Evidence-based treatment algorithm for BCLC C advanced hepatocellular carcinoma: A comprehensive review and meta-analysis.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15649-e15649
Author(s):  
Hasmukh J. Prajapati ◽  
Hyun S. "Kevin" Kim
Keyword(s):  
Hepatocellular Carcinoma ◽  
Survival Benefit ◽  
Treatment Algorithm ◽  
Advanced Hepatocellular Carcinoma ◽  
Comprehensive Review ◽  
Advanced Hcc ◽  
Vein Thrombosis ◽  
Class A ◽  
Pugh Class ◽  
Ecog Ps

e15649 Background: Barcelona clinic liver cancer (BCLC) C advanced hepatocellular carcinoma (aHCC) has a poor prognosis. Different treatment methods have shown a survival benefit. The purpose of the study is to suggest the treatment algorithm based on a comprehensive review of the literature on aHCC treated with different methods. Methods: Studies were identified by searching Google Scholar using the following keywords: ‘‘advanced hepatocellular carcinoma’’ or ‘‘advanced HCC’’ or “BCLC C” in a time period from 2008 to 2017. Search identified more than 700 articles. Then, articles were searched manually for BCLC C HCC. Articles were excluded if they dealt with only liver metastases or portal vein thrombosis, or if they did not report median survival. A total of 3 randomized control studies (RCT) and 21 non-RCT studies met the inclusion criteria and were reviewed. Results:Overall median survivals (OS) according to different methods is shown in table 1. OSs of aHCC treated with TACE, Yittrium 90 transarterial radioembolization (Y90 TARE) and sorafenib were not significantly different (p>0.5). The pooled results of NRCT demonstrated that Child Pugh class A or without portal vein thrombosis (PVT) or ECOG PS 0 treated with TACE had best median survivals of 15 months(m), 17 m and 20 m respectively. Conclusions: No treatment method appears clearly better than any other. However, aHCC patients with Child Pugh class A or ECOG PS 0 or without PVT treated with TACE showed highest survival. Sorafenib/TACE or sorafenib/Y90 TARE combinations show promise as an effective and a tolerable treatment strategy for advanced HCC. Radiation therapy alone showed poor survival benefit. [Table: see text]

scholarly journals SEARCH: A Phase III, Randomized, Double-Blind, Placebo-Controlled Trial of Sorafenib Plus Erlotinib in Patients With Advanced Hepatocellular Carcinoma

2015 ◽  
Vol 33 (6) ◽  
pp. 559-566 ◽  
Author(s):  
Andrew X. Zhu ◽  
Olivier Rosmorduc ◽  
T.R. Jeffry Evans ◽  
Paul J. Ross ◽  
Armando Santoro ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Overall Response Rate ◽  
Controlled Trial ◽  
Phase Iii ◽  
Advanced Hepatocellular Carcinoma ◽  
Double Blind ◽  
Phase Iii Trial ◽  
Advanced Hcc ◽  
Class A ◽  
Pugh Class

Purpose To compare the clinical outcomes of sorafenib plus either erlotinib or placebo in patients with advanced hepatocellular carcinoma (HCC) in a multicenter, multinational, randomized, phase III trial. Patients and Methods Patients with advanced HCC and underlying Child-Pugh class A cirrhosis, who were naive to systemic treatment (N = 720), were randomly assigned to sorafenib plus either erlotinib (n = 362) or placebo (n = 358). The primary end point was overall survival (OS). Results Median OS was similar in the sorafenib plus erlotinib and sorafenib plus placebo groups (9.5 v 8.5 months, respectively; hazard ratio [HR], 0.929; P = .408), as was median time to progression (3.2 v 4.0 months, respectively; HR, 1.135; P = .18). In the sorafenib/erlotinib arm versus the sorafenib/placebo arm, the overall response rate trended higher (6.6% v 3.9%, respectively; P = .102), whereas the disease control rate was significantly lower (43.9% v 52.5%, respectively; P = .021). The median durations of treatment with sorafenib were 86 days in the sorafenib/erlotinib arm and 123 days in the sorafenib/placebo arm. In the sorafenib/erlotinib and sorafenib/placebo arms, the rates of treatment-emergent serious AEs (58.0% v 54.6%, respectively) and drug-related serious AEs (21.0% v 22.8%, respectively) were similar. AEs matched the known safety profiles of both agents, but rates of rash/desquamation, anorexia, and diarrhea were higher in the sorafenib/erlotinib arm, whereas rates of alopecia and hand-foot skin reaction were higher in the sorafenib/placebo arm. Withdrawal rates for AEs during cycles 1 to 3 were higher in the sorafenib/erlotinib arm. Conclusion Adding erlotinib to sorafenib did not improve survival in patients with advanced HCC.

