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Neoadjuvant Therapy for Hepatocellular Carcinoma.

ABSTRACT: Hepatocellular carcinoma (HCC) is characterized by low resection and high postoperative recurrence rates, and conventional treatment strategies have failed to meet clinical needs. Neoadjuvant therapy (NAT) is widely employed in the routine management of several solid tumors because it increases resectability and reduces the rate of postoperative recurrence. However, a consensus has not been reached regarding the effects of NAT on HCC. As systemic therapy, particularly targeted therapy and immunotherapy, is given for HCC treatment, accumulating evidence shows that the "spring" of NAT for HCC is imminent. In the future, HCC researchers should focus on identifying biomarkers for treatment response, explore the mechanisms of resistance, and standardize the endpoints of NAT.

SUBMITTER: Yin Z

PROVIDER: S-EPMC9441170 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Neoadjuvant Therapy for Hepatocellular Carcinoma.

Yin Zongyi Z Chen Dongying D Liang Shuang S Li Xiaowu X

Journal of hepatocellular carcinoma 20220831

Hepatocellular carcinoma (HCC) is characterized by low resection and high postoperative recurrence rates, and conventional treatment strategies have failed to meet clinical needs. Neoadjuvant therapy (NAT) is widely employed in the routine management of several solid tumors because it increases resectability and reduces the rate of postoperative recurrence. However, a consensus has not been reached regarding the effects of NAT on HCC. As systemic therapy, particularly targeted therapy and immuno ...[more]

PMID: 36068876

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Project description:BackgroundHepatocellular carcinoma (HCC) recurrence rates following locoregional treatment are high. As multireceptor tyrosine kinase inhibitors targeting vascular endothelial growth factor receptors (VEGFRs) are effective in advanced HCC, we assessed the efficacy and safety of neoadjuvant systemic treatment with dovitinib in early- and intermediate-stage HCC.Materials and methodsTwenty-four patients with modified Child-Pugh class A early- and intermediate-stage HCC received neoadjuvant oral dovitinib 500 mg daily (5 days on/2 days off) for 4 weeks, followed by locoregional therapy. Primary endpoints were objective response rates and intratumoral blood flow changes. Secondary endpoints were safety, pharmacodynamical plasma markers of VEGFR-blockade, time to progression (TTP), and overall survival (OS).ResultsModified RECIST overall response rate was 48%, including 13% complete remission, and despite dose reduction/interruption in 83% of patients, intratumoral perfusion index decreased significantly. Grade 3-4 adverse events, most frequently (on-target) hypertension (54%), fatigue (25%), and thrombocytopenia (21%), occurred in 88% of patients. Plasma VEGF-A, VEGF-D, and placental growth factor increased significantly, whereas sTie-2 decreased, consistent with VEGFR-blockade. Following neoadjuvant dovitinib, all patients could proceed to their original planned locoregional treatment. No delayed toxicity occurred. Seven patients (three early, four intermediate stage) underwent orthotopic liver transplant after median 11.4 months. Censoring at transplantation, median TTP and OS were 16.8 and 34.8 months respectively; median cancer-specific survival was not reached.ConclusionAlready after a short 4-week dovitinib treatment period, intratumoral blood flow reduction and modest antitumor responses were observed. Although these results support use of systemic neoadjuvant strategies, the poor tolerability indicates that dovitinib dose adaptations are required in HCC.Implications for practiceOrthotopic liver transplantation may cure early and intermediate-stage hepatocellular carcinoma. Considering the expected waiting time >6 months because of donor liver scarcity, there is an unmet need for effective neoadjuvant downsizing strategies. Angiogenesis inhibition by dovitinib does not negatively affect subsequent invasive procedures, is safe to administer immediately before locoregional therapy, and may provide a novel treatment approach to improve patient outcomes if tolerability in patients with hepatocellular carcinoma can be improved by therapeutic drug monitoring and personalized dosing.

Project description:Background & aimsThe combination of atezolizumab and bevacizumab offers a novel approach to immunomodulation, showing efficacy as a primary treatment in advanced hepatocellular carcinoma (HCC). Concerns about graft safety and rejection have limited its exploration in the neoadjuvant setting of liver transplantation (LT). In this study, we investigate the clinical efficacy and the safety profile of pre-transplant administration of atezolizumab and bevacizumab for HCC.MethodsHerein, we performed a prospective assessment of 17 patients with HCC treated with neoadjuvant preoperative atezolizumab and bevacizumab prior to LT for HCC, obtained from December 2020 and December 2023 at seven Western transplant centers.ResultsAmong the 17 patients with HCC included in the study, 16 (94.1%) had a tumor burden outside of Milan criteria. Neoadjuvant locoregional therapies along with the administration of atezolizumab plus bevacizumab (median: 5 months; discontinued at least 4 weeks prior to LT) led to an objective response rate of 94% (complete response: 59%), downstaging to within Milan criteria (82%) and a pathological response at explant examination of 88%. Grade 3-4 treatment-related adverse events accounted for 17.6% of cases and were manageable. During the 25-month median follow-up period, two cases of mild (rejection activity index ≤4), biopsy-proven rejection were reported but no instances of severe allograft rejection or graft loss were reported. The 1-year and 3-year post-LT survival rates were 94.2% and 88.2%, respectively.ConclusionsThis study highlights the favorable oncological and survival outcomes associated with atezolizumab and bevacizumab treatment in the pre-LT setting. This immune-based combination was safe in terms of treatment-related adverse events, and absence of severe post-transplant rejection or graft loss. These preliminary results could pave the way for expanding transplant eligibility criteria in patients at more advanced HCC stages.Impact and implicationsStudies on the combination of atezolizumab and bevacizumab in the neoadjuvant setting prior to liver transplantation for hepatocellular carcinoma have been limited, despite its potential to enhance anti-tumor responses and downstaging, owing to concerns about its safety profile. Among 17 patients who underwent successful liver transplantation following neoadjuvant atezolizumab/bevacizumab, 82% achieved downstaging to within Milan criteria, 94% radiological objective response and 88% pathology response, without drop-outs due to treatment-related adverse events or graft loss. The neoadjuvant combination of atezolizumab plus bevacizumab prior to liver transplantation for hepatocellular carcinoma shows an encouraging safety profile and stands out as a promising pre-transplant optimization treatment, leading to improved oncological outcomes.

Dataset Information

Neoadjuvant Therapy for Hepatocellular Carcinoma.

Publications

Neoadjuvant Therapy for Hepatocellular Carcinoma.

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