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原发性肝癌诊疗指南（2026年版）
Guidelines for diagnosis and treatment of hepatocellular carcinoma (2026 edition)
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This article is the first of a series providing guidance for use of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system of rating quality of evidence and grading strength of recommendations in systematic reviews, health technology assessments (HTAs), and clinical practice guidelines addressing alternative management options. The GRADE process begins with asking an explicit question, including specification of all important outcomes. After the evidence is collected and summarized, GRADE provides explicit criteria for rating the quality of evidence that include study design, risk of bias, imprecision, inconsistency, indirectness, and magnitude of effect. Recommendations are characterized as strong or weak (alternative terms conditional or discretionary) according to the quality of the supporting evidence and the balance between desirable and undesirable consequences of the alternative management options. GRADE suggests summarizing evidence in succinct, transparent, and informative summary of findings tables that show the quality of evidence and the magnitude of relative and absolute effects for each important outcome and/or as evidence profiles that provide, in addition, detailed information about the reason for the quality of evidence rating. Subsequent articles in this series will address GRADE's approach to formulating questions, assessing quality of evidence, and developing recommendations.Copyright © 2011 Elsevier Inc. All rights reserved.
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This article introduces the approach of GRADE to rating quality of evidence. GRADE specifies four categories-high, moderate, low, and very low-that are applied to a body of evidence, not to individual studies. In the context of a systematic review, quality reflects our confidence that the estimates of the effect are correct. In the context of recommendations, quality reflects our confidence that the effect estimates are adequate to support a particular recommendation. Randomized trials begin as high-quality evidence, observational studies as low quality. "Quality" as used in GRADE means more than risk of bias and so may also be compromised by imprecision, inconsistency, indirectness of study results, and publication bias. In addition, several factors can increase our confidence in an estimate of effect. GRADE provides a systematic approach for considering and reporting each of these factors. GRADE separates the process of assessing quality of evidence from the process of making recommendations. Judgments about the strength of a recommendation depend on more than just the quality of evidence.Copyright © 2011 Elsevier Inc. All rights reserved.
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American Society of Clinical Oncology. ASCO Guidelines Methodology Manual[EB/OL]. (2021-09-09) [2023-12-15]. https://cdn.bfldr.com/KOIHB2Q3/as/qr3pjw3xfmq2svntp76hpbm/Guidelines-Methodology-Manual.
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Hepatocellular carcinoma (HCC) is the leading cause of death in patients with chronic hepatitis. In this international collaboration, we sought to develop a global universal HCC risk score to predict the HCC development for patients with chronic hepatitis.A total of 17,374 patients, comprising 10,578 treated Asian patients with chronic hepatitis B (CHB), 2,510 treated Caucasian patients with CHB, 3,566 treated patients with hepatitis C virus (including 2,489 patients with cirrhosis achieving a sustained virological response) and 720 patients with non-viral hepatitis (NVH) from 11 international prospective observational cohorts or randomised controlled trials, were divided into a training cohort (3,688 Asian patients with CHB) and 9 validation cohorts with different aetiologies and ethnicities (n = 13,686).We developed an HCC risk score, called the aMAP score (ranging from 0 to 100), that involves only age, male, albumin-bilirubin and platelets. This metric performed excellently in assessing HCC risk not only in patients with hepatitis of different aetiologies, but also in those with different ethnicities (C-index: 0.82-0.87). Cut-off values of 50 and 60 were best for discriminating HCC risk. The 3- or 5-year cumulative incidences of HCC were 0-0.8%, 1.5-4.8%, and 8.1-19.9% in the low- (n = 7,413, 43.6%), medium- (n = 6,529, 38.4%), and high-risk (n = 3,044, 17.9%) groups, respectively. The cut-off value of 50 was associated with a sensitivity of 85.7-100% and a negative predictive value of 99.3-100%. The cut-off value of 60 resulted in a specificity of 56.6-95.8% and a positive predictive value of 6.6-15.7%.This objective, simple, reliable risk score based on 5 common parameters accurately predicted HCC development, regardless of aetiology and ethnicity, which could help to establish a risk score-guided HCC surveillance strategy worldwide.In this international collaboration, we developed and externally validated a simple, objective and accurate prognostic tool (called the aMAP score), that involves only age, male, albumin-bilirubin and platelets. The aMAP score (ranged from 0 to 100) satisfactorily predicted the risk of hepatocellular carcinoma (HCC) development among over 17,000 patients with viral and non-viral hepatitis from 11 global prospective studies. Our findings show that the aMAP score had excellent discrimination and calibration in assessing the 5-year HCC risk among all the cohorts irrespective of aetiology and ethnicity.Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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Current hepatocellular carcinoma (HCC) risk scores do not reflect changes in the HCC risk assessment resulting from liver disease progression/regression over time. We aimed to develop and validate two novel prediction models using multivariate longitudinal data, with or without incorporating cell-free DNA (cfDNA) signatures.13,728 patients from two nationwide multicentre prospective observational cohorts with majority of chronic hepatitis B virus (HBV) infection were enrolled. aMAP score, as one of the most promising HCC prediction models, was evaluated for each patient. Low-pass whole genome sequencing was used to derive multi-modal cfDNA fragmentomics features. Longitudinal Discriminant Analysis (LoDA) algorithm was used to model longitudinal profiles of patient biomarkers and estimate HCC development risk.We developed and externally validated two novel HCC prediction models having a greater accuracy called aMAP-2 and aMAP-2 Plus scores. The aMAP-2 score, calculated with longitudinal data of aMAP score and α-fetoprotein values during up to 8-year follow-up, performed superbly in the training and external validation cohorts (AUC 0.83 - 0.84). The aMAP-2 score showed further improvement and accurately divided aMAP defined high-risk patients into two groups with 5-year cumulative HCC incidence of 23.4% and 4.1%, respectively (p=0.0065). The aMAP-2 Plus score, which incorporates cfDNA signatures (Nucleosome, Fragment and Motif scores), optimized the performance in predicting HCC development, especially for cirrhotic patients (AUC 0.85 - 0.89). Importantly, the stepwise approach (aMAP -> aMAP-2 -> aMAP-2 Plus) identified 90.0% and 10.0% of cirrhotic patients with annual HCC incidence of 0.8% and 12.5%, respectively (p<0.0001).AMAP-2 and aMAP-2 Plus scores are highly accurate in predicting HCC. The stepwise application of aMAP scores provides an improved enrichment strategy of high-risk HCC patients, which could effectively guide nationwide individualized HCC surveillance.Copyright © 2023. Published by Elsevier B.V.
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We aimed to determine the surveillance performance of alpha-fetoprotein (AFP), lectin-reactive AFP (AFP-L3), des-gamma-carboxy prothrombin (DCP), and their combinations for the early detection of hepatocellular carcinoma (HCC) by using prospectively collected longitudinal samples in patients at risk. Among 689 patients with cirrhosis and/or chronic hepatitis B who participated in four prospective studies, 42 HCC cases were diagnosed, selected, and matched with 168 controls for age, sex, etiology, cirrhosis, and duration of follow-up in a 1:4 ratio. Levels of AFP, AFP-L3, and DCP at the time of HCC diagnosis, month -6, and month -12 were compared between cases and controls. Of 42 HCC cases, 39 (93%) had cirrhosis, 36 (85.7%) had normal alanine aminotransferase levels, and 31 (73.8%) had very early-stage HCC (single <2 cm). AFP and AFP-L3 began to increase from 6 months before diagnosis of HCC in cases (P < 0.05), while they remained unchanged in controls. At HCC diagnosis, the area under the receiver operator characteristic curves (AUROCs) for AFP, AFP-L3, and DCP were 0.77, 0.73, and 0.71, respectively. Combining AFP and AFP-L3 showed a higher AUROC (0.83), while adding DCP did not further improve the AUROC (0.86). With the optimal cutoff values (AFP, 5 ng/mL; AFP-L3, 4%), the sensitivity and specificity of AFP and AFP-L3 combination were 79% and 87%, respectively. The sensitivity of ultrasonography was 48.6%, which was increased to 88.6% and 94.3% by adding AFP and AFP + AFP-L3, respectively. Conclusion: Among three biomarkers, AFP showed the best performance in discriminating HCC cases from controls; the AFP and AFP-L3 combination, adopting cutoff values (5 ng/mL and 4%, respectively), significantly improved the sensitivity for detecting HCC at a very early stage.© 2018 by the American Association for the Study of Liver Diseases.
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中华医学会肝病学分会. 代谢相关(非酒精性)脂肪性肝病防治指南(2024 年版)[J]. 中华肝脏病杂志, 2024, 32(5):418-434.DOI:10.3760/cma.j.cn501113-20240428-00162.
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郝新, 樊蓉, 郭亚兵, 等. 创建医院社区一体化 “金字塔” 肝癌筛查模式,实现肝癌早筛早诊早治[J]. 中华肝脏病杂志, 2021, 29(4):289-292.DOI:10.3760/cma.j.cn501113-20210408-00174-1.
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Current literature on the role of contrast-enhanced ultrasound (CEUS) in the diagnosis of hepatocellular carcinoma (HCC) in non-cirrhotic patients is limited. The aim of this retrospective multicenter study was to analyze CEUS features of histologically proven HCC in patients with non-cirrhotic liver. In this multicenter study, 96 patients from eight medical institutions with histologically proven HCC lesions in non-cirrhotic liver were retrospectively reviewed regarding SonoVue-enhanced CEUS features. Two ultrasound experts assessed the CEUS enhancement pattern and came to a consensus using the World Federation of Societies for Ultrasound in Medicine and Biology guideline criteria. The mean size of HCC lesions included was 60.3 ± 37.8 mm (mean ± standard deviation). Most of the lesions were heterogeneous but predominantly hypo-echoic on B-mode ultrasound (64.5%, 62/96), with ill-defined margins and irregular shapes. During the arterial phase of CEUS, most of the HCC lesions in non-cirrhotic liver exhibited heterogeneous hyperenhancement (78.1%, 75/96) compared with the surrounding liver parenchyma. Almost 30% of HCC lesions (28.1%, 27/96) exhibited early wash-out (<60 s). All lesions exhibited wash-out and hypo-enhancement in the late phase. CEUS features of HCC lesions in non-cirrhotic patients typically include hyperenhancement in the arterial phase and relatively rapid wash-out in the portal venous phase, which is different from HCC in cirrhotic livers and more similar to liver metastasis.Copyright © 2022 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.
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To explore the enhancement features of early hepatocellular carcinoma (HCC, including well‐differentiated HCC and high‐grade dysplastic nodules with a focus of HCC) and high‐grade dysplastic nodules (HGDNs) on contrast‐enhanced ultrasound (CEUS), correlated with the histopathologic findings.
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To evaluate the value of simultaneous display of contrast‐enhanced ultrasound and micro‐flow imaging technology (CEUS‐MFI) in intra‐tumoral vessel detection and hepatic tumor diagnosis.
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The present, updated document describes the fourth iteration of recommendations for the hepatic use of contrast-enhanced ultrasound, first initiated in 2004 by the European Federation of Societies for Ultrasound in Medicine and Biology. The previous updated editions of the guidelines reflected changes in the available contrast agents and updated the guidelines not only for hepatic but also for non-hepatic applications. The 2012 guideline requires updating as, previously, the differences in the contrast agents were not precisely described and the differences in contrast phases as well as handling were not clearly indicated. In addition, more evidence has been published for all contrast agents. The update also reflects the most recent developments in contrast agents, including U.S. Food and Drug Administration approval and the extensive Asian experience, to produce a truly international perspective. These guidelines and recommendations provide general advice on the use of ultrasound contrast agents (UCAs) and are intended to create standard protocols for the use and administration of UCAs in liver applications on an international basis to improve the management of patients.Copyright © 2020 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.
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The first edition of the guidelines for the use of ultrasound contrast agents was published in 2004, dealing with liver applications. The second edition of the guidelines in 2008 reflected changes in the available contrast agents and updated the guidelines for the liver, as well as implementing some nonliver applications. The third edition of the contrast-enhanced ultrasound (CEUS) guidelines was the joint World Federation for Ultrasound in Medicine and Biology-European Federation of Societies for Ultrasound in Medicine and Biology (WFUMB-EFSUMB) venture in conjunction with other regional US societies such as Asian Federation of Societies for Ultrasound in Medicine and Biology, resulting in a simultaneous duplicate on liver CEUS in the official journals of both WFUMB and EFSUMB in 2013. However, no guidelines were described mainly for Sonazoid due to limited clinical experience only in Japan and Korea. The new proposed consensus statements and recommendations provide general advice on the use of Sonazoid and are intended to create standard protocols for the use and administration of Sonazoid in hepatic and pancreatobiliary applications in Asian patients and to improve patient management.Copyright: © 2020 Journal of Medical Ultrasound.
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To develop a contrast-enhanced ultrasound (CEUS)-based model for differentiating cirrhotic liver lesions and for active surveillance of hepatocellular carcinoma (HCC).Patients with focal liver lesions (FLLs) with biopsy/resection-proven pathology and pre-procedure CEUS were enrolled from our institution between January 2011 and November 2014. Univariable and multivariable regression models were constructed using qualitative CEUS features and/or contrast arrival time ratio (CAT). The optimism-adjusted Harrell's generalized concordance index (C) was used to quantify the discriminatory ability of each CEUS feature and model.A total of 149 patients (113 men and 36 women) with 162 FLLs were enrolled with mean age 53.4 ± 12.7 years. A 0.1-unit reduction in CAT was associated with a 68% increase in the odds of having a higher nodule ranking (RN < DN < small HCC) (OR, 0.32; 95% CI, 0.20-0.50, p < .001). Arterial phase hypoenhancement and isoenhancement were inversely associated with a higher nodule ranking compared to hyperenhancement. Late-phase isoenhancement was associated with lower odds of a higher nodule ranking. The CEUS + CAT model (C 0.92, 0.89-0.95) provided greater discriminatory ability when compared to the CAT model (ΔC 0.09, 0.04-0.13, p < .001) and the CEUS model (ΔC 0.03, 0.01-0.05, p = .02).Our results provide preliminary evidence that multivariable regression model constructed using both qualitative CEUS features and CAT provides the greatest discriminatory ability to differentiate RN, DN, and small HCC in patients with cirrhosis, and might allow for active surveillance of the progression of cirrhotic liver lesions.• Proportional odds logistic regression models based on qualitative CEUS features and/or CAT can be used for differentiating cirrhotic liver lesions and for active surveillance of HCC. • The reduction of CAT (RN < DN < small HCC) was strongly associated with high-risk cirrhotic liver nodules. • Inclusion of CAT in the CEUS prediction model significantly improved its performance for cirrhotic liver lesions risk-stratification.
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European Association for the Study of the Liver. EASL Clinical Practice Guidelines on the management of hepatocellular carcinoma[J]. J Hepatol, 2025, 82(2):315-374. DOI: 10.1016/j.jhep.2024.08.028.
Liver cancer is the third leading cause of cancer-related deaths worldwide, with hepatocellular carcinoma (HCC) accounting for approximately 90% of primary liver cancers. Advances in diagnostic and therapeutic tools, along with improved understanding of their application, are transforming patient treatment. Integrating these innovations into clinical practice presents challenges and necessitates guidance. These clinical practice guidelines offer updated advice for managing patients with HCC and provide a comprehensive review of pertinent data. Key updates from the 2018 EASL guidelines include personalised surveillance based on individual risk assessment and the use of new tools, standardisation of liver imaging procedures and diagnostic criteria, use of minimally invasive surgery in complex cases together with updates on the integrated role of liver transplantation, transitions between surgical, locoregional, and systemic therapies, the role of radiation therapies, and the use of combination immunotherapies at various stages of disease. Above all, there is an absolute need for a multiparametric assessment of individual risks and benefits, considering the patient's perspective, by a multidisciplinary team encompassing various specialties.Copyright © 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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To develop and validate a preoperative prediction model based on multimodal ultrasound and biochemical indicator for identifying microvascular invasion (MVI) in patients with a single hepatocellular carcinoma (HCC) ≤ 5 cm.
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王文平, 季正标, 董怡, 等. 实时导航超声造影在小肝癌诊断中的应用研究[J]. 中华医学超声杂志: 电子版, 2016, 13(1): 56-60. DOI:10.3877/cma.j.issn.1672-6448.2016.01.014.
