The combination of atezolizumab and bevacizumab (A + B) is the new standard of care for the systemic first-line treatment of hepatocellular carcinoma (HCC). However, up to now there are only few data ...on the safety and efficacy of A + B in real life. We included patients with advanced HCC treated with A + B as first-line therapy at four cancer centers in Germany and Austria between December 2018 and August 2021. Demographics, overall survival (OS), and adverse events were assessed until 15 September 2021. We included 66 patients. Most patients had compensated cirrhosis (n = 34; 52%), while Child-Pugh class B cirrhosis was observed in 23 patients (35%), and class C cirrhosis in 5 patients (8%). The best responses included a complete response (CR) in 7 patients (11%), a partial response (PR) in 12 patients (18%), stable disease (SD) in 22 patients (33%), and progressive disease in 11 patients (17%)
The median progression-free (PFS) survival was 6.5 months, while the median overall survival (OS) was not reached in this cohort (6-month OS: 69%, 12-month OS: 60%, 18-month OS: 58%). Patients with viral hepatitis seemed to have a better prognosis than patients with HCC of non-viral etiology. The real-world PFS and OS were comparable to those of the pivotal IMBRAVE trial, despite including patients with worse liver function in this study. We conclude that A + B is also highly effective in a real-life setting, with manageable toxicity, especially in patients with compensated liver disease. In patients with compromised liver function (Child B and C), the treatment showed low efficacy and, therefore, it should be well considered before administration to these patients.
Introduction
MDRO-colonization has been shown to impair survival in patients with hematological malignancies and solid tumors as well as in patients with liver disease. Despite the increasing spread ...of multidrug-resistant organisms (MDRO), its impact on patients with hepatocellular carcinoma (HCC) has not been studied. We conducted this retrospective study to analyze the impact of MDRO-colonization on overall prognosis in HCC patients.
Materials and methods
All patients with confirmed HCC diagnosed between January 2008 and December 2017 at the University Hospital Frankfurt were included in this study. HCC patients with a positive MDRO screening before or within the first 90 days after diagnosis of HCC were defined as colonized HCC patients, HCC patients with a negative MDRO screening were defined as noncolonized HCC patients.
Results
59 (6%) colonized and 895 (94%) noncolonized HCC patients were included.
Enterobacterales
with extended-spectrum β-lactamase-like phenotype with or without resistance to fluoroquinolones (ESBL/ ± FQ) were the most frequently found MDRO with 59%, followed by vancomycin-resistant
Enterococcus faecium
with 37%. Colonized HCC patients had more severe cirrhosis and more advanced HCC stage compared to noncolonized HCC patients. Colonized HCC patients showed an impaired survival with a median OS of 189 days (6.3 months) compared to a median OS of 1001 days (33.4 months) in noncolonized HCC patients. MDRO-colonization was identified as an independent risk factor associated with survival in multivariate analysis.
Conclusion
MDRO-colonization is an independent risk factor for survival in patients with HCC highlighting the importance of regular MDRO screening, isolation measures as well as interdisciplinary antibiotic steward-ship programs to guide responsible use of antibiotic agents.
Atezolizumab plus bevacizumab is the standard of care for first-line systemic therapy for advanced hepatocellular carcinoma (aHCC). Data on the efficacy and safety of atezolizumab plus bevacizumab in ...patients with aHCC who have received prior systemic therapy are not available.
Patients with aHCC who received atezolizumab plus bevacizumab after at least one systemic treatment between December 2018 and March 2022 were retrospectively identified in 13 centers in Germany and Austria. Patient characteristics, tumor response rates, progression-free survival (PFS), overall survival (OS), and adverse events (AE) were analyzed.
A total of 50 patients were identified; 41 (82%) were male. The median age at initiation of treatment with atezolizumab plus bevacizumab was 65 years, 41 (82%) patients had cirrhosis, 30 (73%) Child A, 9 (22%) B, and 2 (5%) C. A total of 34 patients (68%) received atezolizumab plus bevacizumab in the second-line setting and 16 (32%) in later lines. The best radiologic tumor responses were complete remission (2%), partial remission (30%), stable disease (36%), and progressive disease (18%), resulting in an objective response rate of 32% and a disease control rate of 68%. Median OS was 16.0 months (95% confidence interval 5.6-26.4 months), and median PFS was 7.1 months (95% confidence interval 4.4-9.8 months). AE grades 3-4 were observed in seven (14%) and resulted in death in three patients (6%). There were five (10%) bleeding events with a grade ≥ 3, including one (2%) with a fatal outcome.
