastrointestinal hemorrhage (n = 5; 12.5%), wound infection (n = 2; 5%) thrombocytopenia (n = 1; 2.5%), and proteinuria, hyperbilirubinemia, back pain, hyperkalemia, and anorexia (n = 1 each). Conclusion The combination of B + E in patients who had advanced HCC showed significant, clinically meaningful antitumor activity. B + E warrant additional evaluation in randomized controlled trials.

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Phase Ib trial of tepotinib in Asian patients with advanced hepatocellular carcinoma (HCC): Final data including long-term outcomes.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.4087 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 4087-4087 ◽

Cited By ~ 2

Author(s):

Shukui Qin ◽

Tae-You Kim ◽

Ho Yeong Lim ◽

Baek-Yeol Ryoo ◽

Jürgen Scheele ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Progression Free Survival ◽

Response Duration ◽

Complete Response ◽

Maximum Tolerated Dose ◽

Advanced Hepatocellular Carcinoma ◽

Modest Improvement ◽

Phase Ib ◽

Advanced Hcc ◽

Ecog Ps

4087 Background: The incidence of hepatocellular carcinoma (HCC), a leading cause of cancer death, is increasing with the increasing incidence of chronic liver disease. Sorafenib, the only approved systemic therapy for advanced HCC, provides modest improvement in overall survival. Preclinical studies suggest c-Met is a valid target in HCC, but non-selective TKIs with c-Met inhibitory activity have not shown efficacy in trials, possibly due to lack of c-Met inhibition. Tepotinib (MSC2156119J) is a highly selective c-Met inhibitor that has favorable safety and promising activity, particularly against c-Met+ solid tumors. We report the final results of a phase Ib trial of tepotinib in patients (pts) with advanced HCC. Methods: Pts were Asian adults with confirmed HCC of BCLC Stage C, Child-Pugh Class A liver function without encephalopathy, and ECOG PS 0–2. Pts received tepotinib 300, 500 (the RP2D) or 1,000 mg/day on a 21-day cycle. c-Met expression status was retrospectively determined by IHC. Results: 27 pts were enrolled (median age 57 [38-69]; male 23; ECOG PS 0/1 11/16); 7 received tepotinib 300 mg/day, 14 500 mg/day, and 6 1,000 mg/day (3 with dose reduction). No DLTs were observed. 22 pts experienced treatment-related treatment-emergent adverse events (TRTEAEs), most commonly diarrhea (n = 10), nausea (8), elevated AST (7), and elevated ALT (6). 9 pts had grade ≥3 TRTEAEs, including elevated AST (3) and elevated ALT (3). Best overall response (BOR) was partial response (PR) in 2 pts, one of whom received tepotinib 500 mg (response duration 16.1 months) and one 1,000 mg (4.4 months); both had c-Met+ tumors. A further 8 pts had a BOR of stable disease (SD), 1 pt non-complete response (CR)/non-progressive disease (PD), and 14 pts had PD (2 pts not evaluable). Five pts had progression free survival > 8 months. PK were as expected from previous studies. Conclusions: Tepotinib at doses of up to 1,000 mg/day was well tolerated by Asian pts with advanced HCC and a maximum tolerated dose was not reached. Antitumor activity was observed, particularly in pts with c-Met+ tumors. The ongoing phase II part of this study is comparing the efficacy and safety of first-line tepotinib and sorafenib in pts with c-Met+ HCC. Clinical trial information: NCT01988493.