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中华医学会超声医学分会, 中国医师协会外科医师分会, 中国医师协会介入医师分会, 等. 肝移植超声临床实践指南 (2023 版)[J]. 中华医学杂志, 2023, 103(31):2365-2388. DOI:10.3760/cma.j.cn112137-20230510-00768.
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Hepatocellular carcinoma (HCC) is a highly prevalent form of liver cancer diagnosed annually in 600,000 people worldwide. A common treatment is transarterial chemoembolization (TACE), which interrupts the blood supply of oxygen and nutrients to the tumor mass. The need for repeat TACE treatments may be assessed in the weeks after therapy with contrast-enhanced ultrasound (CEUS) imaging. Although the spatial resolution of traditional CEUS has been restricted by the diffraction limit of ultrasound (US), this physical barrier has been overcome by a recent innovation known as super-resolution US (SRUS) imaging. In short, SRUS enhances the visible details of smaller microvascular structures on the 10 to 100 µm scale, which unlocks a host of new clinical opportunities for US.In this study, a rat model of orthotopic HCC is introduced and TACE treatment response (to a doxorubicin-lipiodol emulsion) is assessed using longitudinal SRUS and magnetic resonance imaging (MRI) performed at 0, 7 and 14 d. Animals were euthanized at 14 d for histological analysis of excised tumor tissue and determination of TACE response, that is, control, partial response or complete response. CEUS imaging was performed using a pre-clinical US system (Vevo 3100, FUJIFILM VisualSonics Inc.) equipped with an MX201 linear array transducer. After administration of a microbubble contrast agent (Definity, Lantheus Medical Imaging), a series of CEUS images were collected at each tissue cross-section as the transducer was mechanically stepped at 100 μm increments. SRUS images were formed at each spatial position, and a microvascular density metric was calculated. Microscale computed tomography (microCT, OI/CT, MILabs) was used to confirm TACE procedure success, and tumor size was monitored using a small animal MRI system (BioSpec 3T, Bruker Corp.).Although there were no differences at baseline (p > 0.15), both microvascular density levels and tumor size measures from the complete responder cases at 14 d were considerably lower and smaller, respectively, than those in the partial responder or control group animals. Histological analysis revealed tumor-to-necrosis levels of 8.4%, 51.1% and 100%, for the control, partial responder and complete responder groups, respectively (p < 0.005).SRUS imaging is a promising modality for assessing early changes in microvascular networks in response to tissue perfusion-altering interventions such as TACE treatment of HCC.Copyright © 2023 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.
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Noninvasive and functional imaging of the focal liver lesion (FLL) vasculature at microscopic scales is clinically challenging. We investigated the feasibility of using super-resolution ultrasound (SR-US) imaging for visualizing and quantifying the microvasculature of intraparenchymal FLLs.
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The aim of this study is to explore the value of volume navigation image fusion‐assisted contrast‐enhanced ultrasound (CEUS) in detection for radiofrequency ablation guidance of hepatocellular carcinomas (HCCs), which were undetectable on conventional ultrasound.
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To evaluate the value of fusion imaging with post-treatment contrast-enhanced ultrasound (CEUS) and pre-treatment contrast-enhanced CT/MRI (CECT/CEMRI) in evaluating ablative safety margin after percutaneous ultrasound (US)-guided radiofrequency ablation (RFA) for liver cancers.
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Purpose To investigate the value of two-dimensional (2D) shear-wave elastography (SWE) in the assessment of hepatic fibrosis in patients with chronic hepatitis B (CHB) and to compare the diagnostic performance of this modality with that of liver fibrosis indexes. Materials and Methods The ethics committee approved this study, and informed consent was obtained. From July 2015 to May 2016, 539 subjects who underwent partial hepatectomy were divided into groups according to the Scheuer system by using a resected liver specimen. All patients were examined with 2D SWE and underwent preoperative serologic testing to measure liver stiffness and values of serum fibrosis models, which were compared with histologic findings. Performance of noninvasive methods was determined for index (304 patients) and validation (155 patients) cohorts by using areas under the receiver operating characteristic curve (AUCs). Results For association with substantial fibrosis (≥S2), severe fibrosis (≥S3), and cirrhosis (S4) in the index cohort, the optimal cutoff values of liver stiffness were 7.6, 9.2, and 10.4 kPa, respectively, and AUC values were 0.97, 0.96, and 0.98, respectively. The 2D SWE findings, aspartate transaminase-to-platelet ratio index (APRI), fibrosis index based on the four factors (FIB-4), King's score, and Forns index significantly correlated with hepatic fibrosis stages (ρ = 0.88, ρ = 0.41, ρ = 0.40, ρ = 0.43 and ρ = 0.45, respectively; P <.05). The AUCs for APRI, FIB-4, King's score, and Forns index were 0.77, 0.73, 0.79, and 0.77, respectively, in the diagnosis of substantial fibrosis and 0.70, 0.71, 0.72, and 0.74, respectively, in the diagnosis of cirrhosis. In the validation cohort, AUCs of noninvasive methods used to assess different fibrosis stages did not significantly differ from those for the index cohort. AUCs of 2D SWE in the diagnosis of substantial fibrosis, severe fibrosis, and cirrhosis were 0.97, 0.97, and 0.98, respectively, which were significantly higher than those in serum models (P <.05). Conclusion The 2D SWE protocol could be used to predict substantial fibrosis, severe fibrosis, and cirrhosis in patients with CHB with notably higher diagnostic accuracy than that attained with serum fibrosis models. RSNA, 2016.
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To explore the pathologic basis and prognostic value of tumor and liver stiffness measured pre-operatively by two-dimensional shear wave elastography (2D-SWE) in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients who undergo hepatic resection.
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To develop and validate a nomogram based on liver stiffness (LS) for predicting symptomatic post-hepatectomy (PHLF) in patients with hepatocellular carcinoma (HCC).A total of 266 patients with HCC were enrolled prospectively from three tertiary referral hospitals from August 2018 to April 2021. All patients underwent preoperative laboratory examination to obtain parameters of liver function. Two-dimensional shear wave elastography (2D-SWE) was performed to measure LS. Three-dimensional virtual resection obtained the different volumes including future liver remnant (FLR). A nomogram was developed by using logistic regression and determined by receiver operating characteristic (ROC) curve analysis and calibration curve analysis, which was validated internally and externally.A nomogram was constructed with the following variables: FLR ratio (FLR of total liver volume), LS greater than 9.5 kPa, Child-Pugh grade, and the presence of clinically significant portal hypertension (CSPH). This nomogram enabled differentiation of symptomatic PHLF in the derivation cohort (area under curve [AUC], 0.915), internal fivefold cross-validation (mean AUC, 0.918), internal validation cohort (AUC, 0.876) and external validation cohort (AUC, 0.845). The nomogram also showed good calibration in the derivation, internal validation, and external validation cohorts (Hosmer-Lemeshow goodness-of-fit test, p = 0.641, p = 0.06, and p = 0.127, respectively). Accordingly, the safe limit of the FLR ratio was stratified using the nomogram.An elevated level of LS was associated with the occurrence of symptomatic PHLF in HCC. A preoperative nomogram integrating LS, clinical and volumetric features was useful in predicting postoperative outcomes in patients with HCC, which might help surgeons in the management of HCC resection.A serial of the safe limit of the future liver remnant was proposed by a preoperative nomogram for hepatocellular carcinoma, which might help surgeons in 'how much remnant is enough in liver resection'.• An elevated liver stiffness with the best cutoff value of 9.5 kPa was associated with the occurrence of symptomatic post-hepatectomy liver failure in hepatocellular carcinoma. • A nomogram based on both quality (Child-Pugh grade, liver stiffness, and portal hypertension) and quantity of future liver remnant was developed to predict symptomatic post-hepatectomy liver failure for HCC, which enabled good discrimination and calibration in both derivation and validation cohorts. • The safe limit of future liver remnant volume was stratified using the proposed nomogram, which might help surgeons in the management of HCC resection.© 2023. The Author(s), under exclusive licence to European Society of Radiology.
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To evaluate the agreement between quantitative ultrasound system fat fraction (USFF) and proton magnetic resonance spectroscopy (1H-MRS) and the diagnostic value of USFF in assessing metabolic-associated fatty liver disease (MAFLD).
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The goal of the study described here was to define the predictive value of pre-operative clinical information and contrast-enhanced ultrasound (CEUS) imaging characteristics in combined hepatocellular-cholangiocarcinoma (CHC) patients with microvascular invasion (MVI). Seventy-six patients with pathologically confirmed CHC were enrolled in this study, comprising 18 patients with MVI-positive status and 58 with MVI-negative CHC nodules. The pre-operative clinical data and CEUS imaging features were retrospectively analyzed. Univariate and multivariate analyses were performed to identify the potential predictors of MVI in CHC. Recurrence-free survival (RFS) after hepatectomy was compared between patients with different MVI status using the log-rank test and Kaplan-Meier survival curves. Univariate analysis indicated that the following parameters of patients with CHC significantly differed between the MVI-positive and MVI-negative groups (p<0.05): tumor size, α-fetoprotein ≥400 ng/mL, enhancement patterns in arterial phase and marked washout during the portal venous phase on CEUS. On multivariate logistic regression analysis, only the CEUS characteristics of heterogeneous enhancement (odds ratio = 6.807; 95% confidence interval [CI]: 1.099, 42.147; p = 0.039) and marked washout (odds ratio = 4.380; 95% CI: 1.050,18.270; p = 0.043) were identified as independent predictors of MVI in CHC. The combination of the two risk factors in predicting MVI achieved a better diagnostic performance than each parameter alone, with an area under the receiver operating characteristic curve of 0.736 (0.622, 0.830). After hepatectomy, CHC patients with MVI exhibited earlier recurrence compared with those without MVI (hazard ratio = 1.859; 95% CI: 0.8699-3.9722, p = 0.046). The CEUS imaging features of heterogeneous enhancement in the arterial phase and marked washout during the portal venous phase were the potential predictors of MVI in CHC. Aside from that, CHC patients with MVI had an earlier recurrence rate than those without MVI after surgery.Copyright © 2022. Published by Elsevier Inc.
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Tumor recurrence is an abomination for hepatocellular carcinoma (HCC) patients receiving local treatment.The aim of the study was to build a hybrid machine learning model to recommend optimized first treatment (laparoscopic hepatectomy [LH] or microwave ablation [MWA]) for naïve single 3-5-cm HCC patients based on early recurrence (ER, ≤2 years) probability.This retrospective study collected 20 semantic variables of 582 patients (LH: 300, MWA: 282) from 13 hospitals with at least 24 months follow-up. Both groups were divided into training, validation, and test set, respectively. Five algorithms (logistics regression, random forest, neural network, stochastic gradient boosting, and eXtreme Gradient Boosting [XGB]) were used for model building. A model with highest area under the receiver operating characteristic curve (AUC) in a validation set of LH and MWA was selected to connect as a hybrid model which made decision based on ER probability. Model testing was performed in a comprehensive set comprising LH and MWA test sets.Four variables in each group were selected to build LH and MWA models, respectively. LH-XGB model (AUC = 0.744) and MWA-stochastic gradient method (AUC = 0.750) model were selected for model building. In the comprehensive set, a treatment confusion matrix was established based on recommended and actual treatment. The predicted ER probabilities were comparable with the actual ER rates for various types of patients in matrix (> 0.05). ER rate of patients whose actual treatment consistent with recommendation was lower than that of inconsistent patients (LH: 21.2% vs. 46.2%, = 0.042; MWA: 26.3% vs. 54.1%, = 0.048). By recommending optimal treatment, the hybrid model can significantly reduce ER probability from 38.2% to 25.6% for overall patients (< 0.001).The hybrid model can accurately predict ER probability of different treatments and thereby provide reliable evidence to make optimal treatment decision for patients with single 3-5-cm HCC.Copyright © 2022 by S. Karger AG, Basel.
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We aimed to evaluate the performance of a deep learning (DL)-based Radiomics strategy designed for analyzing contrast-enhanced ultrasound (CEUS) to not only predict the progression-free survival (PFS) of radiofrequency ablation (RFA) and surgical resection (SR) but also optimize the treatment selection between them for patients with very-early or early-stage hepatocellular carcinoma (HCC).We retrospectively enrolled 419 patients examined by CEUS within 1 week before receiving RFA or SR (RFA: 214, SR: 205) from January 2008 to 2016. Two Radiomics signatures were constructed by the Radiomics model R-RFA and R-SR to stratify PFS of different treatment groups. Then, RFA and SR nomograms were built by incorporating Radiomics signatures and significant clinical variables to achieve individualized 2-year PFS prediction. Finally, we applied both Radiomics models and both nomograms to each enrolled patient to investigate whether there were space for treatment optimization and how much prognostic improvement could be expected.R-RFA and R-SR showed remarkable discrimination (C-index: 0.726 for RFA, 0.741 for SR). RFA and SR nomograms provided good 2-year PFS prediction accuracy and good calibrations. We identified 17.3% RFA patients and 27.3% SR patients should swap their treatment, so their average probability of 2-year PFS would increase 12 and 15%, respectively.The proposed Radiomics models and nomograms achieved accurate preoperative prediction of PFS for RFA and SR, and they could facilitate the optimized treatment selection between them for patients with very-early or early-stage HCC.Copyright © 2020 by S. Karger AG, Basel.
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To perform a systematic review and meta-analysis of the diagnostic performance of computed tomography (CT) and magnetic resonance (MR) imaging as noninvasive modalities for evaluating hepatocellular carcinoma (HCC) in patients with chronic liver disease.A search of the MEDLINE, EMBASE, and Cochrane Library databases was performed to identify studies providing per-patient or per-lesion diagnostic accuracies of multidetector CT and MR imaging for HCCs in patients with chronic liver disease. Studies published from January 2000 to December 2012 that used a reference standard based on histopathologic findings and/or findings at follow-up were included. Summary estimates of diagnostic accuracy were obtained by using a random-effects model with further exploration with meta-regression and subgroup analyses.Forty studies (six on multidetector CT, 22 on MR imaging, and 12 on both CT and MR imaging) were included. The studies evaluated a total of 1135 patients with multidetector CT and 2489 patients with MR imaging. The overall per-patient sensitivity of MR imaging was 88% (95% confidence interval [CI]: 83%, 92%), with a specificity of 94% (95% CI: 85%, 98%). The overall per-lesion sensitivity of MR imaging was higher than that of multidetector CT when the paired data of the 11 available studies were pooled (80% vs 68%, P =.0023). Gadoxetic acid-enhanced MR imaging showed significantly higher per-lesion sensitivity than MR imaging performed with other contrast agents (87% vs 74%, P =.03). Per-lesion sensitivity was significantly lower for HCCs smaller than 1 cm than that for HCCs 1 cm or larger (P <.001 for CT, P =.02 for MR imaging) and for those in explanted livers (P =.04 for CT, P <.001 for MR imaging).MR imaging showed higher per-lesion sensitivity than multidetector CT and should be the preferred imaging modality for the diagnosis of HCCs in patients with chronic liver disease.© RSNA, 2015 Online supplemental material is available for this article.
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| [53] |
Early detection of small hepatocellular carcinoma (HCC) lesions can improve longterm patient survival. A systematic review and meta‐analysis of the diagnostic performance of gadoxetic acid disodium (Gd‐EOB‐DTPA)–enhanced magnetic resonance imaging (MRI) and multidetector computed tomography (MDCT) was performed in diagnosing small HCCs measuring up to 2 cm (≤2 cm). Two investigators searched multiple databases for studies in which the performances of either Gd‐EOB‐DTPA–enhanced MRI or MDCT were reported with sufficient data to construct 2 × 2 contingency tables for diagnosing HCCs up to 2 cm on a per‐lesion or per‐patient level. Diagnostic performances were quantitatively pooled by a bivariate random‐effect model with further meta‐regression and subgroup analyses. A total of 27 studies (14 on Gd‐EOB‐DTPA–enhanced MRI, 9 on MDCT, and 4 on both) were included, enrolling a total of 1735 patients on Gd‐EOB‐DTPA–enhanced MRI and 1781 patients on MDCT. Gd‐EOB‐DTPA–enhanced MRI demonstrated significantly higher overall sensitivity than did MDCT (0.96 versus 0.65;P < 0.01), without substantial loss of specificity (0.94 versus 0.98;P > 0.05). Area under the summary receiver operating characteristic curve was 0.97 with Gd‐EOB‐DTPA–enhanced MRI and 0.85 with MDCT. Regarding Gd‐EOB‐DTPA–enhanced MRI, sensitivity was significantly higher for studies from non‐Asian countries than Asian countries (0.96 versus 0.93;P < 0.01), for retrospective studies than prospective studies (0.95 versus 0.91;P < 0.01), and for those with Gd‐EOB‐DTPA injection rate ≥ 1.5 mL/s than that of<1.5 mL/s (0.97 versus 0.90;P < 0.01). In conclusion, Gd‐EOB‐DTPA–enhanced MRI demonstrated higher sensitivity and overall diagnostic accuracy than MDCT, and thus should be the preferred imaging modality for diagnosing small HCCs measuring up to 2 cm.Liver Transplantation 23 1505–1518 2017AASLD.
