Tivantinib (ARQ 197), a selective, oral MET inhibitor, improved overall survival and progression-free survival compared with placebo in a randomised phase 2 study in patients with high MET expression ...(MET-high) hepatocellular carcinoma previously treated with sorafenib. The aim of this phase 3 study was to confirm the results of the phase 2 trial.
We did a phase 3, randomised, double-blind, placebo-controlled study in 90 centres in Australia, the Americas, Europe, and New Zealand. Eligible patients were 18 years or older and had unresectable, histologically confirmed, hepatocellular carcinoma, an Eastern Cooperative Oncology Group performance status of 0–1, high MET expression (MET-high; staining intensity score ≥2 in ≥50% of tumour cells), Child-Pugh A cirrhosis, and radiographically-confirmed disease progression after receiving sorafenib-containing systemic therapy. We randomly assigned patients (2:1) in block sizes of three using a computer-generated randomisation sequence to receive oral tivantinib (120 mg twice daily) or placebo (twice daily); patients were stratified by vascular invasion, extrahepatic spread, and α-fetoprotein concentrations (≤200 ng/mL or >200 ng/mL). The primary endpoint was overall survival in the intention-to-treat population. Efficacy analyses were by intention to treat and safety analyses were done in all patients who received any amount of study drug. This study is registered with ClinicalTrials.gov, number NCT01755767.
Between Dec 27, 2012, and Dec 10, 2015, 340 patients were randomly assigned to receive tivantinib (n=226) or placebo (n=114). At a median follow-up of 18·1 months (IQR 14·1–23·1), median overall survival was 8·4 months (95% CI 6·8–10·0) in the tivantinib group and 9·1 months (7·3–10·4) in the placebo group (hazard ratio 0·97; 95% CI 0·75–1·25; p=0·81). Grade 3 or worse treatment-emergent adverse events occurred in 125 (56%) of 225 patients in the tivantinib group and in 63 (55%) of 114 patients in the placebo group, with the most common being ascites (16 7% patients), anaemia (11 5% patients), abdominal pain (nine 4% patients), and neutropenia (nine 4% patients) in the tivantinib group. 50 (22%) of 226 patients in the tivantinib group and 18 (16%) of 114 patients in the placebo group died within 30 days of the last dose of study medication, and general deterioration (eight 4% patients) and hepatic failure (four 2% patients) were the most common causes of death in the tivantinib group. Three (1%) of 225 patients in the tivantinib group died from a treatment-related adverse event (one sepsis, one anaemia and acute renal failure, and one acute coronary syndrome).
Tivantinib did not improve overall survival compared with placebo in patients with MET-high advanced hepatocellular carcinoma previously treated with sorafenib. Although this METIV-HCC trial was negative, the study shows the feasibility of doing integral tissue biomarker studies in patients with advanced hepatocellular carcinoma. Additional randomised studies are needed to establish whether MET inhibition could be a potential therapy for some subsets of patients with advanced hepatocellular carcinoma.
ArQule Inc and Daiichi Sankyo (Daiichi Sankyo Group).
The potential impact of direct-acting antivirals (DAAs) in patients with Barcelona Clinic Liver Cancer (BCLC)-B/C stage hepatocellular carcinoma (HCC) is understudied. Patients with HCC have been ...systematically excluded from randomised controlled trials evaluating the effectiveness of DAAs. Thus, the benefits of DAAs in patients with HCC are less well defined. The presence of active HCC before the initiation of DAA treatment is reported to be a predictor of DAA failure, and studies in patients without HCC have demonstrated that improvements in cirrhosis complications were lower or absent after DAA failure. Even if viral eradication is achieved using DAAs, reversal of liver function impairment may take longer than the development of end-stage cancer status. Additionally, the impact of DAAs on HCC recurrence is still a controversial topic. Thus, the decision of whether to use DAAs should be made on a patient-by-patient basis, and each patient should be informed of all the potential risks and benefits associated with their usage. This document summarises the current data on the usage of DAAs in BCLC-B/C patients, discusses the concept of “the point of no return” in the setting of DAAs, and proposes tools for deciding the best option for each patient profile. If liver function improvement overlaps with symptomatic HCC progression, the benefits of DAAs could be minimised, worsened, or fully counterbalanced. If the BCLC stage is defined using only liver dysfunction, the decision to prioritise DAA treatment should be based on the option (or lack thereof) of liver transplantation and/or the HCC stage. We propose applying a shared decision-making approach, informing each patient of all the potential risks and benefits of the proposed medical intervention.