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Evolution of Survival Impact of Molecular Target Agents in Patients with Advanced Hepatocellular Carcinoma

Liver Cancer ◽

10.1159/000519868 ◽

2021 ◽

pp. 1-13

Author(s):

Kazufumi Kobayashi ◽

Sadahisa Ogasawara ◽

Aya Takahashi ◽

Yuya Seko ◽

Hidemi Unozawa ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Treatment Duration ◽

Molecular Target ◽

Advanced Hepatocellular Carcinoma ◽

Advanced Stage ◽

First Line ◽

Advanced Hcc ◽

Period 2 ◽

Study Population ◽

The Impact

Background and Aims: The prognosis of patients with advanced hepatocellular carcinoma (HCC) is expected to improve as multiple molecular target agents (MTAs) are now available. However, the impact of the availability of sequential MTAs has not been fully verified yet. Approach and Results: We retrospectively collected the data on the whole clinical course of 877 patients who received any MTAs as first-line systemic therapy for advanced HCC between June 2009 and March 2019. The study population was divided into 3 groups according to the date of first-line MTA administration (period 1: 2009–2012, n = 267; period 2: 2013–2016, n = 352; period 3: 2017–2019, n = 258). Then, we compared the number of MTAs used, overall survival (OS), and MTA treatment duration among the 3 groups. Analysis was also performed separately for advanced-stage and nonadvanced-stage HCC. The proportion of patients who received multiple MTAs was remarkably increased over time (1.1%, 10.2%, and 42.6% in periods 1, 2, and 3, respectively, p < 0.001). The median OS times were prolonged to 10.4, 11.3, and 15.2 months in periods 1, 2, and 3, respectively (p = 0.016). Similarly, the MTA treatment durations were extended (2.7, 3.2, and 6.6 months in periods 1, 2, and 3, respectively; p < 0.001). We confirmed that the correlation between OS and MTA treatment duration was strengthened (period 1: 0.395, period 2: 0.505, and period 3: 0.667). All these trends were pronounced in the patients with advanced-stage HCC but limited in the patients with nonadvanced-stage HCC. Conclusions: The availability of multiple MTAs had steadily improved the prognosis of patients with advanced HCC patients, particularly advanced-stage HCC patients.

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Phase I studies of peptide vaccine cocktails derived from GPC3, WDRPUH and NEIL3 for advanced hepatocellular carcinoma

Immunotherapy ◽

10.2217/imt-2020-0278 ◽

2021 ◽

Vol 13 (5) ◽

pp. 371-385

Author(s):

Masafumi Ikeda ◽

Takuji Okusaka ◽

Izumi Ohno ◽

Shuichi Mitsunaga ◽

Shunsuke Kondo ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Phase I ◽

Peptide Vaccine ◽

Complete Response ◽

Advanced Hepatocellular Carcinoma ◽

Two Phase ◽

Good Tolerability ◽

Clinical Trial Registration ◽

Phase I Studies ◽

Advanced Hcc

Aim: Two peptide cocktail vaccines using glypican-3, WD-repeat-containing protein up-regulated in hepatocellular carcinoma (HCC) and nei endonuclease VIII-like three epitopes were evaluated in advanced HCC in two Phase I studies. Patients & methods: Study 1 evaluated dose-limiting toxicities (DLTs) of peptides 1–3 (HLA-A24-restricted) and study 2 evaluated DLTs of peptides 1–6 (HLA-A24 or A02-restricted). Results: Overall, 18 and 14 patients were enrolled in studies 1 and 2, respectively. No DLTs were observed up to 7.1 mg of the vaccine cocktail. No complete response/partial response was observed. Stable disease was reported in nine and five patients with a disease control rate of 52.9% and 35.7% in studies 1 and 2, respectively. Conclusion: Both vaccines showed good tolerability and potential usefulness against HCC. Clinical trial registration: JapicCTI-121933 ; JapicCTI-142477

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Lenvatinib Plus Immune Checkpoint Inhibitors Improve Survival in Advanced Hepatocellular Carcinoma: A Retrospective Study

Frontiers in Oncology ◽

10.3389/fonc.2021.751159 ◽

2021 ◽

Vol 11 ◽

Author(s):

Xiaozhun Huang ◽

Lin Xu ◽

Teng Ma ◽

Xin Yin ◽

Zhangkan Huang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Objective Response ◽

