Systemic therapy in HCC: Lessons from brivanib

Bolos, David; Finn, Richard S.

doi:10.1016/j.jhep.2014.06.019

Cited by 16 publications

(16 citation statements)

References 14 publications

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“…As a matter of fact in the second‐line Brisk‐PS study of brivanib the survival times of patients on active treatment were not significantly longer than those in the placebo group . Reassessment of survival figures of the placebo arm of numerous randomized control trials disclosed a significant heterogeneity of survival, likely reflecting inclusion of patients at different stages of tumor disease and with different molecular and biological profiles of their tumors, a variable that is not incorporated in any tumor staging system, as already demonstrated in previous meta‐analyses . This makes it even more compelling to standardize the assessment of survival in treated patients with respect to sorafenib interruption with the aims of (1) evaluating the natural history and validating the predictive power of biological or radiological surrogate markers, (2) controlling for confounding factors in observational studies, (3) calculating the sample size and stratifying subjects in phase II and III randomized control trials, and (4) assessing treatment effect size to formulate therapeutic strategies.…”

Section: Discussionmentioning

confidence: 89%

Predictors of survival in patients with advanced hepatocellular carcinoma who permanently discontinued sorafenib

et al. 2015

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Treatment with sorafenib of patients with advanced hepatocellular carcinoma is challenged by anticipated discontinuation due to tumor progression, liver decompensation, or adverse effects. While postprogression survival is clearly determined by the pattern of tumor progression, understanding the factors that drive prognosis in patients who discontinued sorafenib for any reason may help to improve patient management and second-line trial design. Patients consecutively admitted to three referral centers who were receiving best supportive care following permanent discontinuation of sorafenib for any reason were included. Postsorafenib survival (PSS) was calculated from the last day of treatment to death or last visit available. Two hundred and sixty patients were included in this prospective study, aged 67 years, 60% with hepatitis C, 51% Child-Pugh A, 83% performance status (PS) 1, 41% with macroscopic vascular invasion, and 38% with extrahepatic tumor spread. Overall, median PSS was 4.1 (3.3-4.9) months, resulting from 4.6 (3.3-5.7) months for 123 progressors, 7.3 (6.0-10.0) months in 77 with adverse effects, and 1.8 (1.6-2.4) months in 60 decompensated patients (P < 0.001). Postsorafenib survival was independently predicted by PS, prothrombin time, extrahepatic tumor spread, macrovascular invasion, and reason for discontinuation. Two hundred patients potentially eligible for second-line therapy had a PSS of 5.3 (4.6-7.1) months, which was dependent on reasons of discontinuation (P 5 0.004), PS (P < 0.001), macrovascular invasion (P < 0.001), and extrahepatic metastases (P < 0.002). Conclusion: Discontinuation due to adverse effects in the absence of macrovascular invasion, extrahepatic metastases, and deteriorated PS predicts the best PSS in compensated patients, thereby setting the stage for both improved patient counseling and selection for second-line therapy. (HEPATOLOGY 2015;62:784-791)

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Section: Discussionmentioning

confidence: 89%

Predictors of survival in patients with advanced hepatocellular carcinoma who permanently discontinued sorafenib

et al. 2015

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“…Secondly, improved hepatic reserve phenotyping might help mitigating the risks stemming from systemic toxicity, a nontrivial issue in patients with HCC where treatment discontinuation due to AEs is higher than other malignancies, and has in the past led to the premature termination of development of sunitinib due to concerns over excessive mortality in the treatment arm. Although exploring the relationship between ALBI grade and toxicity from systemic treatment was beyond the aims of our study, this should be formally evaluated in future prospective trials.…”

Section: Discussionmentioning

confidence: 99%

The albumin–bilirubin grade improves hepatic reserve estimation post‐sorafenib failure: implications for drug development