There have been major advances in the armamentarium for hepatocellular carcinoma (HCC) since the last official update of the Barcelona Clinic Liver Cancer prognosis and treatment strategy published ...in 2018. Whilst there have been advances in all areas, we will focus on those that have led to a change in strategy and we will discuss why, despite being encouraging, data for select interventions are still too immature for them to be incorporated into an evidence-based model for clinicians and researchers. Finally, we describe the critical insight and expert knowledge that are required to make clinical decisions for individual patients, considering all of the parameters that must be considered to deliver personalised clinical management.
Whether preoperative clinically significant portal hypertension (CSPH) has or not an impact on the outcome of surgery for hepatocellular carcinoma (HCC) in patients with compensated cirrhosis is ...debated. This systematic review assesses the impact of CSPH on the outcome of HCC in patients with compensated cirrhosis treated with surgery. We performed a systematic search of the MEDLINE database (articles published in full in English language from 1996 to October 2013) and related bibliography for studies reporting on the postoperative outcomes (3‐ and 5‐year mortality and/or early clinical decompensation) of patients with HCC and compensated cirrhosis treated with surgery according to the presence or absence of CSPH. Independent extraction of articles by two authors using predefined data fields, including study quality indicators, was used; pooled analyses were based on random‐effects models. Eleven studies in total met our inclusion criteria (eight studies for 3‐ and 5‐year postoperative mortality and eight for postoperative clinical decompensation). Moderate heterogeneity among studies for both outcomes was observed, which disappeared after pooling studies using similar methods to assess CSPH. The presence of CSPH increased the risk of 3‐ and 5‐year mortality versus absence of CSPH (pooled odds ratio OR for 3‐year mortality: 2.09; 95% confidence interval CI: 1.52‐2.88; for 5‐year mortality: 2.07; 95% CI: 1.51‐2.84). CSPH also increased the risk of postoperative clinical decompensation (pooled OR: 3.04; 95% CI: 2.02‐4.59). Conclusions: CSPH (evaluated by any method) significantly increases the risk of 3‐ and 5‐year mortality and of clinical decompensation after surgery for HCC. (Hepatology 2015;61:526‐536)
The success of direct-acting antivirals (DAA) against hepatitis C is a major breakthrough in hepatology. Until now, however, there are very few data on the effect of hepatitis C virus (HCV) ...eradication in patients who have already developed hepatocellular carcinoma.
The study included patients with HCV infection and prior history of treated hepatocellular carcinoma who achieved complete response and lacked ‘non-characterized nodules’ at the time they underwent anti-HCV treatment with all-oral DAAs in 4 hospitals. Patients receiving interferon as part of the antiviral regimen were excluded. The baseline characteristics, laboratory and radiologic tumor response were registered in all patients before starting antiviral therapy and during the follow-up according to the clinical practice policy.
Between 2014 and 2015, 103 patients with prior hepatocellular carcinoma received DAA, 58 of them met the inclusion criteria. After a median follow-up of 5.7months, 3 patients died and 16 developed radiologic tumor recurrence (27.6%). The pattern of recurrence was: intrahepatic growth (3 patients), new intrahepatic lesion (1 nodule in 5 patients, up to 3 nodules less or equal to 3cm in 4 cases and multifocal in one patient) and infiltrative ill-defined hepatocellular carcinoma and/or extra-hepatic lesions in 3 patients.