Analysis of Post-Progression Survival in Patients with Unresectable Hepatocellular Carcinoma Treated with Lenvatinib

Oncology ◽  
2020 ◽  
Vol 98 (11) ◽  
pp. 787-797 ◽  
Author(s):  
Yuwa Ando ◽  
Tomokazu Kawaoka ◽  
Yosuke Suehiro ◽  
Kenji Yamaoka ◽  
Yumi Kosaka ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Multivariate Analysis ◽  
Liver Function ◽  
Second Line ◽  
First Line ◽  
Second Line Therapy ◽  
Class A ◽  
Line Therapy ◽  
Pugh Class ◽  
Ecog Ps

<b><i>Background:</i></b> Although a strong antitumor effect of lenvatinib (LEN) has been noted for patients with unresectable hepatocellular carcinoma (HCC), there are still no reports on the prognosis for patients with disease progression after first-line LEN therapy. <b><i>Methods:</i></b> Patients (<i>n</i> = 141) with unresectable HCC, Child-Pugh class A liver function, and an Eastern Cooperative Oncology Group performance status (ECOG-PS) of 0 or 1 who were treated with LEN from March 2018 to December 2019 were enrolled. <b><i>Results:</i></b> One hundred and five patients were treated with LEN as first-line therapy, 53 of whom had progressive disease (PD) at the radiological evaluation. Among the 53 patients with PD, there were 27 candidates for second-line therapy, who had Child-Pugh class A liver function and an ECOG-PS of 0 or 1 at progression. After progression on first-line LEN, 28 patients were treated with a molecular targeted agent (MTA) as second-line therapy (sorafenib: <i>n</i> = 26; ramucirumab: <i>n</i> = 2). Multivariate analysis identified modified albumin-bilirubin grade 1 or 2a at LEN initiation (odds ratio 5.18, 95% confidence interval [CI] 1.465–18.31, <i>p</i> = 0.011) as a significant and independent factor for candidates. The median post-progression survival after PD on first-line LEN was 8.3 months. Cox hazard multivariate analysis showed that a low alpha-fetoprotein level (&#x3c;400 ng/mL; hazard ratio [HR] 0.297, 95% CI 0.099–0.886, <i>p</i> = 0.003), a relative tumor volume &#x3c;50% at the time of progression (HR 0.204, 95% CI 0.07–0.592, <i>p</i> = 0.03), and switching to MTAs as second-line treatment after LEN (HR 0.299, 95% CI 0.12–0.746, <i>p</i> = 0.01) were significant prognostic factors. <b><i>Conclusion:</i></b> Among patients with PD on first-line LEN, good liver function at introduction of LEN was an important and favorable factor related to eligibility for second-line therapy. In addition, post-progression treatment with MTAs could improve the prognosis for patients who had been treated with first-line LEN.

Tumor c-Met expression and prognosis of advanced hepatocellular carcinoma patients treated with sorafenib.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 317-317
Author(s):  
Yu Yun Shao ◽  
Chi-Huang Hsiao ◽  
Ray Lee ◽  
Oscar Puig ◽  
Soa-Yu Chan ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Clinical Score ◽  
Advanced Hepatocellular Carcinoma ◽  
Advanced Hcc ◽  
First Line Therapy ◽  
Clinical Scores ◽  
Tumor Tissues ◽  
Pugh Class ◽  
Tumor Expression