Atezolizumab plus bevacizumab is effective in patients with aHCC who did not have access to this option as first-line therapy. The safety profile was consistent with previous reports.
Introduction: The impact of etiology on response to immunotherapy in advanced hepatocellular carcinoma (HCC) is being debated, with contrasting findings between early and recent post hoc analyses of ...IMbrave-150 and metanalyses of clinical trials of PD-1/PD-L1 blockers. As a results, it is not clear whether the first-line systemic treatment atezolizumab plus bevacizumab (A + B) is equally effective in viral and nonviral patients. Methods: We retrospectively analyzed 885 HCC patients treated with the first-line A + B from multiple centers from Eastern and Western countries, 53.9% having viral and 46.1% nonviral etiology. Baseline clinical and laboratory characteristics were analyzed with uni- and multivariate models to explore potential differences on overall survival (OS), time-to-progression (TTP), disease control rates (DCRs) based on etiology and to identify putative prognostic factors in etiology subgroups. Treatment toxicities and access to the second-line treatments and outcomes were also reported and compared between etiologies. Results: Overall, no statistically significant differences were found in median OS (mOS: viral 15.9 months; nonviral 16.3 months), TTP (mTTP: viral 8.3 months; nonviral 7.2 months), and DCRs (viral 78.1%; nonviral 80.8%) based on etiology. Prognostic factors of survival and progression were mainly shared between viral and nonviral etiologies, including alpha-fetoprotein, aspartate transaminase, neutrophil-to-lymphocyte ratio (NLR) and ALBI score. Exploratory analyses highlighted a possible stronger association of immunological factors, i.e., NLR and eosinophil count, to treatment outcomes in viral patients. The toxicity profile, the access to and type of the second-line treatments and their outcome in terms of OS almost overlap in the two etiology subgroups. Conclusion: Atezolizumab plus bevacizumab efficacy does not vary according to underlying etiology of HCC in a multicenter, real-world population, matching recent post hoc findings from the IMbrave-150 trial. Preliminary analyses suggest that some prognostic factors differ between viral and nonviral patients, potentially due to biological and immunological differences. Prospective and comparative trials stratifying by etiology are warranted to validate these findings and guide clinical practice.
Immunotherapy with atezolizumab plus bevacizumab represents the new standard of care in systemic front-line treatment of hepatocellular carcinoma (HCC). However, biomarkers that predict treatment ...success and survival remain an unmet need.
Patients with HCC put on PD-(L)1-based immunotherapy were included in a training set (n = 190; 6 European centers) and a validation set (n = 102; 8 European centers). We investigated the prognostic value of baseline variables on overall survival using a Cox model in the training set and developed the easily applicable CRAFITY (CRP and AFP in ImmunoTherapY) score. The score was validated in the independent, external cohort, and evaluated in a cohort of patients treated with sorafenib (n = 204).
Baseline serum alpha-fetoprotein ≥100 ng/ml (hazard ratio HR 1.7; p = 0.007) and C-reactive protein ≥1 mg/dl (HR, 1.7; p = 0.007) were identified as independent prognostic factors in multivariable analysis and were used to develop the CRAFITY score. Patients who fulfilled no criterion (0 points; CRAFITY-low) had the longest median overall survival (27.6 (95% CI 19.5-35.8) months), followed by those fulfilling 1 criterion (1 point; CRAFITY-intermediate; 11.3 (95% CI 8.0-14.6) months), and patients meeting both criteria (2 points; CRAFITY-high; 6.4 (95% CI 4.8-8.1) months; p <0.001). Additionally, best radiological response (complete response/partial response/stable disease/progressive disease) was significantly better in patients with lower CRAFITY score (CRAFITY-low: 9%/20%/52%/20% vs. CRAFITY-intermediate: 3%/25%/36%/36% vs. CRAFITY-high: 2%/15%/22%/61%; p = 0.003). These results were confirmed in the independent validation set and in different subgroups, including Child-Pugh A and B, performance status 0 and ≥1, and first-line and later lines. In the sorafenib cohort, CRAFITY was associated with survival, but not radiological response.