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| [54] |
The CT/MRI Liver Imaging Reporting and Data System version 2024 Treatment Response Assessment (TRA) algorithm now has two independent cores with tailored TRA criteria after nonradiation or radiation-based liver-directed therapy and incorporates MRI ancillary features (diffusion restriction and mild to moderate T2 hyperintensity).
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| [55] |
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| [56] |
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| [57] |
There is great geographical variation in the distribution of hepatocellular carcinoma (HCC), with the majority of all cases worldwide found in the Asia-Pacific region, where HCC is one of the leading public health problems. Since the "Toward Revision of the Asian Pacific Association for the Study of the Liver (APASL) HCC Guidelines" meeting held at the 25th annual conference of the APASL in Tokyo, the newest guidelines for the treatment of HCC published by the APASL has been discussed. This latest guidelines recommend evidence-based management of HCC and are considered suitable for universal use in the Asia-Pacific region, which has a diversity of medical environments.
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| [58] |
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| [59] |
Many improvements have been made in diagnosing hepatocellular carcinoma (HCC), but the radiological hallmarks of HCC have remained the same for many years. We prospectively evaluated the imaging criteria of HCC, early HCC and high-grade dysplastic nodules (HGDNs) in patients under surveillance for chronic liver disease, using gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) MRI and diffusion-weighted imaging.Our study population included 420 nodules >1 cm in 228 patients. The MRI findings of each nodule were collected in all sequences/phases. The diagnosis of HCC was made according to the American Association for the Study of Liver Diseases (AASLD) criteria; all atypical nodules were diagnosed using histology.A classification and regression tree was developed using three MRI findings which were independently significant correlated variables for early HCC/HCC, and the best sequence of their application in a new diagnostic algorithm (hepatobiliary hypointensity, arterial hyperintensity and diffusion restriction) was suggested. This algorithm demonstrated, both in the entire study population and for nodules ≤2 cm, higher sensitivity (96% [95% CI 93.5% to 97.6%] and 96.6% [95% CI 93.9% to 98.5%], P<0.001, respectively) and slightly lower specificity (91.8% [95% CI 88.6% to 94.1%], P=0.063, and 92.7% [95% CI 88.9% to 95.4%], P=0.125, respectively) than those of the AASLD criteria. Our new diagnostic algorithm also showed a very high sensitivity (94.7%; 95% CI 92% to 96.6%) and specificity (99.3%; 95% CI 97.7% to 99.8%) in classifying HGDN.Our new diagnostic algorithm demonstrated significantly higher sensitivity and comparable specificity than those of the AASLD imaging criteria for HCC in patients with cirrhosis evaluated using Gd-EOB-DTPA MRI, even for lesions ≤2 cm. Moreover, this diagnostic algorithm allowed evaluating other lesions which could arise in a cirrhotic liver, such as early HCC and HGDN.© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
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| [60] |
To compare the diagnostic performance of magnetic resonance (MR) imaging features, including those on diffusion-weighted (DW) and T2-weighted images, in differentiating between hypovascular hepatocellular carcinoma (HCC) and dysplastic nodules seen as hypointense nodules at hepatobiliary phase gadoxetic acid-enhanced MR imaging.The institutional review board approved this retrospective study and waived the need to obtain informed patient consent. There were 53 patients (39 men and 14 women; age range, 32-75 years) with histologically proven hypovascular HCCs (n = 25) and/or dysplastic nodules (n = 31) who underwent gadoxetic acid-enhanced MR imaging at 3.0-T between March 2011 and January 2014. Images of 25 HCCs and 31 dysplastic nodules were analyzed for nodule size; signal intensity on T1- and T2-weighted, portal venous phase, and DW (b value = 800 sec/mm(2)) images; and intralesional fat. Correlations between the hyperintensity grade of lesions and the liver-to-lesion signal intensity ratio at T2-weighted and DW imaging were determined by means of analysis with generalized estimating equations.Hyperintensity at T2-weighted and DW imaging and hypointensity in the portal venous phase were significant features for differentiating hypovascular HCCs from dysplastic nodules (P <.05). The sensitivity of DW imaging tended to be higher than that of T2-weighted imaging (72.0% [18 of 25] vs 40.0% [10 of 25]; P =.008 for grade 2 and 3 hyperintensity). Use of the parameter of hyperintensity similar to or slightly lower than the signal intensity of the spleen on DW images (b value = 800 sec/mm(2)) yielded a specificity of 100% (31 of 31) for the diagnosis of hypovascular HCC by differentiating it from a dysplastic nodule.Hyperintensity at DW imaging could be a useful MR imaging feature for differentiating hypovascular HCCs from dysplastic nodules seen as hypointense nodules at gadoxetic acid-enhanced MR imaging.
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| [61] |
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| [62] |
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| [63] |
To prospectively evaluate the safety and efficacy of combined unenhanced and gadoxetic acid disodium (Gd-EOB-DTPA)-enhanced magnetic resonance (MR) imaging compared with unenhanced MR imaging and triphasic contrast-enhanced spiral computed tomography (CT) for the detection and characterization of focal liver lesions.The study was reviewed and approved by the institutional review board at each of the 15 centers involved in the study, and informed written consent was given by all patients. In total, 178 patients with suspected focal hepatic lesions (based, in most patients, on CT, tumor marker and ultrasound examinations) underwent combined MR imaging with a single, rapid injection of Gd-EOB-DTPA 0.025 mmol/kg, including T1-weighted dynamic and delayed MR images 20 to 40 minutes postinjection. Triphasic contrast-enhanced CT, the comparator examination, was performed within 4 weeks of MR imaging. Standard of references (SOR) were resection histopathology and intraoperative ultrasonography, or combined CT during arterial portography and CT hepatic arteriography; in cases where, although the major lesions were treated, some lesion(s) were not treated, follow-up superparamagnetic iron oxide-enhanced MR imaging was additionally performed. All images were assessed for differences in lesion detection and characterization (specific lesion type) by on-site readers and 3, blinded (off-site) reviewers. All adverse events (AEs) occurring within 72 hours after Gd-EOB-DTPA administration were reported.Overall, 9.6% of patients who received Gd-EOB-DTPA reported 21 drug-related AEs. A total of 151 patients were included in the efficacy analysis. Combined MR imaging showed statistically higher sensitivity in lesion detection (67.5%-79.5%) than unenhanced MR imaging (46.5%-59.1%; P < 0.05 for all). Combined MR imaging also showed higher sensitivity in lesion detection than CT (61.1%-73.0%), with the results being statistically significant (P < 0.05) for on-site readers and 2 of 3 blinded readers. Higher sensitivity in lesion detection with combined MR imaging compared with CT was also clearly demonstrated in the following subgroups: lesions with a diameter <or=20 mm (lesions <or=10 mm: 38.0%-55.4% vs. 26.1%-47.3%, respectively; lesions 10-20 mm: 71.1%-87.3% vs. 65.7%-78.4%, respectively); in cirrhotic patients (64.5%-75.4% vs. 54.5%-70.3%, respectively); and in patients with hepatocellular carcinoma (66.6%-78.6% vs. 59.1%-71.6%, respectively). Combined MR imaging demonstrated a higher proportion of correctly characterized lesions (50.5%-72.1%) than unenhanced MR imaging (30.2%-50.0%; P < 0.05 for all), whereas there were no significant differences compared with CT (49.0%-68.1%), except for one blinded reader (P < 0.05).In this study, hepatocyte-specific Gd-EOB-DTPA was shown to be safe and to improve the detection and characterization of focal hepatic lesions compared with unenhanced MR imaging. When compared with spiral CT, Gd-EOB-DTPA enhanced MRI seems to be beneficial especially for the detection for smaller lesions or hepatocellular carcinoma underlying cirrhotic liver.
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| [64] |
Small recurrent hepatocellular carcinoma (HCC) can show atypical imaging patterns, and a specific diagnostic algorithm for HCC is lacking. This study aimed to better characterize postoperative recurrent HCCs <20 mm in size with gadoxetic acid–enhanced magnetic resonance imaging (MRI). We evaluated 373 newly developed nodules after hepatectomy in 204 HCC patients with chronic hepatitis B virus infection. The diagnostic performance of Liver Imaging Reporting and Data System (LI‐RADS) version 2018 was calculated with gadoxetic acid–enhanced MRI to characterize recurrent HCC. Modified diagnostic algorithms were proposed by combining significant imaging biomarkers related to subcentimeter and 10‐19 mm recurrence, and the algorithms were then compared with the LI‐RADS system. A total of 256 recurrent HCCs (108 recurrent HCCs <10 mm in size; 148 recurrent HCCs 10‐19 mm in size) were confirmed via histology or follow‐up imaging. Nonrim arterial phase hyperenhancement (APHE) and 3 LI‐RADS ancillary features (AFs; hepatobiliary phase hypointensity, mild‐moderate T2 hyperintensity, and restricted diffusion) were significantly related to recurrent HCCs <20 mm in size according to a multivariate analysis. For subcentimeter recurrence, combining at least 2 of the 3 AFs only achieved better specificity (sensitivity, 83.3%; specificity, 87.7%) than the LR‐4 category (sensitivity, 88.9%, P = 0.21; specificity, 70.8%, P = 0.006). For 10‐19 mm recurrences, combining nonrim APHE and at least 1 of the 3 AFs achieved only a significantly enhanced sensitivity of 85.1% but a lower specificity of 86.5% compared with the LR‐5 category (sensitivity: 63.5%, P < 0.001; specificity: 94.2%, P = 0.13). In conclusion, the diagnostic algorithms for subcentimeter and 10‐19 mm recurrent HCCs should be stratified. Combining at least 2 AFs demonstrated comparable sensitivity with significantly enhanced specificity compared with the LR‐4 category for characterizing subcentimeter recurrence.
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| [65] |
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| [66] |
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| [67] |
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| [68] |
Transarterial chemoembolization (TACE) is a standard treatment for intermediate-stage hepatocellular carcinoma (HCC). In this review, we summarize recent updates on the use of TACE for HCC. TACE can be performed using two techniques; conventional TACE (cTACE) and drug-eluting beads using TACE (DEB-TACE). The anti-tumor effect of the two has been reported to be similar; however, DEB-TACE carries a higher risk of hepatic artery and biliary injuries and a relatively lower risk of post-procedural pain than cTACE. TACE can be used for early stage HCC if other curative treatments are not feasible or as a neoadjuvant treatment before liver transplantation. TACE can also be considered for selected patients with limited portal vein thrombosis and preserved liver function. When deciding to repeat TACE, the ART (Assessment for Retreatment with TACE) score and ABCR (AFP, BCLC, Child-Pugh, and Response) score can guide the decision process, and TACE refractoriness needs to be considered. Studies on the combination therapy of TACE with other treatment modalities, such as local ablation, radiation therapy, or systemic therapy, have been actively conducted and are still ongoing. Recently, new prognostic models, including analysis of the neutrophil-lymphocyte ratio, radiomics, and deep learning, have been developed to help predict survival after TACE.
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| [69] |
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death not only in Japan but also worldwide. Clinical practice guidelines for HCC were first published in 2001 by the European Society of Study of the Liver (EASL) followed by the American Association for the Study of Liver Disease (AASLD) published in 2005 and updated in 2010. However, these guidelines have proven to be somewhat unsuitable for Japanese patients. In 2005, supported by the Japanese Ministry of Health, Labour and Welfare, evidence-based clinical practice guidelines for HCC were compiled in Japan. In 2009, a revised version of evidence-based guidelines was published. Based on both 'evidence-based' guidelines and the consensus of an expert panel on HCC, the Japan Society of Hepatology (JSH) published the Consensus-Based Clinical Practice Manual in 2007 and updated in 2010. In this article, the 2010 updated version of this manual, especially issues on prevention, surveillance, pathology, diagnosis, staging, and treatment algorithm are summarized.Copyright © 2011 S. Karger AG, Basel.
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| [70] |
The role of liver resection in patients with hepatocellular carcinoma (HCC) accompanying with portal vein tumor thrombus (PVTT) remains controversial. This article aimed to evaluate the significance of different location and extent of PVTT on surgical outcomes after liver resection for HCC.A retrospective study was carried out on patients who underwent partial hepatectomy with or without portal thrombectomy for HCC with PVTT in a single tertiary center from January 2001 to December 2003. According to the extent, PVTT was divided into 4 types (I-segmental/sectoral branches of portal vein, II-left and/or right portal vein, III-main portal vein trunk, and IV-superior mesenteric vein).A total of 406 patients with HCC and PVTT who underwent partial hepatectomy were studied. The complication rate and hospital mortality rate were 32.8 and 0.2%, respectively. After a median follow-up of 6.4 months, 128 patients (31.5%) died. The 1- and 3-year overall survival rates were 34.4 and 13.0%, respectively. The 1- and 3-year disease-free survival rates were 13.3 and 4.7%, respectively. Patients with PVTT located in the segmental, sectoral, or right and/or left portal veins (types I and II) showed significantly better survival than those with PVTT extended to the main trunk of the portal vein or the superior mesenteric vein (types III and IV).Liver resection is justified in selected patients with PVTT located in the segmental or sectoral branches of the portal vein. However, surgical resection for PVTT involving the portal bifurcation or the main trunk is still controversial.
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| [71] |
The preoperative selection of patients with intermediate-stage hepatocellular carcinoma (HCC) who are likely to have an objective response to first transarterial chemoembolization (TACE) remains challenging.To develop and validate a clinical-radiomic model (CR model) for preoperatively predicting treatment response to first TACE in patients with intermediate-stage HCC.A total of 595 patients with intermediate-stage HCC were included in this retrospective study. A tumoral and peritumoral (10 mm) radiomic signature (TPR-signature) was constructed based on 3,404 radiomic features from 4 regions of interest. A predictive CR model based on TPR-signature and clinical factors was developed using multivariate logistic regression. Calibration curves and area under the receiver operating characteristic curves (AUCs) were used to evaluate the model's performance.The final CR model consisted of 5 independent predictors, including TPR-signature (< 0.001), AFP (= 0.004), Barcelona Clinic Liver Cancer System Stage B (BCLC B) subclassification (= 0.01), tumor location (= 0.039), and arterial hyperenhancement (= 0.050). The internal and external validation results demonstrated the high-performance level of this model, with internal and external AUCs of 0.94 and 0.90, respectively. In addition, the predicted objective response via the CR model was associated with improved survival in the external validation cohort (hazard ratio: 2.43; 95% confidence interval: 1.60-3.69; < 0.001). The predicted treatment response also allowed for significant discrimination between the Kaplan-Meier curves of each BCLC B subclassification.The CR model had an excellent performance in predicting the first TACE response in patients with intermediate-stage HCC and could provide a robust predictive tool to assist with the selection of patients for TACE.Copyright © 2021 by S. Karger AG, Basel.