Our data show an unexpected high rate and pattern of tumor recurrence coinciding with HCV clearance and, although based in a very small cohort of patients, should be taken as a note of caution and prime a large scale assessment that exceeds the individual investigators capacity.
High rate of cancer recurrence after DAA treatment in patients with prior hepatocellular carcinoma. Disruption of immune surveillance may facilitate the emergence of metastatic clones.
Hepatocellular carcinoma appears frequently in patients with cirrhosis. Surveillance by biannual ultrasound is recommended for such patients because it allows diagnosis at an early stage, when ...effective therapies are feasible. The best candidates for resection are patients with a solitary tumour and preserved liver function. Liver transplantation benefits patients who are not good candidates for surgical resection, and the best candidates are those within Milan criteria (solitary tumour ≤5 cm or up to three nodules ≤3 cm). Image-guided ablation is the most frequently used therapeutic strategy, but its efficacy is limited by the size of the tumour and its localisation. Chemoembolisation has survival benefit in asymptomatic patients with multifocal disease without vascular invasion or extrahepatic spread. Finally, sorafenib, lenvatinib, which is non-inferior to sorafenib, and regorafenib increase survival and are the standard treatments in advanced hepatocellular carcinoma. This Seminar summarises the scientific evidence that supports the current recommendations for clinical practice, and discusses the areas in which more research is needed.
•Sorafenib is indicated for advanced and intermediate (post-TACE failure) HCC.•Sorafenib should be given early to ensure patients can benefit from all therapies.•Sorafenib toxicities can be ...effectively prevented and managed for treatment benefit.•Sorafenib, lenvatinib, regorafenib, cabozantinib, and ramucirumab improve survival.•New systemic agents are emerging for the treatment of patients with advanced HCC.
The hepatocellular carcinoma (HCC) treatment landscape changed a decade ago, with sorafenib demonstrating survival benefit in the first-line setting and becoming the first systemic therapy to be approved for HCC. More recently, regorafenib and nivolumab have received approval in the second-line setting after sorafenib, with further positive phase 3 studies emerging in the first line (lenvatinib non-inferior to sorafenib) and second line versus placebo (cabozantinib and ramucirumab). A key recommendation in the management of patients receiving sorafenib is to promote close communication between the patient and the physician so that adverse events (AEs) are detected early and severe AEs can be prevented. Sorafenib-related AEs have been identified as clinical biomarkers for sorafenib efficacy. Healthcare professionals have become more efficient in managing AEs, identifying patients who are likely to benefit from treatment, and assessing response to treatment, resulting in a trend towards increased overall survival in the sorafenib arms of clinical studies. The rapidly changing treatment landscape due to the emergence of new treatment options (sorafenib and lenvatinib equally effective in first line; regorafenib, cabozantinib, and ramucirumab showing OS benefit in second line with nivolumab approved by the FDA based on response rate) underscores the importance of re-assessing the role of the first approved systemic agent in HCC, sorafenib.
The cost of Floating Offshore Wind (FOW) is driven by the foundation, thus it can be reduced by optimising the floater design from the early stage. Most of the numerical tools for the platform design ...integrate radiation–diffraction theory-based software, but it can make the whole process very time-consuming since the preliminary design phases usually imply the analysis of a large number of designs. In order to accelerate the first stages of design, and consequently, achieve the foundation cost reduction, this study proposes an efficient methodology for the hydrodynamic added mass, radiation damping, and excitation loads calculation. The method is implemented for a semi-submersible platform, and it is verified against the radiation–diffraction commercial software AQWA. The methodology is validated through a comparative analysis of the response of ten different platforms, and it has shown that the hydrodynamic coefficients derived from either radiation–diffraction analysis or from the proposed method lead to equivalent conclusions. The maximum values of the platform’s pitch angle and the nacelle acceleration are assessed, achieving a maximum deviation among the most critical designs of 3% and 17%, respectively. This methodology has demonstrated to provide with reasonable accuracy the dynamic behaviour of the offshore wind substructures achieving a significant computational cost reduction compared to the state-of-the-art methods, which enables to accelerate the optimisation process and thus, resulting in a more accurate floater preliminary design.