The CRAFITY score is associated with survival and radiological response in patients receiving PD-(L)1 immunotherapy. The score may help with patient counseling but requires prospective validation.
The immunotherapy-based regimen of atezolizumab plus bevacizumab represents the new standard of care in systemic first-line therapy of hepatocellular carcinoma (HCC). Biomarkers to predict treatment outcome are an unmet need in patients undergoing immunotherapy for HCC. We developed and externally validated a score that predicts outcome in patients with HCC undergoing immunotherapy with immune checkpoint blockers.
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•Baseline serum AFP ≥100 ng/ml and CRP ≥1 mg/dl were independently associated with worse OS in ICB-treated patients with HCC.•A score based on these two variables predicts disease control rate and overall survival in ICB-treated patients with HCC.•The score was validated in an independent cohort of ICB-treated patients with HCC.•In sorafenib-treated patients with HCC, the score was prognostic for overall survival but not predictive for disease control rate.
Atezolizumab plus bevacizumab and lenvatinib have not been compared in a randomised controlled trial. We conducted a retrospective multi-centre study to compare the clinical efficacy and safety of ...lenvatinib and atezolizumab with bevacizumab as a first-line treatment for patients with unresectable HCC in the real-world scenario.
Clinical features of lenvatinib and atezolizumab plus bevacizumab patients were balanced through inverse probability of treatment weighting (IPTW) methodology, which weights patients' characteristics and measured outcomes of each patient in both treatment arms. Overall survival (OS) was the primary end-point.
The analysis included 1341 patients who received lenvatinib, and 864 patients who received atezolizumab plus bevacizumab. After IPTW adjustment, atezolizumab plus bevacizumab did not show a survival advantage over lenvatinib HR 0.97 (p = 0.739). OS was prolonged by atezolizumab plus bevacizumab over lenvatinib in viral patients (HR: 0.76; p = 0.024). Conversely, OS was prolonged by lenvatinib in patients with non-alcoholic steatohepatitis/non-alcoholic fatty liver disease (HR: 1.88; p = 0.014).
In the IPTW-adjusted population, atezolizumab plus bevacizumab provided better safety profile for most of the recorded adverse events.
Our study did not identify any meaningful difference in OS between atezolizumab plus bevacizumab and lenvatinib. Although some hints are provided suggesting that patients with non-alcoholic steatohepatitis/non-alcoholic fatty liver disease might benefit more from lenvatinib therapy and patients with viral aetiology more from atezolizumab plus bevacizumab.
•No randomised trial has been conducted to compare atezolizumab plus bevacizumab to lenvatinib.•Atezolizumab plus bevacizumab did not show a survival advantage over lenvatinib.•Lenvatinib provided longer in patients with NASH/NAFLD.•Atezolizumab plus bevacizumab provided longer in patients with viral aetiology.•Atezolizumab plus bevacizumab consistently reduced any toxicity and those graded as 3–4.
Liver cancer was the fourth leading cause of cancer death in 2015 with increasing incidence between 1990 and 2015. Orthotopic liver transplantation, surgical resection and ablation comprise the only ...curative therapy options. However, due to the late manifestation of clinical symptoms, many patients present with intermediate or advanced disease, resulting in no curative treatment option being available. Whereas intermediate-stage hepatocellular carcinoma (HCC) is usually still addressable by transarterial chemoembolization (TACE), advanced-stage HCC is amenable only to pharmacological treatments. Conventional cytotoxic agents failed demonstrating relevant effect on survival also because their use was severely limited by the mostly underlying insufficient liver function. For a decade, tyrosine kinase inhibitor (TKI) sorafenib was the only systemic therapy that proved to have a clinically relevant effect in the treatment of advanced HCC. In recent years, the number of substances for systemic treatment of advanced HCC has increased enormously. In addition to tyrosine kinase inhibitors, immune checkpoint inhibitors (ICI) and antiangiogenic drugs are increasingly being applied. The combination of anti-programmed death ligand 1 (PD-L1) antibody atezolizumab and anti-vascular endothelial growth factor (VEGF) antibody bevacizumab has become the new standard of care for advanced HCC due to its remarkable response rates. This requires more and more complex clinical decisions regarding tumor therapy. This review aims at summarizing recent developments in systemic therapy, considering data on first- and second-line treatment, use in the neoadjuvant and adjuvant setting and combination with locoregional procedures.