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| [72] |
Microvascular invasion (MVI) impairs surgical outcomes in patients with hepatocellular carcinoma (HCC). As there is no single highly reliable factor to preoperatively predict MVI, we developed a computational approach integrating large-scale clinical and imaging modalities, especially radiomic features from contrast-enhanced CT, to predict MVI and clinical outcomes in patients with HCC.In total, 495 surgically resected patients were retrospectively included. MVI-related radiomic scores (R-scores) were built from 7,260 radiomic features in 6 target volumes. Six R-scores, 15 clinical factors, and 12 radiographic scores were integrated into a predictive model, the radiographic-radiomic (RR) model, with multivariate logistic regression.Radiomics related to tumor size and intratumoral heterogeneity were the top-ranked MVI predicting features. The related R-scores showed significant differences according to MVI status (p <0.001). Regression analysis identified 8 MVI risk factors, including 5 radiographic features and an R-score. The R-score (odds ratio [OR] 2.34) was less important than tumor capsule (OR 5.12), tumor margin (OR4.20), and peritumoral enhancement (OR 3.03). The RR model using these predictors achieved an area under the curve (AUC) of 0.909 in training/validation and 0.889 in the test set. Progression-free survival (PFS) and overall survival (OS) were significantly different between the RR-predicted MVI-absent and MVI-present groups (median PFS: 49.5 vs. 12.9 months; median OS: 76.3 vs. 47.3 months). RR-computed MVI probability, histologic MVI, tumor size, and Edmondson-Steiner grade were independently associated with disease-specific recurrence and mortality.The computational approach, integrating large-scale clinico-radiologic and radiomic features, demonstrates good performance for predicting MVI and clinical outcomes. However, radiomics with current CT imaging analysis protocols do not provide statistically significant added value to radiographic scores.The most effective treatment for hepatocellular carcinoma (HCC) is surgical removal of the tumor but often recurrence occurs, partly due to the presence of microvascular invasion (MVI). Lacking a single highly reliable factor able to preoperatively predict MVI, we developed a computational approach to predict MVI and the long-term clinical outcome of patients with HCC. In particular, the added value of radiomics, a newly emerging form of radiography, was comprehensively investigated. This computational method can enhance the communication with the patient about the likely success of the treatment and guide clinical management, with the aim of finding drugs that reduce the risk of recurrence.Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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| [73] |
To develop radiomics-based nomograms for preoperative microvascular invasion (MVI) and recurrence-free survival (RFS) prediction in patients with solitary hepatocellular carcinoma (HCC) ≤ 5 cm.
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| [74] |
Radiomics has emerged as a new approach that can help identify imaging information associated with tumor pathophysiology. We developed and validated a radiomics nomogram for preoperative prediction of microvascular invasion (MVI) in hepatocellular carcinoma (HCC).Two hundred and eight patients with pathologically confirmed HCC (training cohort: = 146; validation cohort: = 62) who underwent preoperative gadoxetic acid-enhanced magnetic resonance (MR) imaging were included. Least absolute shrinkage and selection operator logistic regression was applied to select features and construct signatures derived from MR images. Univariate and multivariate analyses were used to identify the significant clinicoradiological variables and radiomics signatures associated with MVI, which were then incorporated into the predictive nomogram. The performance of the radiomics nomogram was evaluated by its calibration, discrimination, and clinical utility.Higher α-fetoprotein level (= 0.046), nonsmooth tumor margin (= 0.003), arterial peritumoral enhancement (0.001), and the radiomics signatures of hepatobiliary phase (HBP) T1-weighted images (0.001) and HBP T1 maps (0.001) were independent risk factors of MVI. The predictive model that incorporated the clinicoradiological factors and the radiomic features derived from HBP images outperformed the combination of clinicoradiological factors in the training cohort (area under the curves [AUCs] 0.943 vs. 0.850; = 0.002), though the validation did not have a statistical significance (AUCs 0.861 vs. 0.759; = 0.111). The nomogram based on the model exhibited C-index of 0.936 (95% CI 0.895-0.976) and 0.864 (95% CI 0.761-0.967) in the training and validation cohort, fitting well in calibration curves (> 0.05). Decision curve analysis further confirmed the clinical usefulness of the nomogram.The nomogram incorporating clinicoradiological risk factors and radiomic features derived from HBP images achieved satisfactory preoperative prediction of the individualized risk of MVI in patients with HCC.Copyright © 2018 by S. Karger AG, Basel.
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| [75] |
The presence of microvascular invasion (MVI) decreases surgical outcomes of hepatocellular carcinoma (HCC). An accurate preoperative prediction of MVI can help surgeons to better choose surgical procedures, but accuracy is still difficult to achieve.To develop a nomogram to predict MVI presence before liver resection for hepatitis B virus (HBV)-related HCC within the Milan criteria (solitary nodule ≤5 cm; ≤3 nodules, none >3 cm; and no macrovascular invasion).Data on 1004 consecutive patients who underwent liver resection for HBV-related HCC within the Milan criteria at the Eastern Hepatobiliary Surgery Hospital between April 6, 2004, and February 22, 2011, were prospectively collected. Of these, patients who underwent surgery in an earlier period formed the training cohort (n = 707) for nomogram development, and those who underwent surgery thereafter formed the validation cohort (n = 297) to confirm the model's performance. Data analysis was conducted from August 1 to November 11, 2014.Liver resection for HCC.Overall survival and time to recurrence after liver resection were measured. Multivariate logistic regression was used to identify the independent risk factors associated with MVI that then were incorporated into the nomogram.Histopathologically identified MVI was found in 211 of 707 patients (29.8%) and 89 of 297 patients (30.0%) in the training and validation cohorts, respectively. In the training cohort, the 5-year recurrence and overall survival rates were 78.5% and 46.9%, respectively, in patients with MVI and 58.4%, and 70.9%, respectively, in patients without MVI (both P < .001). The preoperative factors associated with MVI were large tumor diameter, multiple nodules, incomplete capsule, α-fetoprotein level greater than 20 ng/mL, platelet count less than 100 × 103/µL, hepatitis B virus DNA load greater than 104 IU/mL, and a typical dynamic pattern of tumors on contrast-enhanced magnetic resonance imaging. Incorporating these 7 factors, the nomogram achieved good concordance indexes of 0.81 (95% CI, 0.78-0.85) and 0.80 (95% CI, 0.75-0.86) in predicting MVI in the training and validation cohorts, respectively, and had well-fitted calibration curves. The positive and negative predictive values (95% CIs) of the nomogram were calculated, resulting in positive predictive values of 57.2% (52.0%-64.9%) and 57.9% (49.2%-68.5%) and negative predictive values of 87.2% (83.2%-89.4%) and 83.2% (76.0%-87.7%) for the training and validation cohorts, respectively. Patients who had a nomogram score of less than 200 or 200 or greater were considered to have low or high risks of MVI presence, respectively.The nomogram achieved an optimal preoperative prediction of MVI in HBV-related HCC within the Milan criteria. Using the model, the risk for an individual patient to harbor MVI can be determined, which can lead to a rational therapeutic choice.
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| [76] |
Transarterial chemoembolization (TACE) is considered a standard local-regional treatment for intermediate-stage hepatocellular carcinoma (HCC) and the most common bridging therapy. This treatment is offered to more than 70% of patients who are on the waiting list for liver transplantation in the United States. HCC typically receives its blood supply from the hepatic artery; however, it can recruit a parasitic supply from extrahepatic collateral (EHC) arteries. The development of an EHC arterial blood supply can interfere with the therapeutic efficacy of TACE and result in treatment failure and poor outcome. Cross-sectional imaging-specifically computed tomography and magnetic resonance imaging-has some limitations in depicting the presence or absence of an EHC arterial supply during the pre-TACE evaluation. Catheterization and angiography of every possible EHC artery during a routine TACE procedure would be time consuming and technically challenging and would not always be feasible. Therefore, the prediction of a potential EHC arterial supply on the basis of tumor location before, during, and after TACE is fundamental to achieving optimal therapeutic efficacy. To perform TACE through EHC arteries, special considerations are necessary to avoid potentially serious complications. The authors review the factors influencing the development of an EHC arterial blood supply to HCC and describe a systematic approach to enhance the ability to predict the presence of EHC arteries. They also describe the proper technique for TACE of each EHC artery and how to avoid potential technique-related complications. RSNA, 2017.
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| [77] |
中国医师协会介入医师分会临床诊疗指南专委会. 锥形束 CT 应用于肝脏恶性肿瘤介入诊疗的专家共识[J]. 中华放射学杂志, 2024, 58(6):596-602.DOI:10.3760/cma.j.cn112149-20240102-00003.
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| [78] |
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| [79] |
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| [80] |
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| [81] |
Improvements in radiologic imaging technology and therapeutic options available for management of tumors have necessitated the revision of guidelines for the imaging-based assessment of tumor response to therapy. The purpose of this article is to familiarize radiologists with the modifications to the Response Evaluation Criteria in Solid Tumors (RECIST) that have been incorporated in the latest version of the guidelines, RECIST 1.1. The most important differences between this version and the previous one, RECIST 1.0, include reductions in the maximum number of lesions per patient and per organ that may be targeted for measurement, augmentation of the criteria defining progressive disease, additional guidelines for reporting findings of lesions that are too small to measure and for measuring lesions that appear to have fragmented or coalesced at follow-up imaging, new criteria for characterizing lymphadenopathy, new criteria for selecting bone lesions and cystic lesions as targets for measurement, and the inclusion of findings at positron emission tomography among the indicators of disease response.
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| [82] |
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| [83] |
The purpose of the present study was to evaluate the possibility of detection, staging and differentiation assessment of hepatocellular carcinoma (HCC) using a combination of dual-phase computed tomography (CT)-angiography in the arterial and portal phase with positron emission tomography (PET) imaging using (18)F-fluorodeoxyglucose ((18)FDG).From a set of 10,000 patients who underwent (18)FDG-PET/CT, we examined a total of 65 patients (52 males, 13 females; mean age=61.7 years, ranging from 35-82 years) with HCC. The imaging included CT data acquisition after intravenous application of iodinated contrast material in arterial and portal phases, allowed to obtain data in CT angiography quality. Histological diagnosis of the resection sample (21), biopsy (37) or necropsy (7), including the evaluation of the hepatocytary origin of the tumor and the grade of its differentiation, was determined in all patients.The most sensitive sign in the detection of HCC was the alternative presence of hypervascularity or hyperaccumulation of (18)F FDG that reached 93.8%. The high level of (18)F-FDG accumulation showed sensitivity of 84.1% and specificity of 75.0% for distinguishing between well- and poorly differentiated HCC.The combination of the dual-phase CT angiography with (18)FDG PET helps in the assessment of staging and differentiation of HCC and has an important role in treatment decision-making.Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.
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| [84] |
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| [85] |
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| [86] |
The role of fluorine-18-fluorodeoxygluose positron emission tomography/computed tomography ((18)F-FDG PET/CT) in hepatocellular carcinoma (HCC) has not been firmly established yet and its sensitivity has been reported to be in the range of 40-60 %. Because of this relatively low sensitivity alternative tracers have been proposed. The aim of our review is to analyse the literature data on the diagnostic role of (18)F/(11)C-choline PET/CT in the evaluation of HCC. A comprehensive computer literature search of PubMed/MEDLINE, Embase and Scopus databases was conducted to find relevant published articles about the role of whole-body (18)F-choline or (11)C-choline PET or PET/CT in patients with HCC. Furthermore, a meta-analysis about the detection rate of this method in HCC was performed. Six articles were included in this systematic review and discussed. The meta-analysis of five out of six articles showed a DR of 84 % (95 % CI 79-89 %). The DR increased when poorly differentiated HCC was excluded from the analysis. Radiolabelled choline PET or PET/CT could be a valuable tool in detecting HCC and it is better than (18)F-FDG PET/CT, especially in well to moderately differentiated lesions; on the other hand, poorly differentiated and higher-stage HCC could be better evaluated with (18)F-FDG and dual tracer imaging should be considered and could be potentially useful to increase accuracy.
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| [87] |
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| [88] |
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| [89] |
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| [90] |
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| [91] |
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| [92] |
More than 60% of patients with hepatocellular carcinoma (HCC) do not receive curative therapy as a result of late clinical presentation and diagnosis. We aimed to identify plasma microRNAs for diagnosing hepatitis B virus (HBV) -related HCC.Plasma microRNA expression was investigated with three independent cohorts including 934 participants (healthy, chronic hepatitis B, cirrhosis, and HBV-related HCC), recruited between August 2008 and June 2010. First, we used microarray to screen 723 microRNAs in 137 plasma samples for diagnosing HCC. Quantitative reverse-transcriptase polymerase chain reaction assay was then applied to evaluate the expression of selected microRNAs. A logistic regression model was constructed using a training cohort (n = 407) and then validated using an independent cohort (n = 390). Area under the receiver operating characteristic curve (AUC) was used to evaluate diagnostic accuracy.We identified a microRNA panel (miR-122, miR-192, miR-21, miR-223, miR-26a, miR-27a and miR-801) that provided a high diagnostic accuracy of HCC (AUC = 0.864 and 0.888 for training and validation data set, respectively). The satisfactory diagnostic performance of the microRNA panel persisted regardless of disease status (AUCs for Barcelona Clinic Liver Cancer stages 0, A, B, and C were 0.888, 0.888, 0.901, and 0.881, respectively). The microRNA panel can also differentiate HCC from healthy (AUC = 0.941), chronic hepatitis B (AUC = 0.842), and cirrhosis (AUC = 0.884), respectively.We found a plasma microRNA panel that has considerable clinical value in diagnosing early-stage HCC. Thus, patients who would have otherwise missed the curative treatment window can benefit from optimal therapy.
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| [93] |
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| [94] |
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| [95] |
Early detection of hepatocellular carcinoma (HCC) among hepatitis B virus (HBV)-infected patients remains a challenge, especially in China. We sought to create an online calculator of serum biomarkers to detect HCC among patients with chronic hepatitis B (CHB).Participants with HBV-HCC, CHB, HBV-related liver cirrhosis (HBV-LC), benign hepatic tumors, and healthy controls (HCs) were recruited at 11 Chinese hospitals. Potential serum HCC biomarkers, protein induced by vitamin K absence or antagonist-II (PIVKA-II), α-fetoprotein (AFP), lens culinaris agglutinin A-reactive fraction of AFP (AFP-L3) and α-l-fucosidase (AFU) were evaluated in the pilot cohort. The calculator was built in the training cohort via logistic regression model and validated in the validation cohort.In the pilot study, PIVKA-II and AFP showed better diagnostic sensitivity and specificity compared with AFP-L3 and AFU and were chosen for further study. A combination of PIVKA-II and AFP demonstrated better diagnostic accuracy in differentiating patients with HBV-HCC from patients with CHB or HBV-LC than AFP or PIVKA-II alone [area under the curve (AUC), 0.922 (95% CI, 0.908-0.935), sensitivity 88.3% and specificity 85.1% for the training cohort; 0.902 (95% CI, 0.875-0.929), 87.8%, and 81.0%, respectively, for the validation cohort]. The nomogram including AFP, PIVKA-II, age, and sex performed well in predicting HBV-HCC with good calibration and discrimination [AUC, 0.941 (95% CI, 0.929-0.952)] and was validated in the validation cohort [AUC, 0.931 (95% CI, 0.909-0.953)].Our results demonstrated that a web-based calculator including age, sex, AFP, and PIVKA-II accurately predicted the presence of HCC in patients with CHB.NCT03047603.© 2019 American Association for Clinical Chemistry.
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| [96] |
In the present study, we assessed the clinical value of circulating tumor cells (CTC) with stem-like phenotypes for diagnosis, prognosis, and surveillance in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) by an optimized qPCR-based detection platform. Differing subsets of CTCs were investigated, and a multimarker diagnostic CTC panel was constructed in a multicenter patient study with independent validation (total = 1,006), including healthy individuals and patients with chronic hepatitis B infection (CHB), liver cirrhosis (LC), benign hepatic lesion (BHL), and HBV-related HCC, with area under the receiver operating characteristic curve (AUC-ROC) reflecting diagnostic accuracy. The role of the CTC panel in treatment response surveillance and its prognostic significance were further investigated. The AUC of the CTC panel was 0.88 in the training set [sensitivity = 72.5%, specificity = 95.0%, positive predictive value (PPV) = 92.4, negative predictive value (NPV) = 77.8] and 0.93 in the validation set (sensitivity = 82.1%, specificity = 94.2%, PPV = 89.9, NPV = 89.3). This panel performed equally well in detecting early-stage and α-fetoprotein-negative HCC, as well as differentiating HCC from CHB, LC, and BHL. The CTC load was decreased significantly after tumor resection, and patients with persistently high CTC load showed a propensity of tumor recurrence after surgery. The prognostic significance of the CTC panel in predicting tumor recurrence was further confirmed [training: HR = 2.692; 95% confidence interval (CI), 1.617-4.483; < 0.001; and validation: HR = 3.127; 95% CI, 1.360-7.190; = 0.007]. Our CTC panel showed high sensitivity and specificity in HCC diagnosis and could be a real-time parameter for risk prediction and treatment monitoring, enabling early decision-making to tailor effective antitumor strategies..©2018 American Association for Cancer Research.
