scholarly journals A Changing Paradigm for the Treatment of Intermediate-Stage Hepatocellular Carcinoma: Asia-Pacific Primary Liver Cancer Expert Consensus Statements

Liver Cancer ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 245-260 ◽  
Author(s):  
Masatoshi Kudo ◽  
Kwang-Hyub Han ◽  
Sheng-Long Ye ◽  
Jian Zhou ◽  
Yi-Hsiang Huang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Targeted Therapy ◽  
Liver Function ◽  
Primary Liver Cancer ◽  
Intermediate Stage ◽  
Asia Pacific ◽  
First Line ◽  
First Choice ◽  
Consensus Statements ◽  
Choice Of Treatment

The Asia-Pacific Primary Liver Cancer Expert (APPLE) Consensus Statement on the treatment strategy for patients with intermediate-stage hepatocellular carcinoma (HCC) was established on August 31, 2019, in Sapporo, Hokkaido during the 10th Annual APPLE Meeting. This manuscript summarizes the international consensus statements developed at APPLE 2019. Transarterial chemoembolization (TACE) is the only guideline-recommended global standard of care for intermediate-stage HCC. However, not all patients benefit from TACE because intermediate-stage HCC is a heterogeneous disease in terms of tumor burden and liver function. Ten important clinical questions regarding this stage of HCC were raised, and consensus statements were generated based on high-quality evidence. In intermediate-stage HCC, preservation of liver function is as important as achieving a high objective response (OR) because the treatment goal is to prolong overall survival. Superselective conventional TACE (cTACE) is recommended as the first choice of treatment in patients eligible for effective (curative) TACE, whereas in patients who are not eligible, systemic therapy is recommended as the first choice of treatment. TACE is not indicated as the first-line therapy in TACE-unsuitable patients. Another important statement is that TACE should not be continued in patients who develop TACE failure/refractoriness in order to preserve liver function. Targeted therapy is the recommended first-line treatment for TACE-unsuitable patients. Especially, the drug, which can have higher OR rate, is preferred. Immunotherapy, transarterial radioembolization, TACE + targeted therapy or other modalities may be considered alternative options in TACE-unsuitable patients who are not candidates for targeted therapy. Better liver function, such as albumin-bilirubin grade 1, is an important factor for maximizing the therapeutic effect of systemic therapy.

Treatment of Hepatocellular Carcinoma

2016 ◽  
Vol 34 (5) ◽  
pp. 597-602 ◽  
Author(s):  
Álvaro Díaz-González ◽  
María Reig ◽  
Jordi Bruix
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cancer ◽  
Liver Function ◽  
Primary Liver Cancer ◽  
Performance Status ◽  
Intermediate Stage ◽  
Extrahepatic Disease ◽  
Stage Migration ◽  
Advanced Stage ◽  
Tumour Burden

Hepatocellular carcinoma (HCC) represents the most frequent primary liver cancer. This disease usually arises as a result of a chronic liver disease, but may appear without any underlying disease. In most units, the staging and treatment decision in patients with HCC follows the Barcelona Clínic Liver Cancer (BCLC) strategy. Following this approach, patients diagnosed with HCC are classified according to tumour burden, liver function and ECOG-Performance Status (PS). This stratifies patients according to prognosis and links each stage with the evidence-based treatment approach to be first considered. Patients correspond to BCLC stage 0 (very early) when the tumour burden accounts for just one nodule and it measures 2 cm or less. BCLC stage A includes patients with just one nodule or 3 nodules under 3 cm. Both stages 0 and A gather patients with preserved liver function according to Child-Pugh score, being Child-Pugh A. Patients in BCLC B stage (intermediate stage) are patients with multinodular liver cancer confined to the liver, without extrahepatic disease, ECOG-PS 0 and preserved liver function (Child-Pugh A or B). Patients with portal venous invasion, extrahepatic disease or cancer-related symptoms measured by PS (1-2) and still with preserved liver function correspond to BCLC C (advanced) stage. Finally, patients classified in BCLC stage D are those with a severe alteration of liver function (Child-Pugh C) or severe cancer-related symptoms with PS above 2. In very early and early stages (BCLC 0 and A), treatment options include surgical treatment, ablation and liver transplantation. Intermediate stage (BCLC B) patients should be considered for transarterial chemoembolization. At advanced stage (BCLC C), the recommended treatment is sorafenib. Finally, at the end stage (BCLC D), symptomatic treatment is the suggested option. The treatment stage migration concept refers to patients who at first glance would be treated with the option that corresponds to their BCLC stage but, because of any coexisting comorbidity, technical issue or even treatment failure/progression but still within the original stage cannot be treated by the initial suggested treatment. These patients then move to the treatment that would correspond to the next stage/s.