Progression Free Survival ◽

Complete Response ◽

Advanced Hepatocellular Carcinoma ◽

Advanced Hcc ◽

New Strategy

BackgroundNivolumab and pembrolizumab disrupt the programmed cell death-1 immune checkpoint and display promising efficacy and safety results in advanced hepatocellular carcinoma (HCC). However, the benefits remain limited. The preliminary results of lenvatinib (LEN) combined with immune checkpoint inhibitors (ICIs) reveal that the combinations were well-tolerated and encouraging. This study aimed to analyze the safety and efficacy of LEN plus ICIs in a real-world cohort of patients with advanced HCC.MethodBetween June 4, 2017, and June 30, 2019, 16 patients received LEN plus nivolumab, and 13 patients were treated with LEN plus pembrolizumab, with the confirmed advanced HCC retrospectively analyzed. The clinical parameters, as well as the outcomes, were assessed.ResultsAll the patients had Barcelona Clinical Liver Cancer Stage C. LEN with ICIs was used as systemic second-, third-, and fourth-line treatments in seven (24.1%), 14 (48.3%), and eight (27.6%) patients, respectively. At the time of data cutoff, six patients (37.5%) were still receiving LEN with nivolumab, while another six patients (46.2%) were still receiving LEN with pembrolizumab. An objective response was recorded in seven patients (25.9%), while the best overall responses were from one complete response and six partial responses. The 6- and 12-month over survival (OS) rates were 62.6% and 53.7%, respectively. Furthermore, the 6- and 12-month progression-free survival (PFS) rates were 43.5% and 31.8%, respectively. In the subgroup analyses, the 6- and 12-month OS and PFS rates for patients treated with LEN plus nivolumab were 62.5% and 52.1%, respectively, and 43.8% and 30.0%, respectively. The 6- and 12-month OS and PFS rates for patients treated with LEN plus pembrolizumab were 51.3% and 51.3%, respectively, and 49.2% and 49.2%, respectively. A total of 11 (31%) deaths were reported in this study, four of which were attributed to grade 5 adverse events presented as fatal treatment-related hepatitis.ConclusionThe combination of LEN and ICIs is a promising new strategy for the treatment of HCC patients. However, high-grade hepatic toxicity was observed and further evaluation of this combination is still required.

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Advanced hepatocellular carcinoma treated by radiofrequency ablation combined with oncolytic virus and anti-PD-1 antibody therapy: a case report and literature review

Journal of International Medical Research ◽

10.1177/03000605211044596 ◽

2021 ◽

Vol 49 (9) ◽

pp. 030006052110445

Author(s):

Anqing Xie ◽

Feng Xia ◽

Jun Pei ◽

Ximing Sun ◽

Zongtao Song

Keyword(s):

Hepatocellular Carcinoma ◽

Radiofrequency Ablation ◽

Literature Review ◽

Oncolytic Virus ◽

Antibody Therapy ◽

Human Adenovirus ◽

Adenovirus Type ◽

Complete Response ◽

Advanced Hepatocellular Carcinoma ◽

Advanced Hcc

The development of an effective therapy for advanced hepatocellular carcinoma (HCC) represents an important global concern. In recent years, the combination of multiple treatment methods with immunotherapy has achieved great progress in patients with advanced HCC. Patient survival has been significantly prolonged, but cases of complete response (CR) remain rare. Here, we report two cases in which CR was achieved by radiofrequency ablation combined with an oncolytic virus (recombinant human adenovirus type 5) and anti-programmed cell death protein 1 antibody. Additionally, a literature review is presented to describe similar advancements in this field and explore viable methods for the treatment of advanced HCC.