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| [97] |
Early detection of primary liver cancer (PLC), including HCC, intrahepatic cholangiocarcinoma (ICC), and combined HCC‐ICC (cHCC‐ICC), is essential for patients’ survival. This study aims to develop an accurate and affordable method for PLC early detection and differentiating ICC from HCC using plasma cell‐free DNA (cfDNA) fragmentomic profiles.
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| [98] |
Liquid biopsies, based on cell free DNA (cfDNA) and proteins, have shown the potential to detect early stage cancers of diverse tissue types. However, most of these studies were retrospective, using individuals previously diagnosed with cancer as cases and healthy individuals as controls. Here, we developed a liquid biopsy assay, named the hepatocellular carcinoma screen (HCCscreen), to identify HCC from the surface antigen of hepatitis B virus (HBsAg) positive asymptomatic individuals in the community population. The training cohort consisted of individuals who had liver nodules and/or elevated serum α-fetoprotein (AFP) levels, and the assay robustly separated those with HCC from those who were non-HCC with a sensitivity of 85% and a specificity of 93%. We further applied this assay to 331 individuals with normal liver ultrasonography and serum AFP levels. A total of 24 positive cases were identified, and a clinical follow-up for 6-8 mo confirmed four had developed HCC. No HCC cases were diagnosed from the 307 test-negative individuals in the follow-up during the same timescale. Thus, the assay showed 100% sensitivity, 94% specificity, and 17% positive predictive value in the validation cohort. Notably, each of the four HCC cases was at the early stage (<3 cm) when diagnosed. Our study provides evidence that the use of combined detection of cfDNA alterations and protein markers is a feasible approach to identify early stage HCC from asymptomatic community populations with unknown HCC status.
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| [99] |
The lack of highly sensitive and specific diagnostic biomarkers is a major contributor to the poor outcomes of patients with hepatocellular carcinoma (HCC). We sought to develop a non-invasive diagnostic approach using circulating cell-free DNA (cfDNA) for the early detection of HCC.Applying the 5hmC-Seal technique, we obtained genome-wide 5-hydroxymethylcytosines (5hmC) in cfDNA samples from 2554 Chinese subjects: 1204 patients with HCC, 392 patients with chronic hepatitis B virus infection (CHB) or liver cirrhosis (LC) and 958 healthy individuals and patients with benign liver lesions. A diagnostic model for early HCC was developed through case-control analyses using the elastic net regularisation for feature selection.The 5hmC-Seal data from patients with HCC showed a genome-wide distribution enriched with liver-derived enhancer marks. We developed a 32-gene diagnostic model that accurately distinguished early HCC (stage 0/A) based on the Barcelona Clinic Liver Cancer staging system from non-HCC (validation set: area under curve (AUC)=88.4%; (95% CI 85.8% to 91.1%)), showing superior performance over α-fetoprotein (AFP). Besides detecting patients with early stage or small tumours (eg, ≤2.0 cm) from non-HCC, the 5hmC model showed high capacity for distinguishing early HCC from high risk subjects with CHB or LC history (validation set: AUC=84.6%; (95% CI 80.6% to 88.7%)), also significantly outperforming AFP. Furthermore, the 5hmC diagnostic model appeared to be independent from potential confounders (eg, smoking/alcohol intake history).We have developed and validated a non-invasive approach with clinical application potential for the early detection of HCC that are still surgically resectable in high risk individuals.© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
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| [100] |
This study prospectively evaluates the accuracy of contrast-enhanced ultrasound (CEUS) and dynamic magnetic resonance imaging (MRI) for the diagnosis of nodules 20 mm or smaller detected during ultrasound (US) surveillance. We included 89 patients with cirrhosis [median age, 65 years; male 53, hepatitis C virus 68, Child-Pugh A 80] without prior hepatocellular carcinoma (HCC) in whom US detected a small solitary nodule (mean diameter, 14 mm). Hepatic MRI, CEUS, and fine-needle biopsy (gold standard) (FNB) were performed at baseline. Non-HCC cases were followed (median 23 months) by CEUS/3 months and MRI/6 months. FNB was repeated up to 3 times and on detection of change in aspect/size. Intense arterial contrast uptake followed by washout in the delayed/venous phase was registered as conclusive for HCC. Final diagnoses were: HCC (n = 60), cholangiocarcinoma (n = 1), and benign lesions (regenerative/dysplastic nodule, hemangioma, focal nodular hyperplasia) (n = 28). Sex, cirrhosis cause, liver function, and alpha-fetoprotein (AFP) levels were similar between HCC and non-HCC groups. HCC patients were older and their nodules significantly larger (P < 0.0001). First biopsy was positive in 42 of 60 HCC patients. Sensitivity, specificity, and positive and negative predictive values of conclusive profile were 61.7%, 96.6%, 97.4%, and 54.9%, for MRI, 51.7%, 93.1%, 93.9%, and 50.9%, for CEUS. Values for coincidental conclusive findings in both techniques were 33.3%, 100%, 100%, and 42%. Thus, diagnosis of HCC 20 mm or smaller can be established without a positive biopsy if both CEUS and MRI are conclusive. However, sensitivity of these noninvasive criteria is 33% and, as occurs with biopsy, absence of a conclusive pattern does not rule out malignancy. These results validate the American Association for the Study of Liver Disease (AASLD) guidelines.
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| [101] |
Multiphasic computed tomography (CT) and magnetic resonance imaging (MRI) are both used for noninvasive diagnosis of hepatocellular carcinoma (HCC) in patients with cirrhosis. To determine if there is a relative diagnostic benefit of one over the other, we synthesized evidence regarding the relative performance of CT, extracellular contrast-enhanced MRI, and gadoxetate-enhanced MRI for diagnosis of HCC in patients with cirrhosis. We also assessed whether liver biopsy versus follow-up with the same versus alternative imaging is best for CT-indeterminate or MRI-indeterminate liver nodules in patients with cirrhosis. We searched multiple databases from inception to April 27, 2016, for studies comparing CT with extracellular contrast-enhanced MRI or gadoxetate-enhanced MRI in adults with cirrhosis and suspected HCC. Two reviewers independently selected studies and extracted data. Of 33 included studies, 19 were comprehensive, while 14 reported sensitivity only. For all tumor sizes, the 19 comprehensive comparisons showed significantly higher sensitivity (0.82 versus 0.66) and lower negative likelihood ratio (0.20 versus 0.37) for MRI over CT. The specificities of MRI versus CT (0.91 versus 0.92) and the positive likelihood ratios (8.8 versus 8.1) were not different. All three modalities performed better for HCCs ≥2 cm. Performance was poor for HCCs <1 cm. No studies examined whether adults with cirrhosis and an indeterminate nodule are best evaluated using biopsy, repeated imaging, or alternative imaging. Concerns about publication bias, inconsistent study results, increased risk of bias, and clinical factors precluded support for exclusive use of either gadoxetate-enhanced or extracellular contrast-enhanced MRI over CT.CT, extracellular contrast-enhanced MRI, or gadoxetate-enhanced MRI could not be definitively preferred for HCC diagnosis in patients with cirrhosis; in patients with cirrhosis and an indeterminate mass, there were insufficient data comparing biopsy to repeat cross-sectional imaging or alternative imaging. (Hepatology 2018;67:401-421).© 2017 by the American Association for the Study of Liver Diseases.
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| [102] |
European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma[J]. J Hepatol, 2018, 69(1):182-236. DOI: 10.1016/j.jhep.2018.03.019.
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| [103] |
WHO Classification of Tumours Editorial Board. WHO classification of tumours.Digestive system tumours[M]. 5th Edition. Lyon: IARC Press, 2019.
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| [104] |
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| [105] |
The aim of this work is to explore the impact of the number of sampling sites (NuSS) and sampling location on microvascular invasion (MVI) detection rate and long-term survival of hepatocellular carcinoma (HCC), and determine the minimum NuSS for sufficient MVI detection.From January 2008 to March 2017, 1144 HCC patients who underwent hepatectomy were retrospectively enrolled. Associations between NuSS and MVI positive rates and overall survival were investigated. NuSS thresholds were determined by Chow test and confirmed prospectively in 305 patients from April 2017 to February 2019. In the prospective cohort, the distribution of MVI in different sampling locations and its prognostic effect was evaluated.MVI positive rates increased as NuSS increased, steadily reaching a plateau when NuSS reached a threshold. A threshold of four, six, eight, and eight sampling sites within paracancerous parenchyma ≤ 1 cm from tumor was required for detecting MVI in solitary tumors measuring 1.0-3.0, 3.1-4.9, and ≥ 5.0 cm and multiple tumors. Patients with adequate NuSS achieved longer survival than those with inadequate NuSS [hazard ratio (HR) = 0.75, P = 0.043]. For all MVI-positive patients, MVI could be detected positive in paracancerous parenchyma ≤ 1 cm from tumor. Patients with MVI positive in paracancerous parenchyma > 1 cm had higher recurrence risk than those with MVI positive only in parenchyma ≤ 1 cm (HR = 6.05, P < 0.001).Adequate NuSS is associated with higher MVI detection rate and better survival of HCC patients. We recommend four, six, eight, and eight as the cut-points for evaluating MVI sampling quality and patients' prognostic stratification in the subgroups of solitary tumors measuring 1.0-3.0 cm, 3.1-4.9 cm and ≥ 5.0 cm and multiple tumors, respectively.
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| [106] |
Microvascular invasion (MVI) is a key pathological factor that severely affects the postoperative prognosis of patients with hepatocellular carcinoma (HCC). However, no MVI classification schemes based on standardized gross sampling protocols of HCC are available at present.119 HCC specimens were sampled at multiple sites (3-, 7-, and 13 points) for the optimum MVI detection rate. 16,144 resected HCCs were graded as M0, M1 or M2 by adopting three-tiered MVI grading (MVI-TTG) scheme based on the seven-point sampling protocol (SPSP). Survival analyses were performed on 2573 patients to explore the advantages of MVI-TTG.The MVI detection rate determined by SPSP was significantly higher than that determined by the 3-point sampling method (34.5% vs. 47.1%, p = 0.048), but was similar to that determined by the 13-point sampling method (47.1% vs. 51.3%, p = 0.517). Among 16,144 resected HCCs, the proportions of M0, M1 and M2 specimens according to SPSP were 53.4%, 26.2% and 20.4%, respectively. Postoperative survival analysis in 2573 HCC patients showed that the 3-year recurrence rates in M0, M1 and M2 MVI groups were 62.5%, 71.6% and 86.1%, respectively (p < 0.001), and the corresponding 3-year overall survival (OS) rates were 94.1%, 87.5% and 67.0%, respectively (p < 0.001). M1 grade was associated with early recurrence, while M2 grade was associated with both early and late recurrence. MVI-TTG had a larger area under the curve and net benefit rate than the two-tiered MVI grading scheme for predicting time to recurrence and OS.SPSP is a practical method to balance the efficacy of sampling numbers and MVI detection rates. MVI-TTG based on SPSP is a better prognostic predictor than the two-tiered MVI scheme. The combined use of SPSP and MVI-TTG is recommended for the routine pathological diagnosis of HCC.
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| [107] |
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| [108] |
Cytokeratin 19-positive (CK19+) hepatocellular carcinoma (HCC) is an aggressive subtype characterized by early recurrence and chemotherapy tolerance. However, there is no specific therapeutic option for CK19+ HCC. The correlation between tumor recurrence and expression status of CK19 were studied in 206 patients undergoing liver transplantation for HCC. CK19-/+ HCC cells were isolated to screen effective antitumor drugs. The therapeutic effects of regorafenib were evaluated in patient-derived xenograft (PDX) models from 10 HCC patients. The mechanism of regorafenib on CK19+ HCC was investigated. CK19 positiveness indicated aggressiveness of tumor and higher recurrence risk of HCC after liver transplantation. The isolated CK19+ HCC cells had more aggressive behaviors than CK19- cells. Regorafenib preferentially increased the growth inhibition and apoptosis of CK19+ cells in vitro, whereas sorafenib, apatinib, and 5-fluorouracil did not. In PDX models from CK19-/+ HCC patients, the tumor control rate of regorafenib achieved 80% for CK19+ HCCs, whereas 0% for CK19- HCCs. RNA-sequencing revealed that CK19+ cells had elevated expression of mitochondrial ribosomal proteins, which are essential for mitochondrial function. Further experiments confirmed that regorafenib attenuated the mitochondrial respiratory capacity in CK19+ cells. However, the mitochondrial respiration in CK19- cells were faint and hardly repressed by regorafenib. The mitochondrial respiration was regulated by the phosphorylation of signal transducer and activator of transcription 3 (STAT3), which was inhibited by regorafenib in CK19+ cells. Hence, CK19 could be a potential marker of the therapeutic benefit of regorafenib, which facilitates the individualized therapy for HCC. STAT3/mitochondria axis determines the distinct response of CK19+ cells to regorafenib treatment.© 2021. The Author(s).
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| [109] |
《肝内胆管癌病理诊断专家共识(2022 版)》编写专家委员会. 肝内胆管癌病理诊断专家共识(2022 版)[J]. 中华病理学杂志, 2022, 51(9):819-827.DOI:10.3760/cma.j.cn112151-20220517-00423.
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| [110] |
Tertiary lymphoid structures (TLSs) are lymphoid formations that are found in nonlymphoid tissues. TLS can develop in inflamed tissues and are associated with chronic inflammatory disorders, autoimmunity, and cancer. In the setting of tumors, TLSs facilitate the influx of immune cells into the tumor site and have therefore attracted interest as a means of improving anticancer immunity and favorable treatment response in patients. Schumacher and Thommen review the biology of TLSs and outline recent advances in TLS research. They discuss how TLSs are detected and defined, the mechanism(s) of formation in cancer, and the potential of targeting TLSs for therapeutic benefit. —PNK
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| [112] |
Tertiary lymphoid structures (TLSs) provide a local and critical microenvironment for generating anti-tumor cellular and humoral immune responses. TLSs are associated with improved clinical outcomes in most solid tumors investigated to date. However, their role in hepatocellular carcinoma (HCC) is debated, as they have recently been shown to promote the growth of malignant hepatocyte progenitors in the non-tumoral liver.We aimed to determine, by pathological review, the prognostic significance of both intra-tumoral and non-tumoral TLSs in a series of 273 patients with HCC treated by surgical resection in Henri Mondor University Hospital. Findings were further validated by gene expression profiling using a public data set (LCI cohort).TLSs were identified in 47% of the tumors, by pathological review, with lymphoid aggregates, primary and secondary follicles in 26%, 16% and 5% of the cases, respectively. Univariate and multivariate analyses showed that intra-tumoral TLSs significantly correlated with a lower risk of early relapse (<2 years after surgery, hazard ratio 0.46, p = 0.005). Interestingly, the risk of recurrence was also related to the degree of TLS maturation (primary or secondary follicles vs. lymphoid aggregates, p = 0.01). A gene expression signature associated with the presence of intra-tumoral TLS was also independently associated with a lower risk of early relapse in the LCI cohort. No association between the density of TLSs located in the adjacent non-tumoral liver and early or late recurrence was observed.We have shown that intra-tumoral TLSs are associated with a lower risk of early relapse in 2 independent cohorts of patients with HCC treated by surgical resection. Thus, intra-tumoral TLSs may reflect the existence of ongoing, effective anti-tumor immunity.Tertiary lymphoid structures provide a critical microenvironment for generating anti-tumor immune responses, and are associated with improved clinical outcome in most cancers investigated. Their role in hepatocellular carcinoma is however debated. We show in the present study that intra-tumoral tertiary lymphoid structures are associated with a low risk of early relapse after surgical resection, suggesting that they reflect the existence of in situ, effective anti-tumor immunity.Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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| [113] |
Tertiary lymphoid structures (TLSs) may promote immune responses to HCC and thereby potentiate PD-1 inhibitor therapy; whether the structures are associated with a better prognosis for patients who receive adjuvant PD-1 inhibitors after curative hepatectomy is unclear.