scholarly journals Lenvatinib for Hepatocellular Carcinoma: A Literature Review

2021 ◽  
Vol 14 (1) ◽  
pp. 36
Author(s):  
Takeshi Hatanaka ◽  
Atsushi Naganuma ◽  
Satoru Kakizaki
Keyword(s):  
Hepatocellular Carcinoma ◽  
Overall Survival ◽  
Liver Cancer ◽  
Liver Function ◽  
Adverse Events ◽  
Therapeutic Response ◽  
Objective Response ◽  
Intermediate Stage ◽  
Tumor Burden ◽  
Asia Pacific

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

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.

scholarly journals Development of a Model to Predict Liver Decompensation prior to Transarterial Chemoembolization Refractoriness in Patients with Intermediate-Stage Hepatocellular Carcinoma

2021 ◽  
pp. 1-9
Author(s):  
Joel Ferreira-Silva ◽  
Pedro Costa-Moreira ◽  
Helder Cardoso ◽  
Rodrigo Liberal ◽  
Pedro Pereira ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Transarterial Chemoembolization ◽  
Objective Response ◽  
Intermediate Stage ◽  
Line Treatment ◽  
First Line ◽  
Hepatic Reserve ◽  
Liver Decompensation ◽  
Pugh Class ◽  
First Line Treatment

<b><i>Introduction:</i></b> Transarterial chemoembolization (TACE) is the first-line treatment for patients with intermediate-stage hepatocellular carcinoma (HCC). For patients without an adequate response, current finding suggests that treatment with molecular target agents, approved for advanced stage, might present benefits. However, this requires a preserved liver function. This study aims to evaluate possible predictors of early deterioration of hepatic reserve, prior to TACE refractoriness, in a cohort of patients treated with TACE. <b><i>Methods:</i></b> Retrospective analysis of 99 patients with<b><i></i></b>Child-Pugh class A and intermediate-stage HCC who underwent TACE as the first-line treatment. All patients were submitted to a biochemical and medical evaluation prior to initial TACE and every month afterward. Response to initial TACE was evaluated at 1 month. The time to Child-Pugh class deterioration before TACE refractoriness was assessed. <b><i>Results:</i></b> Ninety-nine patients were included. Objective response rate (ORR) to initial TACE was assessed as present in 59 (63.4%) and as absent in 34 (36.6%) patients. Liver decompensated before TACE refractoriness in 51 (51.5%) patients, and the median time to liver decompensation was 14 (IQR 8–20) months after first TACE. In multivariate analysis, beyond up-to-7 criteria (HR 2.4, <i>p</i> = 0.031), albumin &#x3c;35 mg/dL (HR 3.5, <i>p</i> &#x3c; 0.001) and absence of ORR (HR 2.4, <i>p</i> = 0.020) were associated with decreased overall survival free of liver decompensation. Moreover, beyond up-to-7 criteria, albumin &#x3c;35 mg/dL and absence of ORR associated negatively with 6-month survival free of liver decompensation. Our model created using those variables was able to predict liver decompensation at 6 months with an AUROC of 0.701 (<i>p</i> = 0.02). <b><i>Conclusions:</i></b> The absence of ORR after initial TACE, beyond up-to-7 criteria and albumin &#x3c;35 mg/dL, was a predictive factor for early liver decompensation before TACE refractoriness in our population. Such patients might benefit from treatment escalation to systemic therapy, in monotherapy or in combination with TACE.

scholarly journals Lenvatinib as an Initial Treatment in Patients with Intermediate-stage Hepatocellular Carcinoma Beyond up-to-seven Criteria and Child-Pugh A Liver Function: A Proof-of-Concept Study

2019 ◽  
Author(s):  
Masatoshi Kudo ◽  
Kazuomi Ueshima ◽  
Stephan Chan ◽  
Tomohiro Minami ◽  
Hirokazu Chishina ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Propensity Score ◽  
Liver Function ◽  
Propensity Score Matching ◽  
Initial Treatment ◽  
Objective Response ◽  
Unmet Need ◽  
Intermediate Stage ◽  
Proof Of Concept ◽  
Concept Study