•Methodology for the estimation hydrodynamic coefficients on semisubmersible floaters.•Efficient method through interpolation and superposition of the hydrodynamic data.•Parametric study to analyse the cross-interaction effects between the columns.•Validation against radiation–diffraction commercial software.•Comparative analysis of different platforms to quantify the method’s accuracy.
Background & Aims Transarterial chemoembolisation (TACE) improves survival of properly selected patients with hepatocellular carcinoma (HCC). Drug eluting beads (DEB) provide a calibrated and ...homogenous procedure while increasing efficacy. Outcome data applying this technology is lacking, and this is instrumental for clinical decision-making and for trial design. We evaluated the survival of HCC patients treated with DEB-TACE following a strict selection (preserved liver function, absence of symptoms, extrahepatic spread or vascular invasion). Methods We registered baseline characteristics, the development of treatment-related adverse events, and the overall survival of all HCC patients treated by DEB-TACE from February 2004 to June 2010. Results One hundred and four patients were treated with DEB-TACE. All but one were cirrhotic, 62.5% HCV+, 95% Child-Pugh A, 41 BCLC-A and 63 BCLC-B. Causes of DEB-TACE treatment in BCLC-A patients were: 35 unfeasible ablation, and six post-treatment recurrences. After a median follow-up of 24.5 months, 38 patients had died, two patients had received transplantation and 24 had received sorafenib because of untreatable tumour progression. Median survival of the cohort was 48.6 months (95% CI: 36.9–61.2), while it was 54.2 months in BCLC stage A and 47.7 months in stage B. Median survival after censoring follow-up at time of transplant/sorafenib was 47.7 (95% CI: 37.9–57.5) months. Conclusions These data validate the safety of DEB-TACE and show that the survival expectancy applying current selection criteria and technique is better than that previously reported. A 50% survival at 4 years should be considered when suggesting treatment for patients fitting into controversial scenarios such as expanded criteria for transplantation/resection for multifocal HCC.
The benefit of direct-acting antivirals (DAAs) against HCV following successful treatment of hepatocellular carcinoma (HCC) remains controversial. This meta-analysis of individual patient data ...assessed HCC recurrence risk following DAA administration.
We pooled the data of 977 consecutive patients from 21 studies of HCV-related cirrhosis and HCC, who achieved complete radiological response after surgical/locoregional treatments and received DAAs (DAA group). Recurrence or death risk was expressed as HCC recurrence or death per 100 person-years (100PY). Propensity score-matched patients from the ITA.LI.CA. cohort (n=328) served as DAA-unexposed controls (no-DAA group). Risk factors for HCC recurrence were identified using random-effects Poisson.
Recurrence rate and death risk per 100PY in DAA-treated patients were 20 (95% CI 13.9 to 29.8, I
=74.6%) and 5.7 (2.5 to 15.3, I
=54.3), respectively. Predictive factors for recurrence were alpha-fetoprotein logarithm (relative risk (RR)=1.11, 95% CI 1.03 to 1.19; p=0.01, per 1 log of ng/mL), HCC recurrence history pre-DAA initiation (RR=1.11, 95% CI 1.07 to 1.16; p<0.001), performance status (2 vs 0, RR=4.35, 95% CI 1.54 to 11.11; 2 vs 1, RR=3.7, 95% CI 1.3 to 11.11; p=0.01) and tumour burden pre-HCC treatment (multifocal vs solitary nodule, RR=1.75, 95% CI 1.25 to 2.43; p<0.001). No significant difference was observed in RR between the DAA-exposed and DAA-unexposed groups in propensity score-matched patients (RR=0.64, 95% CI 0.37 to 1.1; p=0.1).
Effects of DAA exposure on HCC recurrence risk remain inconclusive. Active clinical and radiological follow-up of patients with HCC after HCV eradication with DAA is justified.
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