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| [114] |
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中华医学会传染病与寄生虫病学分会, 中华医学会肝病学分会. 病毒性肝炎防治 方案[J]. 中华传染病杂志, 2001, 19(1):56-62.DOI:10.3760/j.issn:1000-6680.2001.01.027.
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World Health Organization. Guidelines for the prevention, diagnosis, care and treatment for people with chronic hepatitis B infection[EB/OL]. Geneva: World Health Organization, 2024. https://iris.who.int/server/api/core/bitstreams/34470cc8-af90-4d7b-a949-ef27e5d0726f/content.
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| [117] |
Microvascular invasion (MVI) is closely correlated with poor clinical outcomes in patients with hepatocellular carcinoma (HCC). A grading system of MVI is needed to assist in the management of HCC patient.Multicenter data of HCC patients who underwent liver resection with curative intent was analyzed. This grading system was established by detected number and distance from tumor boundary of MVI. Survival outcomes were compared among patients in each group. This system was verified by time-receiver operating characteristic curve, time-area under the curve, calibration curve, and decision curve analyses. Cox regression analysis was performed to study the associated factors of prognosis. Logistic analysis was used to study the predictive factors of MVI.All patients were classified into 4 groups: M0: no MVI; M1: 1~5 proximal MVIs (≤1 cm from tumor boundary); M2a: >5 proximal MVIs (≤1 cm from tumor boundary); M2b: ≥1 distal MVIs (>1 cm from tumor boundary). The recurrence-free survival (RFS), overall survival (OS), and early RFS rates among all the individual groups were significantly different. Based on the number of proximal MVI (0~5 vs >5), patients in the M2b group were further divided into two subgroups which also showed different prognosis. Multiple methods showed this grading system to be significantly better than the MVI two-tiered system in prognostic evaluation. Four multivariate models for RFS, OS, early RFS, late RFS, and a predictive model of MVI were then established and were shown to satisfactorily evaluate prognosis and have a great discriminatory power, respectively.This MVI grading system could precisely evaluate prognosis of HCC patients after liver resection with curative intent and it could be employed in routine pathological reports. The severity of MVI from both adjacent and distant from tumor boundary should be stated. A hypothesis about two occurrence modes of distal MVI was proposed.© 2024 Wang et al.
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| [118] |
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| [119] |
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| [120] |
Albumin, widely recognized as a highly sensitive and specific marker of hepatocellular carcinoma (HCC), is currently unavailable in the diagnostic laboratory because of the lack of a robust platform. In a prior study we detected albumin mRNA in the majority of intrahepatic cholangiocarcinomas using a novel branched chain RNA in situ hybridization (ISH) platform. We now explore the utility of albumin ISH as a marker of hepatocellular differentiation in HCCs, and compare its sensitivity with Hep Par 1 and Arginase-1. We evaluated 93 HCCs and its mimics including neuroendocrine tumors of the gastrointestinal tract (n=31), neuroendocrine tumors of the pancreas (n=163), melanoma (n=15), and gallbladder carcinoma (n=34). We performed ISH for albumin and immunohistochemistry for Hep Par 1 and Arginase-1. Five previously uncharacterized hepatic neoplasms from our files were also evaluated. Immunohistochemistry for Arginase-1 was performed on 59 intrahepatic cholangiocarcinomas. In addition, 43 HCCs evaluated on the manual platform were also examined on the automated instrument. Fifty-five percent of HCCs were moderately differentiated and 39% poorly differentiated. The sensitivity of ISH for albumin was 99%, with 92 of 93 HCCs staining positive for albumin. In contrast to ISH, the sensitivity of immunohistochemistry for Hep Par 1 and Arginase-1 was 84% and 83%, respectively. The sensitivity of albumin for poorly differentiated HCCs was 99%, whereas that for Arginase-1 and Hep Par 1 was 71% and 64%, respectively. Ninety-seven percent of the HCCs showed albumin positivity in >50% of tumor cells using the ISH platform, as compared with 76% and 70% for Hep Par 1 and Arginase-1 immunohistochemistry, respectively. Three of the 5 previously uncharacterized neoplasms were positive for albumin ISH. Automated albumin ISH platform performed equivalently to the manual format, with albumin reactivity in >50% of tumor cells in all 43 cases that were tested on both platforms. All non-HCCs were negative for albumin. All 59 intrahepatic cholangiocarcinomas were negative for Arginase-1. In conclusion, branched chain ISH performed on manual and automated mode is a robust assay for detecting albumin with sensitivity for poorly differentiated HCCs superior to Arginase-1 and Hep Par 1. When interpreted in conjunction with Arginase-1, albumin ISH offers a high level of sensitivity and specificity.
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| [121] |
Pathologic diagnosis of hepatocellular carcinoma (HCC) can be challenging in differentiating from benign and non-hepatocytic malignancy lesions. The aim of this study was to investigate the potential utility of α-fetoprotein (AFP) mRNA RNAscope, a sensitive and specific method, in the diagnosis of HCC.
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| [122] |
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| [123] |
Cholangiolocellular carcinoma (CLC) is a unique subtype of primary liver carcinoma, which sometimes coexists with hepatocellular carcinoma (HCC), cholangiocarcinoma and combined hepatocellular-cholangiocarcinoma (cHCC-CCA). "Ductal plate malformation" (DPM)-pattern of primary liver carcinoma, which resembles biliary lesions in Caroli disease and von Meyenburg complex, is sometimes associated with CLC. We examined genetic alterations of hTERT promoter (hTERT), IDH1 or 2 (IDH1/2), KRAS, ARID1A, PBRM1, ARID2, BAP1, p53 and their association with histologic features such as proportion of CLC and DPM-pattern in 77 patients with primary liver carcinoma diagnosed as cHCC-CCA or CLC. Primary liver carcinomas were histologically subdivided into 29 CLC-predominant (CLC component >80%), 31 with CLC (5% to 80%) and 17 without CLC (<5%). CLC-predominant group was characterized by older age, male-predominant and smaller tumor size. Genetic alterations were detected in hTERT (25%), ARID1A (21%), PBRM1 (20%), ARID2 (3%), BAP1 (1%), p53 (46%), KRAS (5%), and IDH1/2 (8%). ARID1A alteration was more frequent in CLC-predominant group, compared with other groups (P<0.05) and was correlated with the degree of DPM-pattern (P<0.01). Alterations of hTERT and p53 were less frequent in CLC-predominant group compared with "with CLC group" (P<0.05). hTERT mutation was less frequent in carcinomas with DPM-pattern (P<0.01). PBRM1 alteration was more frequent in CLC with focal HCC subgroup and without CLC group compared with other groups (P<0.05). CLC may be a distinct subgroup of primary liver carcinoma, which is different from cHCC-CCA, based on clinicopathologic and genetic alterations. ARID1A alterations may characterize CLC with DPM-pattern and could be a diagnostic immunohistochemical marker for small CLCs with DPM-pattern.
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| [124] |
中国抗癌协会肝癌专业委员会病理学组, 中国抗癌协会肿瘤病理专业委员会肝脏病理学组, 上海市抗癌协会肿瘤病理专业委员会. 肝内胆管癌精准检测专家共识 (2024 版)[J]. 临床肝胆病杂志, 2025, 41(3):432-441.DOI:10.12449/JCH250307.
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| [125] |
Cholangiocarcinoma constitutes a heterogeneous group of malignancies that can emerge at any point of the biliary tree. Cholangiocarcinoma is classified into intrahepatic, perihilar and distal based on its anatomical location. Histologically, conventional perihilar/distal cholangiocarcinomas are mucin‐producing adenocarcinomas or papillary tumours; intrahepatic cholangiocarcinomas are more heterogeneous and can be sub‐classified according to the level or size of the displayed bile duct. Cholangiocarcinoma develops through multistep carcinogenesis and is preceded by dysplastic and in situ lesions. Definition and clinical significance of precursor lesions, including biliary intraepithelial neoplasia, intraductal papillary neoplasms of the bile duct, intraductal tubulopapillary neoplasms and mucinous cystic neoplasm, are discussed in this review. A main challenge in diagnosing cholangiocarcinoma is the fact that tumour tissue for histological examination is difficult to obtain. Thus, a major clinical obstacle is the establishment of the correct diagnosis at a tumour stage that is amenable to surgery which still represents the only curable therapeutic option. Current standards, methodology and criteria for diagnosis are discussed. Cholangiocarcinoma represents a heterogeneous tumour with regard to molecular alterations. In intrahepatic subtype, mainly two distinctive morpho‐molecular groups can currently be discriminated. Large‐duct type intrahepatic cholangiocarcinoma shows a high mutation frequency of oncogenes and tumour suppressor genes, such as KRAS and TP53 while Isocitrate Dehydrogenase 1/2 mutations and Fibroblast Growth Factor Receptor 2‐fusions are typically seen in small‐duct type tumours. It is most important to ensure the separation of the given anatomical subtypes and to search for distinct subgroups within the subtypes on a molecular and morphological basis.
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| [126] |
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| [127] |
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| [128] |
This study aimed to assess the efficacy and safety of camrelizumab plus apatinib in patients with resectable hepatocellular carcinoma (HCC) as neoadjuvant therapy.
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| [129] |
李俊锋, 袁静, 张雯雯, 等. 存活肿瘤细胞比例在初始不可切除肝细胞癌病人转化序贯外科治疗预后评估中的应用[J]. 中华肝胆外科杂志, 2024, 30(4):241-247.DOI:10.3760/cma.j.cn113884-20240226-00056.
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| [130] |
Neoadjuvant use of immune checkpoint inhibitors (ICIs) before liver resection results in pathological tumour regression in patients with hepatocellular carcinoma. We aimed to describe the characteristics of pathological responses after preoperative ICI therapy for hepatocellular carcinoma and to evaluate the association between the depth of tumour regression and relapse-free survival.In this cross-trial, patient-level analysis, we performed a pooled analysis of data from patients with hepatocellular carcinoma receiving ICI therapy before liver resection as part of a global collaborative consortium (NeoHCC) of five phase 1 and 2 clinical trials and standardised observational protocols conducted in 12 tertiary referral centres across the USA, UK, and Taiwan. Eligible patients were adults (aged ≥18 years) diagnosed with hepatocellular carcinoma by tissue core biopsy before treatment initiation, a Liver Imaging Reporting and Data System score of 5 on imaging, or both, with an Eastern Cooperative Oncology Group performance status score of 0-1, and no extrahepatic spread or previous ICI treatment. Pathological response was measured as the percentage of non-viable tumour in the resected surgical specimen, with major pathological response corresponding to at least 70% tumour regression and pathological complete response corresponding to 100% tumour regression. We correlated pathological response with radiological overall response using RECIST criteria (version 1.1) and relapse-free survival, and evaluated the threshold of tumour regression that could be optimally associated with relapse-free survival.At data cutoff on Jan 31, 2024, 111 patients were included in the study, of whom data on pathological response were available for 104 (94%) patients. Patients received treatment from Oct 5, 2017, to Nov 15, 2023, mostly ICI combinations (76 [69%]), for a median of 1·4 months (IQR 0·7-2·9). 87 (78%) patients were men and 24 (22%) were women. Most patients had underlying viral chronic liver disease (73 [66%]) and Barcelona Clinic Liver Cancer stage A hepatocellular carcinoma (61 [55%]), without portal vein thrombosis (87 [78%]). We observed major pathological response in 33 (32%) patients and pathological complete response in 19 (18%) patients. Radiological overall response was associated with major pathological response, with 23 (74%) of 31 patients with radiological response showing major pathological response compared with ten (14%) of 73 patients without radiological response (p<0·0001). However, ten (30%) of 33 major pathological responses were not predicted by radiological response. After a median follow-up of 27·2 months (95% CI 22·3-32·1), median relapse-free survival for the whole cohort was 43·6 months (95% CI 28·3-not evaluable). Relapse-free survival was significantly longer in patients with major pathological response than in those who did not have a major pathological response (not reached [95% CI not evaluable-not evaluable] vs 28·3 months [12·8-43·8]; hazard ratio 0·26 [0·10-0·66]; p=0·0024) and in patients with pathological complete response than in those who did not have a pathological complete response (NR [95% CI not evaluable-not evaluable] vs 32·8 months [15·0-50·5]; 0·19 [0·05-0·78]; p=0·010). Unbiased recursive partitioning of the cohort for the risk of relapse, death, or both identified a threshold of 90% as the optimal cutoff of pathological tumour regression to predict improved relapse-free survival.The extent of tumour regression following neoadjuvant ICI therapy could identify patients with improved relapse-free survival following liver resection. The threshold of at least 90% tumour regression should be validated for its surrogate role for relapse-free survival in phase 3 randomised controlled trials.None.Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.
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| [131] |
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| [132] |
| [133] |
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| [134] |
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| [135] |
(1) Background: Advancements in the field of liver surgery have led to a critical need for precise estimations of preoperative liver function to prevent post-hepatectomy liver failure (PHLF), a significant cause of morbidity and mortality. This study introduces a novel application of artificial intelligence (AI) in determining safe resection volumes according to a patient’s liver function in major hepatectomies. (2) Methods: We incorporated a deep learning approach, incorporating a unique liver-specific loss function, to analyze patient characteristics, laboratory data, and liver volumetry from computed tomography scans of 52 patients. Our approach was evaluated against existing machine and deep learning techniques. (3) Results: Our approach achieved 68.8% accuracy in predicting safe resection volumes, demonstrating superior performance over traditional models. Furthermore, it significantly reduced the mean absolute error in under-predicted volumes to 23.72, indicating a more precise estimation of safe resection limits. These findings highlight the potential of integrating AI into surgical planning for liver resections. (4) Conclusion: By providing more accurate predictions of safe resection volumes, our method aims to minimize the risk of PHLF, thereby improving clinical outcomes for patients undergoing hepatectomy.
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| [136] |
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| [137] |
Portal hypertension is a severe, almost unavoidable complication of chronic liver diseases and is responsible for the main clinical consequences of cirrhosis. Measurement of the hepatic venous pressure gradient (HVPG) is currently the best available method to evaluate the presence and severity of portal hypertension. Clinically significant portal hypertension is defined as an increase in HVPG to >or=10 mmHg; above this threshold, the complications of portal hypertension might begin to appear. Measurement of HVPG is increasingly used in clinical hepatology, and numerous studies have demonstrated that the parameter is a robust surrogate marker for hard clinical end points. The main clinical applications for HVPG include diagnosis, risk stratification, identification of patients with hepatocellular carcinoma who are candidates for liver resection, monitoring of the efficacy of medical treatment, and assessment of progression of portal hypertension. Patients who experience a reduction in HVPG of >or=20% or to <12 mmHg in response to drug therapy are defined as 'responders'. Responders have a markedly decreased risk of bleeding (or rebleeding), ascites, and spontaneous bacterial peritonitis, which results in improved survival.
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| [138] |
Patients with Child-Pugh grade A cirrhosis and clinical evidence of portal hypertension are likely to develop posthepatectomy liver failure (PHLF). Whether such patients are suitable candidates for partial hepatectomy is controversial. This study explored the impact of portal venous pressure (PVP) on PHLF and the possibility of stratifying patients with Child-Pugh grade A cirrhosis for risk of PHLF using clinical data alone.Between April 2009 and May 2011, consecutive patients who underwent partial hepatectomy for hepatocellular carcinoma and intraoperative measurement of PVP were included in this prospective study. Using signs of clinically significant portal hypertension (CSPH), patients with Child-Pugh grade A cirrhosis were subclassified into three groups: no, mild and severe CSPH. Risk factors for PHLF were subjected to univariable and multivariable analysis, and receiver operating characteristic (ROC) curve analysis.Sixty-seven (35·3 per cent) of 190 patients developed PHLF, which was persistent in 12 patients (6·3 per cent). Four patients (2·1 per cent) died from PHLF within 3 months of surgery. Multivariable analysis showed both PVP and CSPH to be independent predictors of PHLF (P < 0·001). PVP values, incidence of PHLF and persistent PHLF were significantly higher in the severe CSPH group than in the other two groups (P < 0·001). Severe CSPH (odds ratio 27·68, P = 0·005) and a preoperative neutrophil : lymphocyte ratio (NLR) of 2·8 or above (odds ratio 49·75, P = 0·002) were independent factors affecting the incidence of persistent PHLF.The severity of CSPH, corresponding to different PVP levels, could be used to stratify patients with Child-Pugh grade A cirrhosis and to predict the incidence of PHLF. Patients with severe CSPH or a NLR of 2·8 or above were more likely to develop persistent PHLF after partial hepatectomy.Copyright © 2012 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.