317 Background: Overexpression of c-Met signaling has been associated with development and progression of hepatocellular carcinoma (HCC). We explored the prognostic role of tumor c-Met expression in patients with advanced HCC. Methods: Patients who had received sorafenib alone as first-line therapy for advanced HCC and had available archival tumor tissues were enrolled. Expression of total c-Met was determined by immunohistochemical staining using CONFIRM anti-total c-MET (SP44) rabbit monoclonal primary antibody (Ventana) on the BenchMark ULTRA staining platform. We evaluated c-Met expression by H scores and by a clinical score as defined in the table. Results: The study enrolled 62 patients, all with Child-Pugh class A status. The HCC etiology was hepatitis B in 48 patients, and hepatitis C in 12 patents; 57 had BCLC disease; 40 had extrahepatic metastasis, and 37 had macrovascular invasion. Clinical scores of c-Met were 0 in 30 (48%) patients, 1 in 31 (50%) patients, 2 in 1 (2%) patients, and 3 in 0 patients. Patients with different clinical scores of c-Met had similar PFS (p = 0.821) or OS (p = 0.533). The median membranous H score and cytoplasmic score were 32.5 and 5, respectively. Patients with higher (≥ median) and lower c-Met membranous H scores or cytoplasmic H scores also had similar PFS and OS. Conclusions: High c-Met expression was rare in this advanced HCC cohort. Tumor expression of c-Met had no obvious associations with the prognosis of advanced HCC. (This study was supported by National Science Council, Taiwan (NSC-102-2314-B-002-120, NSC-103-2314-B-002-181-MY2, NSC-103-2314-B-002-092)). [Table: see text]

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

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4087-4087 ◽  
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.

scholarly journals Sorafenib in patients with Child-Pugh class A and B advanced hepatocellular carcinoma: a prospective feasibility analysis

2013 ◽  
Vol 24 (2) ◽  
pp. 406-411 ◽  
Author(s):  
T. Pressiani ◽  
C. Boni ◽  
L. Rimassa ◽  
R. Labianca ◽  
S. Fagiuoli ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Feasibility Analysis ◽  
Advanced Hepatocellular Carcinoma ◽  
Class A ◽  
Pugh Class

A phase II feasibility study of sorafenib and gemcitabine combination therapy in advanced hepatocellular carcinoma.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 298-298
Author(s):  
N. Naqi ◽  
S. Ahmad ◽  
S. Murad ◽  
J. Khattak
Keyword(s):  
Hepatocellular Carcinoma ◽  
Treatment Protocol ◽  
Uncontrolled Hypertension ◽  
Hematological Toxicity ◽  
Advanced Hepatocellular Carcinoma ◽  
Open Label ◽  
Advanced Hcc ◽  
Class A ◽  
Frequent Dose ◽  
Child Class

298 Background: Sorafenib is considered standard of care in advanced hepatocellular carcinoma (HCC) giving survival benefit of around 4 months. Its combination with gemcitabine, a pyrimidine analogue with limited friendly hepatic profile, may improve results. The primary objective of this study was to evaluate the efficacy and safety of sorafenib and gemcitabine combination in advanced HCC. Methods: 30 patients of advanced HCC were enrolled in this non-randomized, open-label treatment protocol. Sorafenib 400 mg orally twice daily with gemcitabine 1,000mg/m2 intravenous on day 1 and 8 of a 4 week cycle for 4 months. Inclusion criteria: Child class A and B, adequate liver, marrow and renal functions, at least one uni-dimensional measureable lesion, Exclusion criteria: uncontrolled hypertension, serious infections, brain metastasis, bleeding diathesis, pregnant or lactating. National Cancer Institute criteria for adverse events (NCI CTCAE) Version 3.0, and Response evaluation criteria for solid tumors (RECIST) was used for assessment. Results: 30 patients: 23 male and 7 female. 24 (80%) Child class A and 6 (20%) class B. All had chronic liver disease. 22 (73.3%) had significantly high alfa-fetoprotein levels (≥ 500). 20 (66.7%) positive for hepatitis C, 4 (13.3%) for hepatitis B. 6 (20%) had no evidence of viral infection. 19 (63.3%) had multifocal lesions and 11 (36.7%) unifocal. 18 (60%) completing 4 cycles of treatment were assessed for response. 2 partial responses (PR) and 8 stable disease (SD) were seen. No complete response (CR) was observed. 8 patients had progressive disease, 4 progressing on interim assessment were taken off protocol. Toxicity: primarily hematological. Gemcitabine related thrombocytopenia being the most common (40%) requiring frequent dose modifications and delays. Sorafenib specific, hand foot skin reaction and anorexia were next most frequent. Conclusions: Sorafenib and gemcitabine combination is not feasible in advanced HCC due to its hematological toxicity especially thrombocytopenia, requiring frequent dose reductions and delays. No significant financial relationships to disclose.