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Advanced Hepatocellular Carcinoma With Hepatic Arterioportal Shunts: Combination Treatment of Transarterial Chemoembolization With Apatinib

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2020.607520 ◽

2020 ◽

Vol 7 ◽

Author(s):

Tao Sun ◽

Yanqiao Ren ◽

Xuefeng Kan ◽

Lei Chen ◽

Weihua Zhang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Overall Survival ◽

Adverse Events ◽

Tumor Progression ◽

Transarterial Chemoembolization ◽

Protective Factor ◽

Evaluation Criteria ◽

Advanced Hepatocellular Carcinoma ◽

Advanced Hcc ◽

Grade 3

Object: This study aimed to compare the efficacy and safety of transarterial chemoembolization (TACE) combining with apatinib (TACE-apatinib) and TACE-alone for patients with advanced hepatocellular carcinoma (HCC) with hepatic arterioportal shunts (APS).Materials and Methods: This retrospective study evaluated the medical records of patients with advanced HCC with APS who underwent TACE-apatinib or TACE-alone from June 2015 to January 2019. The occlusion of the shunt was performed during the TACE procedure. The time to tumor progression (TTP) and overall survival (OS) of study patients were evaluated. The modified Response Evaluation Criteria in solid tumors (mRECIST) was used to evaluate the treatment response. The apatinib-related adverse events were recorded.Results: Fifty-eight patients were included in this study. Twenty-seven patients underwent the treatment of TACE-apatinib, and 31 received TACE-alone treatment. The median overall survival (OS) and median time of tumor progression (TTP) in the TACE-apatinib group were significantly longer than those of the TACE-alone group (OS: 12.0 vs. 9.0 months, P = 0.000; TTP: 9.0 vs. 5.0 months, P = 0.041). Multivariate analysis revealed that TACE-apatinib was a protective factor for OS, and there was no independent risk factor for TTP. In the TACE-apatinib group, the grade 3 apatinib-related adverse events occurred in four patients.Conclusion: TACE-apatinib was an efficacious and safe treatment for patients with advanced HCC with APS, and apatinib improved the efficacy of TACE in the treatment of these patients.

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Advanced Stage Hepatocellular Carcinoma with Multiple Metastasis and Vascular Thrombosis: A Case of Complete Response to Sorafenib

Acta Médica Portuguesa ◽

10.20344/amp.6799 ◽

2016 ◽

Vol 29 (2) ◽

pp. 139 ◽

Cited By ~ 3

Author(s):

Adélia Simão ◽

Raquel Silva ◽

Lurdes Correia ◽

Filipe Caseiro Alves ◽

Armando Carvalho ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Kinase Inhibitor ◽

Performance Status ◽

Evaluation Criteria ◽

Vena Cava ◽

Complete Response ◽

Response To Treatment ◽

Advanced Hepatocellular Carcinoma ◽

And Performance ◽

The Right

Sorafenib is a multi-targeted tyrosine kinase inhibitor, with antiangiogenic and antiproliferative properties, approved for the treatment of advanced hepatocellular carcinoma. It induces a significant increase in the median overall survival, despite a complete response to treatment being rare. We report a clinical case of a 60-year-old male with hepatic cirrhosis, Child-Pugh class A and performance status 0, and advanced hepatocellular carcinoma. The primary tumor measured 17 x 8 cm and had diffuse intrahepatic metastization, extensive lung and left adrenal invasion, as well as thrombosis of inferior vena cava, with projection to the right atrium. This patient showed a rapid and complete response to sorafenib, evaluated by mRECIST (modified Response Evaluation Criteria in Solid Tumors), that remains after three years of treatment.

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Concomitant chemoradiation using gemcitabine in locally advanced hepatocellular carcinoma

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e15611 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e15611-e15611

Author(s):

A. I. Masood ◽

A. A. Javed ◽

A. Mateen ◽

S. A. Gurchani

Keyword(s):