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| [139] |
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| [140] |
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| [141] |
Post-hepatectomy liver failure (PHLF) is one of the major complications following hepatectomy for hepatocellular carcinoma (HCC). Early identification and precise prediction of PHLF are essential for effective management. This study aimed to evaluate the predictive value of intra-hepatectomy indocyanine green retention rate at 15 min (ICGR15) for the remnant liver for grade B/C PHLF in HCC patients undergoing hemi-hepatectomy.This prospective study recruited 31 HCC patients who underwent hemi-hepatectomy. ICGR15 was measured at three time points: pre-hepatectomy, intra-hepatectomy (for the remnant liver), and post-hepatectomy. The primary endpoint was the occurrence of grade B/C PHLF according to ISGLS criteria. Logistic regression analysis was employed to evaluate the predictive performance of each parameter and to conduct risk assessment. The XGBoost algorithm was utilized to compare the predictive values of various parameters by calculating the mean Shap values.Among the study participants, 25.8% (8 patients) developed grade B/C PHLF. The intra-hepatectomy ICGR15 for remnant liver exhibited the highest predictive accuracy for grade B/C PHLF, with a ROC-AUC of 0.864 and a PR-AUC of 0.791. The optimal threshold for ICGR15-intra was established at 19.8%. Patients with ICGR15-intra value of 19.8% or higher were found at significantly increased risk of grade B/C PHLF (OR[95% CI] = 3.602[1.437-6.750], P value = 0.004), and experienced a higher incidence of severe post-hepatectomy complications.Intra-hepatectomy ICGR15 for the remnant liver was an important predictor of grade B/C PHLF in patients undergoing hemi-hepatectomy for HCC. An intra-hepatectomy ICGR15 threshold of 19.8% might effectively identify patients at high risk of developing grade B/C PHLF and severe post-hepatectomy complications, helping surgeons' final decision-making on the table.© 2025. The Author(s).
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| [142] |
Introduction: The aim of this study was to select qualified patients with hepatocellular carcinoma (HCC) who underwent right hepatectomy (RH) via intraoperative indocyanine green retention test at 15 min (ICG-R15) of the left hemiliver, which prevents severe posthepatectomy liver failure (PHLF).
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| [143] |
中华医学会外科学分会, 中华医学会麻醉学分会. 中国加速康复外科临床实践指南 (2021 版)[J]. 中国实用外科杂志, 2021, 41(9):961-992. DOI:10.19538/j.cjps.issn1005-2208.2021.09.01.
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| [144] |
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| [145] |
<b><i>Introduction:</i></b> It remains unclear which surgery or radiofrequency ablation (RFA) is the more effective treatment for small hepatocellular carcinoma (HCC). We aimed to compare survival between patients undergoing surgery (surgery group) and patients undergoing RFA (RFA group). <b><i>Methods:</i></b> We conducted a randomized controlled trial involving 49 institutions in Japan. Patients with Child-Pugh scores ≤7, largest HCC diameter ≤3 cm, and ≤3 HCC nodules were considered eligible. The co-primary endpoints were recurrence-free survival (RFS) and overall survival (OS). The current study reports the final result of RFS, and the follow-up of OS is still ongoing. <b><i>Results:</i></b> During 2009–2015, 308 patients were registered. After excluding ineligible patients, the surgery and RFA groups included 150 and 151 patients, respectively. Baseline factors did not differ significantly between the groups. In both groups, 90% of patients had solitary HCC. The median largest HCC diameter was 1.8 cm (interquartile range [IQR], 1.5–2.2 cm) in the surgery group and 1.8 cm (IQR, 1.5–2.3 cm) in the RFA group. The median procedure duration (274 vs. 40 min, <i>p</i> < 0.01) and the median duration of hospital stay (17 days vs. 10 days, <i>p</i> < 0.01) were longer in the surgery group than in the RFA group. RFS did not differ significantly between the groups as the median RFS was 3.5 (95% confidence interval [CI], 2.6–5.1) years in the surgery group and 3.0 (95% CI, 2.4–5.6) years in the RFA group (hazard ratio, 0.92; 95% CI, 0.67–1.25; <i>p</i> = 0.58). <b><i>Discussion/Conclusion:</i></b> Our study did not show which surgery or RFA is the better treatment option for small HCC.
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| [146] |
It remains controversial whether surgical resection, compared to radiofrequency ablation (RFA), improves overall survival (OS) in patients with early hepatocellular carcinoma (HCC). This study aimed to compare OS after RFA with that after resection for HCC. This retrospective study included patients who underwent RFA or surgical resection as initial treatment for hepatitis B virus (HBV)-related HCC at a very early or early stage. A total of 761 patients (RFA, n = 194; resection, n = 567) from Seoul National University Hospital (Seoul, South Korea) and 1277 patients (RFA, n = 352; resection, n = 925) from the Korean Primary Liver Cancer Registry were included in the hospital and nationwide cohorts, respectively. Primary and secondary endpoints were OS and recurrence-free survival (RFS), respectively. Additional analysis was performed when the history of the antiviral treatment and the type of prescribed nucleos(t)ide analogue were confirmed. The rate of complications was compared between the two treatment groups in the hospital cohort. Baseline characteristics were balanced, using inverse probability of treatment weighting (IPTW). In the hospital cohort, the RFA group had a smaller mean tumor size (1.7 vs. 3.9 cm) but a higher proportion of cirrhotic patients than the resection group (85.6% vs. 63.1%) (both p < 0.01). During 81.0 (interquartile range, 62.3–107.1) months of follow-up, there was no difference in OS (adjusted hazard ratio (aHR) = 0.870, 95% confidence interval (CI) = 0.400–1.897, p = 0.73) and RFA was associated with shorter RFS (aHR = 1.562, 95% CI = 1.099–2.219, p = 0.01) after employing IPTW. Antiviral treatment was independently associated with longer OS (aHR = 0.444, 95% CI = 0.251–0.786, p = 0.01) as well as RFS (aHR = 0.544, 95% CI = 0.391–0.757, p < 0.01) in the hospital cohort. In the nationwide cohort, there was no difference in OS (aHR = 0.981, 95% CI = 0.661–1.456, p = 0.92) between the two treatment groups when adjusted for antiviral treatment, which was a negative independent risk factor for mortality (aHR = 0.655, 95% CI = 0.451–0.952, p = 0.03) after IPTW. Among patients treated with tenofovir (n = 96) or entecavir (n = 184) in the hospital cohort, there was no difference in either OS (aHR = 0.522, 95% CI = 0.058–4.724, p = 0.56) or RFS (aHR = 1.116, 95% CI = 0.738–1.688, p = 0.60). The overall incidence of complications was higher in the resection group (26.3%) than in the RFA group (13.9%) (p < 0.01). RFA may provide comparable OS to resection in the treatment of very early or early HCC with a lower rate of complications, although RFS is marginally shorter than in the resection group after adjusting for antiviral treatment. Regardless of the type of NA, antiviral treatment in patients with HBV-related HCC is strongly associated with both OS and RFS.
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| [147] |
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| [148] |
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| [149] |
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| [150] |
The aim of this study was to compare the efficacy of radiofrequency ablation (RFA) with surgical resection (RES) in the treatment of small hepatocellular carcinoma (HCC).A total of 168 patients with small HCC with nodular diameters of less than 4 cm and up to two nodules were randomly divided into RES (n=84) and RFA groups (n=84). Outcomes were carefully monitored and evaluated during the 3-year follow-up period.The 1-, 2-, and 3-year survival rates for the RES and RFA groups were 96.0%, 87.6%, 74.8% and 93.1%, 83.1%, 67.2%, respectively. The corresponding recurrence-free survival rates for the two groups were 90.6%, 76.7%, 61.1% and 86.2%, 66.6%, 49.6%, respectively. There were no statistically significant differences between the two groups in overall survival rate (p=0.342) or recurrence-free survival rate (p=0.122). Multivariate analysis demonstrated that the independent risk factors associated with survival were multiple occurrences of tumors at different hepatic locations (relative risk of 2.696; 95% CI: 1.189-6.117; p=0.018) and preoperative indocyanine green retention rate at 15 min (ICG-15) (relative risk of 3.853; 95% CI: 1.647-9.015; p=0.002).In patients with small hepatocellular carcinomas, percutaneous RFA may provide therapeutic effects similar to those of RES. However, percutaneous RFA is more likely to be incomplete for the treatment of small HCCs located at specific sites of the liver, and open or laparoscopic surgery may be the better choice.Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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| [151] |
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| [152] |
Repeat hepatectomy and percutaneous radiofrequency ablation (PRFA) are most commonly used to treat early-stage recurrent hepatocellular carcinoma (RHCC) after initial resection, but previous studies comparing the effectiveness of the 2 treatments have reported conflicting results.To compare the long-term survival outcomes after repeat hepatectomy with those after PRFA among patients with early-stage RHCC.This open-label randomized clinical trial was conducted at the Eastern Hepatobiliary Surgery Hospital and the National Center for Liver Cancer of China. A total of 240 patients with RHCC (with a solitary nodule diameter of ≤5 cm; 3 or fewer nodules, each ≤3 cm in diameter; and no macroscopic vascular invasion or distant metastasis) were randomized 1:1 to receive repeat hepatectomy or PRFA between June 3, 2010, and January 15, 2013. The median (range) follow-up time was 44.3 (4.3-90.6) months (last follow-up, January 15, 2018). Data analysis was conducted from June 15, 2018, to September 28, 2018.Repeat hepatectomy (n = 120) or PRFA (n = 120).The primary outcome was overall survival (OS). Secondary outcomes included repeat recurrence-free survival (rRFS), patterns of repeat recurrence, and therapeutic safety.Among the 240 randomized patients (216 men [90.0%]; median [range] age, 53.0 [24.0-59.0] years), 217 completed the trial. In the intention-to-treat (ITT) population, the 1-year, 3-year, and 5-year OS rates were 92.5% (95% CI, 87.9%-97.3%), 65.8% (95% CI, 57.8%-74.8%), and 43.6% (95% CI, 35.5%-53.5%), respectively, for the repeat hepatectomy group and 87.5% (95% CI, 81.8%-93.6%), 52.5% (95% CI, 44.2%-62.2%), and 38.5% (95% CI, 30.6%-48.4%), respectively, for the PRFA group (P = .17). The corresponding 1-year, 3-year, and 5-year rRFS rates were 85.0% (95% CI, 78.8%-91.6%), 52.4% (95% CI, 44.2%-62.2%), and 36.2% (95% CI, 28.5%-46.0%), respectively, for the repeat hepatectomy group and 74.2% (95% CI, 66.7%-82.4%), 41.7% (95% CI, 33.7%-51.5%), and 30.2% (95% CI, 22.9%-39.8%), respectively, for the PRFA group (P = .09). Percutaneous radiofrequency ablation was associated with a higher incidence of local repeat recurrence (37.8% vs 21.7%, P = .04) and early repeat recurrence than repeat hepatectomy (40.3% vs 23.3%, P = .04). In subgroup analyses, PRFA was associated with worse OS vs repeat hepatectomy among patients with an RHCC nodule diameter greater than 3 cm (hazard ratio, 1.72; 95% CI, 1.05-2.84) or an α fetoprotein level greater than 200 ng/mL (hazard ratio, 1.85; 95% CI, 1.15-2.96). Surgery had a higher complication rate than did ablation (22.4% vs 7.3%, P = .001).No statistically significant difference was observed in survival outcomes after repeat hepatectomy vs PRFA for patients with early-stage RHCC. Repeat hepatectomy may be associated with better local disease control and long-term survival in patients with an RHCC diameter greater than 3 cm or an AFP level greater than 200 ng/mL.ClinicalTrials.gov identifier: NCT00822562.
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| [153] |
The aim of the study was to evaluate the survival benefits of liver resection (LR) compared with transarterial chemoembolization (TACE) for patients with multiple hepatocellular carcinomas (HCCs).Despite significant improvements in diagnostic imaging and the widespread application of screening programs, some patients with HCC continue to present with multiple tumors. The surgical indications for multiple HCCs remain controversial.Among 77,268 patients with HCC reported in a Japanese nationwide survey, 27,164 patients had multiple HCCs. The exclusion criteria were Child-Pugh B/C, treatment other than LR and TACE, >3 tumors, and insufficient available data. Ultimately, 3246 patients (LR: n = 1944, TACE: n = 1302) were included. The survival benefit of LR for patients multiple HCCs was evaluated by using propensity score matching analysis.The study group of 2178 patients (LR: n = 1089, TACE: n = 1089) seemed to be well matched. The overall survival rate in the LR group was 60.0% at 5 years, which was higher than that in the TACE group (41.6%, P < 0.001). Among patients with a tumor size of 30 mm or more, LR showed a survival benefit over TACE at 5 years (53.0% vs 32.7%, P < 0.001). The multivariate analysis indicated that age, serum albumin level, serum alpha-fetoprotein (AFP) level, macrovascular invasion, tumor size, and TACE were independent predictors of poor prognosis in multiple HCCs.LR could offer better long-term survival than TACE for patients with multiple HCCs (up to 3 tumors). If patients have good liver function (Child-Pugh A), LR is recommended, even for those with multiple HCCs with tumor sizes of 30 mm or more.
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| [154] |
The 2022 Barcelona Clinic Liver Cancer algorithm currently discourages liver resection (LR) for patients with multinodular hepatocellular carcinoma (HCC) presenting with 2 or 3 nodules that are each 3 cm or smaller.To compare the efficacy of liver resection (LR), percutaneous radiofrequency ablation (PRFA), and transarterial chemoembolization (TACE) in patients with multinodular HCC.This cohort study is a retrospective analysis conducted using data from the HE.RC.O.LE.S register (n = 5331) for LR patients and the ITA.LI.CA database (n = 7056) for PRFA and TACE patients. A matching-adjusted indirect comparison (MAIC) method was applied to balance data and potential confounding factors between the 3 groups. Included were patients from multiple centers from 2008 to 2020; data were analyzed from January to December 2023.LR, PRFA, or TACE.Survival rates at 1, 3, and 5 years were calculated. Cox MAIC-weighted multivariable analysis and competing risk analysis were used to assess outcomes.A total of 720 patients with early multinodular HCC were included, 543 males (75.4%), 177 females (24.6%), and 350 individuals older than 70 years (48.6%). There were 296 patients in the LR group, 240 who underwent PRFA, and 184 who underwent TACE. After MAIC, LR exhibited 1-, 3-, and 5-year survival rates of 89.11%, 70.98%, and 56.44%, respectively. PRFA showed rates of 94.01%, 65.20%, and 39.93%, while TACE displayed rates of 90.88%, 48.95%, and 29.24%. Multivariable Cox survival analysis in the weighted population showed a survival benefit over alternative treatments (PRFA vs LR: hazard ratio [HR], 1.41; 95% CI, 1.07-1.86; P = .01; TACE vs LR: HR, 1.86; 95% CI, 1.29-2.68; P = .001). Competing risk analysis confirmed a lower risk of cancer-related death in LR compared with PRFA and TACE.For patients with early multinodular HCC who are ineligible for transplant, LR should be prioritized as the primary therapeutic option, followed by PRFA and TACE when LR is not feasible. These findings provide valuable insights for clinical decision-making in this patient population.