Randomized Controlled Trial of Tamoxifen in Advanced Hepatocellular Carcinoma

2005 ◽  
Vol 23 (19) ◽  
pp. 4338-4346 ◽  
Author(s):  
Jean-Claude Barbare ◽  
Olivier Bouché ◽  
Franck Bonnetain ◽  
Jean-Luc Raoul ◽  
Philippe Rougier ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Performance Status ◽  
Univariate Analysis ◽  
Local Treatment ◽  
Cox Proportional Hazards Model ◽  
Tamoxifen Treatment ◽  
Control Group ◽  
Advanced Hepatocellular Carcinoma ◽  
Advanced Hcc ◽  
Pugh Class

Purpose Randomized studies on tamoxifen treatment of hepatocellular carcinoma (HCC) produced conflicting results. The aim of this study was to assess the efficacy of tamoxifen administration in improving overall survival of patients with advanced HCC. Patients and Methods A total of 420 patients with HCC who were not suitable for surgery or local treatment were randomly assigned between April 1995 and May 2000: 210 in the control group and 210 in the tamoxifen group (20 mg/d orally). Patients with WHO performance status greater than 2, belonging to Child-Pugh class C, or with serum creatinine greater than 130 μmol/L were not eligible. Results Tolerance was good and the main reported adverse effects were thrombophlebitis (three patients), nausea (two patients), and hot flushes (three patients). Outcome did not differ between the two treatment arms: estimated median survival was 4.8 and 4.0 months in the tamoxifen and in the control groups, respectively (P = .25). Univariate analysis showed significant association of survival with age, Okuda stage, WHO performance status, Child-Pugh class, intrahepatic tumor stage, alpha-fetoprotein serum concentration, and presence of extrahepatic spread, portal vein thrombosis, hepatomegaly, or hepatalgia. In a Cox proportional hazards model we found a significant beneficial effect of tamoxifen on survival in patients belonging to Okuda I or II stages. Conclusion In this large study, tamoxifen did not improve the survival of patients with advanced HCC, but there is a suggestion that patients without major hepatic insufficiency seem to have some survival benefit. New trials involving this specific population are warranted.

Phase II study of darinaparsin in patients with advanced hepatocellular carcinoma

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15630-e15630 ◽  
Author(s):  
J. Wu ◽  
F. Muggia ◽  
C. Henderson ◽  
L. Feun ◽  
P. V. Veldhuizen ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Confidence Interval ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Performance Status ◽  
Inorganic Arsenic ◽  
Advanced Hepatocellular Carcinoma ◽  
Ecog Performance Status ◽  
Class A ◽  
Pugh Class