Background: Although transcatheter arterial chemoembolisation (TACE) is the standard of care for intermediate-stage hepatocellular carcinoma (HCC), this is a largely heterogeneous disease that includes a subgroup of patients who do not benefit from TACE. The treatment strategy for this subgroup of patients currently remains an unmet need in clinical practice. Here, we performed a proof-of-concept study that lenvatinib may be more favourable treatment option over TACE as an initial treatment in intermediate-stage HCC patients with large or multinodular tumours exceeding the up-to-seven criteria. Methods: This proof-of-concept study included 642 consecutive patients with HCC initially treated with lenvatinib or conventional TACE (cTACE) between January 2006 and December 2018. Of these patients, 176 who received lenvatinib or cTACE as an initial treatment and met the eligibility criteria [unresectable, beyond the up-to-seven criteria, no prior TACE/systemic therapy, no vascular invasion, no extrahepatic spread and Child-Pugh A liver function] were selected for the study. Propensity score matching was used to adjust for patient demographics. Results: After propensity-score matching, outcome of 30 patients prospectively treated with lenvatinib (14 in clinical trials, 1 in early access program and 15 in real world setting) and 60 patients treated with cTACE as the initial treatment was compared. The change of ALBI score from baseline to the end of treatment were -2.61 to -2.61 for 30 patients in lenvatinib group (p = 0.254) and -2.66 to -2.09 in cTACE group (p &lt; 0.01), respectively. The lenvatinib group showed a significantly higher objective response rate (73.3% vs. 33.3%; p &lt; 0.001) and significantly longer median progression-free survival than the cTACE group (16.0 vs. 3.0 months; p &lt; 0.001). Overall survival was significantly longer in the lenvatinib group than in the cTACE group (37.9 vs. 21.3 months; hazard ratio: 0.48, p &lt; 0.01). Conclusion: In patients with large or multinodular intermediate-stage HCC exceeding the up-to-seven criteria with Child-Pugh A liver function, who usually do not benefit from TACE, lenvatinib provides more favorable outcome than TACE.

scholarly journals Combining Chemistry and Engineering for Hepatocellular Carcinoma: Nano-Scale and Smaller Therapies

Pharmaceutics ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 1243
Author(s):  
Danielle L. Stolley ◽  
Anna Colleen Crouch ◽  
Aliçan Özkan ◽  
Erin H. Seeley ◽  
Elizabeth M. Whitley ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Residual Disease ◽  
Primary Liver Cancer ◽  
Intermediate Stage ◽  
Model Systems ◽  
Current Status ◽  
Label Free ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Stage Disease ◽  
New Applications

Primary liver cancer, or hepatocellular carcinoma (HCC), is a major worldwide cause of death from carcinoma. Most patients are not candidates for surgery and medical therapies, including new immunotherapies, have not shown major improvements since the modest benefit seen with the introduction of sorafenib over a decade ago. Locoregional therapies for intermediate stage disease are not curative but provide some benefit. However, upon close scrutiny, there is still residual disease in most cases. We review the current status for treatment of intermediate stage disease, summarize the literature on correlative histopathology, and discuss emerging methods at micro-, nano-, and pico-scales to improve therapy. These include transarterial hyperthermia methods and thermoembolization, along with microfluidics model systems and new applications of mass spectrometry imaging for label-free analysis of pharmacokinetics and pharmacodynamics.

Subclassification of BCLC B Stage Hepatocellular Carcinoma and Treatment Strategies: Proposal of Modified Bolondi's Subclassification (Kinki Criteria)

2015 ◽  
Vol 33 (6) ◽  
pp. 751-758 ◽  
Author(s):  
Masatoshi Kudo ◽  
Tadaaki Arizumi ◽  
Kazuomi Ueshima ◽  
Toshiharu Sakurai ◽  
Masayuki Kitano ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Function ◽  
Treatment Strategies ◽  
Intermediate Stage ◽  
Heterogeneous Population ◽  
Recommended Treatment ◽  
Tumor Number ◽  
Weak Points ◽  
Bclc Staging ◽  
Heterogeneous Tumor

Intermediate stage hepatocellular carcinoma (HCC) is a very heterogeneous tumor in terms of tumor size (>3 cm ∼ over 10 cm), tumor number (4 ∼ over 20) and liver function (Child-Pugh score 5-9). However, transarterial chemoembolization is the only recommended treatment option according to the Barcelona Clinic Liver Cancer (BCLC) staging. Bolondi's subclassification of BCLC B stage is feasible; however, there are several weak points. Therefore, by modifying Bolondi's subclassification, we have proposed a more simplified subclassification, Kinki criteria. The Kinki criteria consist of 2 factors: liver function (Child-Pugh score 5-7 or 8, 9) and tumor status (Beyond Milan and within up-to-7 criteria; IN and OUT). The Kinki criteria classifies BCLC B stage from B1 (Child-Pugh score 5-7 and within up-to-7), B2 (Child-Pugh score 5-7 and beyond up-to-7) and B3 (Child-Pugh score 8, 9 and any tumor status). These criteria are simple and easy to apply to clinical practice. Therefore, these criteria will stratify the heterogeneous population of BCLC B group patient well and give the treatment indication according to each substage. These criteria should be further validated both retrospectively and prospectively.

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