Pinato

Yen

Bettinger

et al. 2017

Aliment Pharmacol Ther

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Abstract.Background: Drug development in hepatocellular carcinoma (HCC) is limited by disease heterogeneity, with hepatic reserve being a major source of variation in survival outcomes. The albumin-bilirubin (ALBI) grade is a validated index of liver function in patients with HCC. Aims:We tested the accuracy of the ALBI grade in predicting post-sorafenib overall survival (PSOS) in patients who permanently discontinued treatment.Methods: From a prospectively maintained international database of 447 consecutive referrals, we derived 386 eligible patients treated with sorafenib within Barcelona Clinic Liver Cancer (BCLC) C stage (62%), 75% of whom were of Child-Turcotte-Pugh (CTP) class A at initiation. Clinical variables at sorafenib discontinuation were analyzed for their impact on PSOS using uni-and multivariable analyses.Results: Median PSOS of the 386 eligible patients was 3.4 months and median sorafenib duration was 2.9 months, with commonest causes of cessation being disease progression (68%) and toxicity (24%). At discontinuation, 92 patients (24%) progressed to terminal stage, due to worsening CTP to class C in 40 (10%). The ALBI grade predicted for PSOS in the whole patient population and in candidates for second line therapies (n=294) with median PSOS of 17.5 and 7.5 months for grades 1 and 2, independently of BCLC stage and subsequent therapies (p<0.001). Conclusions:The ALBI grade at sorafenib discontinuation identifies a subset of patients with prolonged stability of hepatic reserve and superior survival. This may allow

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“…HCC is a highly angiogenic malignancy, which is characterized by a high propensity for vascular invasion [22]. Increasing studies have reported that miRNAs regulated hepatocarcinogenesis-related gene expression, indicating a new insight in the initiation and progression of HCC [23].…”

Section: Discussionmentioning

confidence: 99%

Down-regulated miR-28-5p in human hepatocellular carcinoma correlated with tumor proliferation and migration by targeting insulin-like growth factor-1 (IGF-1)

Shi

Teng

2015

Mol Cell Biochem

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Hepatocellular carcinoma (HCC) is a rapidly progressing, incurable cancer that frequently spreads to portal vein and lung. New insights are needed to identify therapeutic targets to prevent or retard HCC metastatic progression. Because microRNAs (miRNA) often act as tumor regulators, we investigated their role in preclinical models of HCC. Here we found miR-28-5p is a liver-relevant anti-proliferative miRNA whose expression, functions, and mechanisms were analyzed in human hepatoma cells, HepG2 and Huh7. Interestingly, when evaluating the specific targets of miR-28-5p, we found that ectopic miR-28-5p expression down-regulates insulin-like growth factor 1 (IGF1) protein and that the expression of miR-28-5p correlates negatively with IGF1 protein in HCC cells. Luciferase report in HCC cells expressing miR-28-5p suggests that miR-28-5p reduces luciferase activity by targeting the 3'-UTR of IGF1 mRNA. Additionally, we show that the selective inhibition of either the PI3K/AKT pathway prior to miR-28-5p stimulation prevents the expression of previously described tumor suppressor miRNAs that are family and cluster specific. Together, our results defined miR-28-5p as a critical regulator of IGF1 mRNA translation function, down-regulated miR-28-5p in HCC was associated with tumor growth through PI3K/AKT pathway by targeting IGF1. miR-28-5p-IGF1-PI3K/AKT pathway may play an important role in the development of HCC.

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Systemic therapy in HCC: Lessons from brivanib

Cited by 16 publications

References 14 publications

Predictors of survival in patients with advanced hepatocellular carcinoma who permanently discontinued sorafenib

Predictors of survival in patients with advanced hepatocellular carcinoma who permanently discontinued sorafenib

The albumin–bilirubin grade improves hepatic reserve estimation post‐sorafenib failure: implications for drug development

Down-regulated miR-28-5p in human hepatocellular carcinoma correlated with tumor proliferation and migration by targeting insulin-like growth factor-1 (IGF-1)

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