e15630 Background: Inorganic arsenic has reported activity in advanced hepatocellular carcinoma (HCC) in Asia, yet its efficacy is limited by liver toxicity. Darinaparsin is a novel organic arsenic that is capable of reaching higher intracellular concentration in cells with decreased toxicity compared to inorganic arsenic. It is highly active as a single agent in HCC cell lines and animal tumor models. We conducted a multi-center phase II study with darinaparsin in patients with advanced HCC. Methods: Eligibility criteria included unresectable or metastatic measurable HCC, up to two prior systemic treatments, ECOG performance status ≤2, Child Pugh Class A or B and adequate organ functions. Darinaparsin was given at 420 mg/m2 intravenously administered over 60 minutes through a central line, twice weekly at least 72 hours apart for three weeks followed by one-week rest in a four-week cycle. The primary end point of the study was response rate. A Simon two-stage design was used to assess the efficacy of darinaparsin and the study would be terminated if no responses were observed after the first stage. Results: The planned 15 patients of the first stage were enrolled: median age = 60 (35 - 79). M/F = 14/1, ECOG performance status 0/1= 4/11, Child Pugh class A/B = 11/4. Seven patients received prior systemic chemotherapies. No objective responses were observed. Three patients had stable disease. The median number of cycles on study per patient was 2 (1–6). The median progression free survival and overall survival were 55 days (95% confidence interval: 50 - 59) and 190 days (95% confidence interval: 93–227), respectively. Treatment was well tolerated. No treatment related hospitalizations or deaths occurred. Treatment related grade 1–2 toxicities included nausea/vomiting (31%), fatigue (23%), anorexia (15%) and diarrhea (15%). Grade 3 anorexia, wheezing, agitation, right upper quadrant pain and SGPT were observed in 1 patient each (8%), 1 patient experienced grade 4 hypoglycemia (8%). Conclusions: Darinaparsin was safely administered with tolerable toxicity profiles in HCC patients. However, it has shown no objective responses in HCC and this trial was terminated as planned after the first stage of efficacy analysis. [Table: see text]

Phase I study of safety, pharmacokinetics, and efficacy of TSU-68 plus S-1 combination in patients with advanced hepatocellular carcinoma.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 262-262 ◽  
Author(s):  
Masafumi Ikeda ◽  
Shuichiro Shiina ◽  
Kohei Nakachi ◽  
Shuichi Mitsunaga ◽  
Satoshi Shimizu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Area Under The Curve ◽  
Maximum Tolerated Dose ◽  
Advanced Hepatocellular Carcinoma ◽  
Advanced Hcc ◽  
Treatment Dose ◽  
Pugh Class ◽  
Prior Systemic Therapy ◽  
Grade 3 ◽  
Treatment Safety

262 Background: Sorafenib is the standard chemotherapy for advanced hepatocellular carcinoma (HCC), but its efficacy is limited. TSU-68 is an oral anti-angiogenesis agent that blocks VEGFR-2 and PDGFR. TSU-68 and S-1 have shown favorable efficacy and safety profile for advanced HCC (Kanai et al. 2011; Furuse et al. 2010). This study investigated the safety, tolerability, pharmacokinetics (PK), and efficacy of the TSU-68 plus S-1 combination in patients (pts) with advanced HCC. We also determined the maximum tolerated dose of TSU-68 plus S-1 on the basis of the frequency of associated dose-limiting toxicity (DLT) in this population. Methods: Pts who had not received any prior systemic therapy received 400 mg/day TSU-68 orally and one of the following doses of S-1: 50 mg/m2 (level 0), 80 mg/m2 (level 1), or 100 mg/m2 (level 2). Treatment duration was 4 weeks followed by 2-week rest (A group) or 2 weeks followed by 1-week rest (B group). The starting treatment dose and duration level was 1B, followed by progression to levels 2A and 2B. Treatment safety and tolerability at each level were assessed by enrolling 6 pts according to CTCAE v3.0. Results: Eighteen pts (6 each at levels 1B, 2A, and 2B) were enrolled (age, 58-85 years; male/female, 15/3; HCV/HBV/nBnC, 12/3/4; Child-Pugh class A/B, 18/0). Two pts each at levels 1B (grade 3 gastrointestinal bleeding, grade 2 ascites) and 2A (grade 3 fatigue, grade 3 hand-foot skin reaction) showed DLTs, but no pts at level 2B showed DLTs. The common adverse events were hemoglobin decrease, hypoalbuminemia, and anorexia; these were mild in severity (grade 1-2). PK data from 12 pts at levels 1B and 2A indicated that the area under the curve (AUC) of TSU-68 and 5-FU was unlikely to be affected by TSU-68 plus S-1. Response rate, disease control rate, median time to progression, and median overall survival time were 27.8%, 61.1%, 160 days, and 391 days, respectively. Conclusions: Our findings revealed thatthe TSU-68 plus S-1 combination was well tolerated and had favorable efficacy in patients with advanced HCC, and we recommend treatment with 400 mg/day TSU-68 and 100 mg/m2 S-1 for 4 weeks followed by 2-week rest in these patients. Clinical trial information: Japic CTI-121970.

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