Introduction: The tyrosine kinase inhibitors (TKIs) sorafenib and lenvatinib represent the first-line systemic therapy of choice for patients with hepatocellular carcinoma (HCC) recurrence after ...liver transplantation (LT). Under sorafenib and lenvatinib, HCC patients have shown increasingly improved overall survival in clinical studies over the years. In contrast, data on overall survival for patients with HCC recurrence after LT under TKIs are scarce and limited to small retrospective series. In this retrospective, multicenter study, we investigated the efficacy of TKI therapy and the influence of immunosuppression in patients with HCC recurrence after LT. Methods: Retrospective data were collected from four transplant centers from Germany and Austria. We included patients with HCC recurrence after LT between 2007 and 2020 who were treated with a TKI. Results: In total, we analyzed data from 46 patients with HCC recurrence after LT. The most common underlying liver disease was hepatitis C, accounting for 52.2%. The median time to relapse was 11.8 months (range 0–117.7 months). The liver graft was affected in 21 patients (45.7%), and 36 patients (78.3%) had extrahepatic metastases at initial diagnosis of recurrence, with the lung being the most commonly affected (n = 25, 54.3%). Of the total, 54.3% (n = 25) of the patients were initially treated locally; 39 (85.8%) and 7 (15.2%) patients received sorafenib and lenvatinib, respectively, as first-line systemic therapy. Median overall survival of the whole cohort was 10.9 months (95% confidence interval (95% CI) 6.9–14.9 months) and median progression free survival was 5.7 months (95% CI 2.0–9.4 months) from treatment initiation. Conclusion: Since history of liver transplantation is considered a contraindication for immunotherapy, prognosis of patients with HCC recurrence after LT remains poor.
The aim of this retrospective proof-of-concept study was to compare different second-line treatments for patients with hepatocellular carcinoma and progressive disease (PD) after first-line ...lenvatinib or atezolizumab plus bevacizumab.
A total of 1381 patients had PD at first-line therapy. 917 patients received lenvatinib as first-line treatment, and 464 patients atezolizumab plus bevacizumab as first-line.
49.6% of PD patients received a second-line therapy without any statistical difference in overall survival (OS) between lenvatinib (20.6months) and atezolizumab plus bevacizumab first-line (15.7months; p = 0.12; hazard ratio HR= 0.80). After lenvatinib first-line, there wasn’t any statistical difference between second-line therapy subgroups (p = 0.27; sorafenib HR: 1; immunotherapy HR: 0.69; other therapies HR: 0.85). Patients who underwent trans-arterial chemo-embolization (TACE) had a significative longer OS than patients who received sorafenib (24.7 versus 15.8months, p < 0.01; HR=0.64). After atezolizumab plus bevacizumab first-line, there was a statistical difference between second-line therapy subgroups (p < 0.01; sorafenib HR: 1; lenvatinib HR: 0.50; cabozantinib HR: 1.29; other therapies HR: 0.54). Patients who received lenvatinib (17.0months) and those who underwent TACE (15.9months) had a significative longer OS than patients treated with sorafenib (14.2months; respectively, p = 0.01; HR=0.45, and p < 0.05; HR=0.46).
Approximately half of patients receiving first-line lenvatinib or atezolizumab plus bevacizumab access second-line treatment. Our data suggest that in patients progressed to atezolizumab plus bevacizumab, the systemic therapy able to achieve the longest survival is lenvatinib, while in patients progressed to lenvatinib, the systemic therapy able to achieve the longest survival is immunotherapy.
•About half of progressed patients undergo second-line therapy.•Second-line TACE achieve significantly longer survivals than second-line sorafenib.•After lenvatinib, immunotherapy is the systemic treatment with the longest survival.
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