Hepatocellular Carcinoma ◽

Response Rate ◽

Locally Advanced ◽

Evaluation Criteria ◽

Advanced Hepatocellular Carcinoma ◽

Advanced Hcc ◽

Treatment Response Evaluation ◽

Standard Management ◽

Concomitant Chemoradiation ◽

Grade 3

e15611 Background: Hepatocellular carcinoma (HCC) is among the most common malignancies in Pakistan. There is currently no standard management for advanced HCC. Non-surgical modalities have demonstrated minimal improvements in survival. The aim of present study is to assess response rate and toxicity of concomitant gemcitabine and external radiation therapy (ERT) in locally advanced HCC. Methods: Thirty three biopsy proven advanced HCC patients having Okuda stage I and II disease were enrolled. 70 mg/m2 gemcitabine was given once weekly for three weeks during ERT. Partial liver ERT was delivered with 60Co upto 30 gray (Gy), 1.8 Gy/fraction and five fractions in a week. Tumor response was assessed by computed tomography (CT) eight weeks after completion of treatment. Response Evaluation Criteria in Solid Tumors (RECIST) was used to assess complete and partial response (CR, PR); progressive and stable disease (PD, SD). Hematological [neutropenia and thrombocytopenia], gastrointestinal (vomiting and diarrhea) and liver [encephalopathy, bilirubin, alanine and aspartate transferases (ALT and AST), and alkaline phosphatase (ALP)] toxicities were assessed weekly during treatment and then fortnightly upto 2 months according to Common Toxicity Criteria for Adverse Events version (3.0). Primary end point was to assess response rate at eight weeks after completion of treatment and Grade 3 or 4 toxicity during this period. Results: 28/33 patients were evaluable. No CR was seen. PR, SD and PD (%) were seen in 36, 39 and 25 of patients respectively. No grade 3 or 4 neutropenia was observed. 7/28 (25%) of patients developed grade 3 thrombocytopenia during treatment and needed a delay of one week for gemcitabine administration. Grade 3/4 toxicity (%) related to vomiting, diarrhea, encephalopathy, bilirubin, ALT, AST and ALP was seen in 18, 29, 21, 18, 14, 29 and 32 of the patients. Conclusions: The study showed that concomitant chemoradiation using 70mg/m2 gemcitabine is a feasible option with acceptable toxicity in locally advanced HCC. A larger study will be appropriate to define its definite role. No significant financial relationships to disclose.

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Successful Conversion Surgery for Massive Hepatocellular Carcinoma with Tumor Thrombus in Main Portal Vein after Treatment with Lenvatinib Combined with Toripalimab: A Case Report

10.21203/rs.3.rs-840640/v1 ◽

2021 ◽

Author(s):

JingZhong OuYang ◽

Yanzhao Zhou ◽

Zhengzheng Wang ◽

Qingjun Li ◽

Jinxue Zhou

Keyword(s):

Hepatocellular Carcinoma ◽

Portal Vein ◽

Tumor Thrombus ◽

Inflammatory Cells ◽

Complete Response ◽

Advanced Hepatocellular Carcinoma ◽

Main Portal Vein ◽

Advanced Hcc ◽

Dismal Prognosis ◽

The Right

Abstract Background:Advanced hepatocellular carcinoma (HCC) with Portal vein invasion has an extremely dismal prognosis. We report a rare case of advanced HCC with portal vein tumor thrombus (PVTT). First, Lenvatinib(Len) combined with Toripalimab(Tor) was treated. The patient was successfully treated with radical surgical resection after the tumor thrombus shrank. Postoperative pathology showed complete response (CR).Case presentation:A 52-year-old male patient had a massive liver cancer in his right liver, and the tumor thrombus grew to the main portal vein. He passed 4 cycles of Len combined with Tor, the tumor shrank rapidly, the level of tumor markers dropped rapidly, The tumor thrombus was successfully confined from the main portal vein to the right branch of the portal vein. Therefore, the patient underwent a right hepatectomy and successfully removed a complete PVTT. Histopathological results showed that the primary tumor and tumor thrombus were only infiltrated by inflammatory cells, and there were no viable tumor cells.Conclusions:Len combined with Tor can be used as a preoperative neoadjuvant regimen for the treatment of advanced HCC with massive macrovascular invasion.

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