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| [155] |
The aim of this randomized comparative trial (RCT) is to compare partial hepatectomy (PH) with transcatheter arterial chemoembolization (TACE) to treat patients with resectable multiple hepatocellular carcinoma (RMHCC) outside of Milan Criteria.This RCT was conducted on 173 patients with RMHCC outside of Milan Criteria (a solitary tumor up to 5 cm or multiple tumors up to 3 in number and up to 3 cm for each tumor) who were treated in our centre from November 2008 to September 2010. The patients were randomly assigned to the PH group or the TACE group. The primary outcome measure was overall survival (OS) from the date of treatment. A multivariate Cox proportional hazards regression analysis was performed to assess the prognostic risk factors associated with OS.The 1-, 2-, and 3-year OS rates were 76.1%, 63.5%, and 51.5%, respectively, for the PH group compared with 51.8%, 34.8%, and 18.1%, respectively, for the TACE group (Log-rank test, χ(2)=24.246, p<0.001). Multivariate Cox proportional hazards regression analysis revealed the type of treatment (hazard ratio, 0.434; 95% CI, 0.293 to 0.644, p<0.001), number of tumor (hazard ratio, 1.758; 95% CI, 1.213 to 2.548, p=0.003) and gender (hazard ratio, 0.451; 95% CI, 0.236 to 0.862, p=0.016) were significant independent risk factors associated with OS.PH provided better OS for patients with RMHCC outside of Milan Criteria than conventional TACE. The number of tumor and gender were also independent risk factors associated with OS for RMHCC.Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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| [156] |
The aim of this study was to investigate in a retrospective setting the patients' profile and results of those undergoing surgery for hepatocellular carcinoma (HCC) in high-volume surgical centers throughout the world.Whether surgery for HCC is a suitable approach and for which subset of patients is still controversial. The EASL/AASLD (European Association for the Study of Liver Disease/American Association for the Study of Liver Disease) guidelines, based on the Barcelona Clinic Liver Cancer (BCLC) classification, leave little room for hepatic resection; inversely, other reports promote its wider application.On the basis of the network "Hepatocellular Carcinoma: Eastern & Western Experiences," data for 2046 consecutive patients resected for HCC in 10 centers were collected. According to the BCLC classification, 1012 (50%) were BCLC 0-A, 737 (36%) BCLC B, and 297 (14%) BCLC C. Analysis of overall survival and disease-free survival and multivariate analysis of prognostic factors were performed.The 90-day mortality rate was 2.7%. Overall morbidity was 42%. After a median follow-up of 25 months (range, 1-209 months), the 1-, 3-, and 5-year overall survival rates were 95%, 80%, and 61% for BCLC 0-A; 88%, 71%, and 57% for BCLC B; and 76%, 49%, and 38% for BCLC C (P = 0.000). The 1-, 3-, and 5-year disease-free survival rates were as follows: 77%, 41%, and 21% for BCLC 0-A; 63%, 38%, and 27% for BCLC B; and 46%, 28%, and 18% for BCLC C (P = 0.000). The multivariate analysis identified bilirubin, cirrhosis, esophageal varices, tumor size, and macrovascular invasion to be statistical and independent prognostic factors for overall survival.This large multicentric survey shows that surgery is in current practice widely applied among patients with multinodular, large, and macrovascular invasive HCC, providing acceptable short- and long-term results and justifying an update of the EASL/AASLD therapeutic guidelines in this sense.
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| [157] |
According to the American Association for the Study of Liver Diseases (AASLD) treatment guidelines for hepatocellular carcinoma (HCC), the role of surgery has been expanded beyond the Barcelona Clinic Liver Cancer (BCLC) algorithm. We compared primary hepatectomy (PH) with transarterial chemoembolization (TACE) in patients with intermediate- to advanced-stage (BCLC stage B/C) HCC to determine the current evidence. Through a database search, we included 18 high-quality studies (one randomized controlled trial [RCT], five propensity-score matching nonrandomized comparative trials [NRCTs], and 12 NRCTs) that compared survival outcomes of 5,986 patients after PH and TACE. We found significant survival benefits for PH over TACE in BCLC stage B/C patients (hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.51-0.67; P < 0.00001; I = 84%). According to the BCLC, both stage B and stage C patients showed significantly better overall survival (OS) for PH compared to TACE (HR, 0.53; 95% CI, 0.43-0.65; P < 0.00001; I = 77%; HR, 0.67; 95% CI, 0.59-0.77; P < 0.00001; I = 79%, respectively). Five-year survival rates for PH were significantly higher than those for TACE in BCLC stage B/C, stage B, and BCLC stage C patients (odds ratio [OR], 2.71, 2.77, and 3.03, respectively; all P < 0.00001). Survival benefits persisted across subgroup, sensitivity, and metaregression analyses; interstudy heterogeneity remained constant.This meta-analysis suggests that surgical resection provides survival benefits in patients with intermediate- to advanced-stage HCC. The evidence found herein may assist in the choice of treatment modality based on diverse definitions of operability. (Hepatology 2018).© 2018 by the American Association for the Study of Liver Diseases.
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| [158] |
The objective of the current study was to define surgical outcomes after resection of multinodular hepatocellular carcinoma (HCC) beyond the Milan criteria, and develop a prediction tool to identify which patients likely benefit the most from resection.Liver resection for multinodular HCC, especially beyond the Milan criteria, remains controversial. Rigorous selection of the best candidates for resection is essential to achieve optimal outcomes after liver resection of advanced tumors.Patients who underwent resection for HCC between 2000 and 2017 were identified from an international multi-institutional database. Patients were categorized according to Milan criteria status. Pre- and postoperative overall survival (OS) prediction models that included HCC tumor burden score (TBS) among patients with multinodular HCC beyond Milan criteria were developed and validated.Among 1037 patients who underwent resection for HCC, 164 (15.8%) had multinodular HCC beyond the Milan criteria. Among patients with multinodular HCC, 25 (15.2%) patients experienced a serious complication and 90-day mortality was 3.7% (n = 6). Five-year OS after resection of multinodular HCC beyond Milan criteria was 52.8%. A preoperative TBS-based model (5-year OS: low-risk, 73.7% vs intermediate-risk, 45.1% vs high-risk, 13.1%), and postoperative TBS-based model (5-year OS: low-risk, 80.1% vs intermediate-risk, 37.2% vs high-risk, not reached) categorized patients into distinct prognostic groups relative to long-term prognosis (both P < 0.001). Pre- and postoperative models could accurately stratify OS in an external validation cohort (5-year OS; low vs medium vs high risk; pre: 66.3% vs 25.2% vs not reached, P = 0.012; post: 61.4% vs 42.5% vs not reached, P = 0.045) Predictive accuracy of the pre- and postoperative models was good in the training (c-index; pre: 0.68; post: 0.71), internal validation (n = 2000 resamples) (c-index, pre: 0.70; post: 0.72) and external validation (c-index, pre: 0.67; post 0.68) datasets. TBS alone could stratify patients relative to 5-year OS after resection of multinodular HCC beyond Milan criteria (c-index: 0.65; 5-year OS; low TBS: 70.2% vs medium TBS: 54.7% vs high TBS: 16.7%; P < 0.001). The vast majority of patients with low and intermediate TBS were deemed low or medium risk based on both the preoperative (98.4%) and postoperative risk scores (95.3%).Prognosis of patients with multinodular HCC was largely dependent on overall tumor burden. Liver resection should be considered among patients with multinodular HCC beyond the Milan criteria who have a low- or intermediate-TBS.
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| [159] |
The aim of the study was to compare SURG vs SOR regarding the OS and progression-free survival (PFS) in a real-world clinical scenario.The treatment for advanced nonmetastatic HCC belonging to the Barcelona Clinic Liver Cancer stage C (BCLC C) is still controversial.BCLC C patients without extrahepatic spread and tumoral invasion of the main portal trunk were considered. Surgical patients were obtained from the HE.RC.O.LE.S. Register, whereas sorafenib patients were obtained from the ITA.LI.CA register The inverse probability weighting (IPW) method was adopted to balance the confounders between the 2 groups.Between 2008 and 2019, 478 patients were enrolled: 303 in SURG and 175 in SOR group. Eastern Cooperative Oncological Group Performance Status (ECOG-PS), presence of cirrhosis, steatosis, Child-Pugh grade, hepatitis B virus and hepatitis C virus, alcohol intake, collateral veins, bilobar disease, localization of the tumor thrombus, number of nodules, alpha-fetoprotein, age, and Charlson Comorbidity index were weighted by IPW to create two balanced pseudo-populations: SURG = 374 and SOR = 263. After IPW, 1-3-5 years OS was 83.6%, 68.1%, 55.9% for SURG, and 42.3%, 17.8%, 12.8% for SOR (P < 0.001). Similar trends were observed after subgrouping patients by ECOG-PS = 0 and ECOG-PS >0, and by the intrahepatic location of portal vein invasion. At Cox regression, sorafenib treatment (hazard ratio 4.436; 95% confidence interval 3.19-6.15; P < 0.001) and Charlson Index (hazard ratio 1.162; 95% confidence interval 1.06-1.27; P = 0.010) were the only independent predictors of mortality. PFS at 1-3-5 years were 65.9%, 40.3%, 24.3% for SURG and 21.6%, 3.5%, 2.9% for SOR (P = 0.007).In BCLC C patients without extrahepatic spread but with intrahepatic portal invasion, liver resection, if feasible, was followed by better OS and PFS compared with sorafenib.Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.
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| [160] |
The presence of portal vein tumor thrombosis (PVTT) in patients with hepatocellular carcinoma (HCC) is regarded as indicating an advanced stage, and liver resection (LR) is not recommended. The aim of this study was to evaluate the survival benefit of LR for HCC patients with PVTT through the analysis of the data from a Japanese nationwide survey.We analyzed data for 6474 HCC patients with PVTT registered between 2000 and 2007. Of these patients, 2093 patients who underwent LR and 4381 patients who received other treatments were compared. The propensity scores were calculated and we successfully matched 1058 patients (66.1% of the LR group).In the Child-Pugh A patients, the median survival time (MST) in the LR group was 1.77years longer than that in the non-LR group (2.87years vs. 1.10years; p<0.001) and 0.88years longer than that in the non-LR group (2.45years vs. 1.57years; p<0.001) in a propensity score-matched cohort. A subgroup analysis revealed that LR provides a survival benefit regardless of age, etiology of HCC, tumor marker elevation, and tumor number. The survival benefit was not statistically significant only in patients with PVTT invading the main trunk or contralateral branch. In the LR group, the postoperative 90-day mortality rate was 3.7% (68 patients).As long as the PVTT is limited to the first-order branch, LR is associated with a longer survival outcome than non-surgical treatment.The presence of portal vein tumor thrombosis in patients with hepatocellular carcinoma is regarded as indicating an advanced stage, and liver resection is not recommended. We performed a multicenter, nationwide study to assess the survival benefit of liver resection in hepatocellular carcinoma patients with portal vein tumor thrombosis using propensity score-based matching. As long as the portal vein tumor thrombosis is limited to the first-order branch, liver resection is associated with a longer survival outcome than non-surgical treatment.Copyright © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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| [161] |
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| [162] |
Small studies from outside of the USA suggest excellent outcomes after surgical resection for hepatocellular carcinoma (HCC) with vascular invasion. The study aims to (1) compare overall survival after surgical resection and systemic therapy among patients with HCC and vascular invasion and (2) determine factors associated with receipt of surgical resection in a US population.HCC patients with AJCC clinical TNM stage 7th T3BN0M0 diagnosed between 2010 and 2017 from the National Cancer Database were analyzed. Cox and logistic regression analyses identified factors associated with overall survival and receipt of surgical resection.Of 11,259 patients with T3BN0M0 HCC, 325 (2.9%) and 4,268 (37.9%) received surgical resection and systemic therapy, respectively. In multivariable analysis, surgical resection was associated with improved survival compared to systemic therapy (adjusted hazard ratio: 0.496, 95% confidence interval: 0.426-0.578) with a median survival of 21.4 and 8.1 months, respectively. Superiority of surgical resection was observed in noncirrhotic and cirrhotic subgroups and propensity score matching and inverse probability of treatment weighting adjusted analysis. Asians were more likely to receive surgical resection, whereas Charlson comorbidity ≥3, elevated alpha-fetoprotein, smaller tumor size, care in a community cancer program, and the South or West region were associated with a lower likelihood of surgical resection.HCC patients with vascular invasion may benefit from surgical resection compared to systemic therapies. Demographic and clinical features of HCC patients and region and type of treating facility were associated with surgical resection versus systemic treatment.Copyright © 2021 by S. Karger AG, Basel.
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| [163] |
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| [164] |
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| [165] |
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| [166] |
To compare the survival outcomes of neoadjuvant three-dimensional conformal radiotherapy (RT) followed by hepatectomy with hepatectomy alone in patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT).A randomized, multicenter controlled study was conducted from January 2016 to December 2017 in patients with resectable HCC and PVTT. Patients were randomly assigned to receive neoadjuvant RT followed by hepatectomy (n = 82) or hepatectomy alone (n = 82). The modified Response Evaluation Criteria in Solid Tumors (mRECIST) guidelines were used to evaluate the therapeutic effects of RT. The primary end point was overall survival. The expression of interleukin-6 (IL-6) in patients' serum before RT and in surgical specimens was correlated with response to RT.In the neoadjuvant RT group, 17 patients (20.7%) had partial remission. The overall survival rates for the neoadjuvant RT group at 6, 12, 18, and 24 months were 89.0%, 75.2%, 43.9%, and 27.4%, respectively, compared with 81.7%, 43.1%, 16.7%, and 9.4% in the surgery-alone group (<.001). The corresponding disease-free survival rates were 56.9%, 33.0%, 20.3%, and 13.3% versus 42.1%, 14.9%, 5.0%, and 3.3% (<.001). On multivariable Cox regression analyses, neoadjuvant RT significantly reduced HCC-related mortality and HCC recurrence rates compared with surgery alone (hazard ratios, 0.35 [95% CI, 0.23 to 0.54; <.001] and 0.45 [95% CI, 0.31 to 0.64; <.001]). Increased expressions of IL-6 in pre-RT serum and tumor tissues were significantly associated with resistance to RT.For patients with resectable HCC and PVTT, neoadjuvant RT provided significantly better postoperative survival outcomes than surgery alone. IL-6 may predict response to RT in these patients.
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| [167] |
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| [168] |
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| [169] |
The aim of this study was to assess the accuracy of actual resected liver volume (ARLV) in anatomical liver resections (ALRs) guided by 3-dimensional parenchymal staining using fusion indocyanine green fluorescence imaging (IGFI).Patients eligible for hepatic resection were enrolled in the current study from January 2016 to November 2017. All patients underwent surgery planning based on Medical Image Three-Dimensional Visualization System (MI-3DVS) before the operation, in which predicted resected liver volumes (PRLVs) were calculated. Under 3-dimensional guidance by fusion IGFI, ALRs were performed and ARLVs were measured. Simple linear regression, intra-class correlation coefficient (ICC) and Bland-Altman analysis were used to evaluate the relationship and agreement between PRLV and ARLV.Of the 27 patients who achieved valid demarcation by fusion IGFI, 12 (44.4%) received hemihepatectomy, while 10 (37.0%) and five (18.5%) underwent sectionectomy and segmentectomy, respectively. The relationship and agreement between PRLV (481.37 ± 189.47 cm³) and ARLV (450.57 ± 205.19 cm³) were then evaluated. The simple regression equation obtained was PRLV = 0.874 × ARLV + 87.75 (R = 0.946; P = 0.000). Meanwhile, ARLV (ICC = 0.943) achieved an excellent agreement with PRLV (P < 0.001); 25 of 27 dots were in the range of 95% confidence interval in Bland-Altman analysis.In the study, these findings validated the consistency between PRLV calculated by MI-3DVS and ARLV guided by fusion IGFI, which proved that IGFI can accurately guide anatomical hepatectomy. Generally, fusion IGFI can provide a valid, feasible and accurate demarcation line, which can confer precision to hepatic resection.© 2018 Wiley Periodicals, Inc.
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| [170] |
To assess how virtual hepatectomy (VH), conducted using surgical planning software, influences the outcomes of liver surgery.
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| [171] |
中华医学会数字医学分会, 中国研究型医院学会数字智能化专业委员会, 中国医师协会肝癌专业委员会, 等. 计算机辅助联合吲哚菁绿分子荧光影像技术在肝脏肿瘤诊断和手术导航中的应用指南(2019 版)[J]. 中国实用外科杂志, 2019, 39(7):641-650+654.DOI:10.19538/j.cjps.issn1005-2208.2019.07.01.
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| [172] |
Three-dimensional reconstruction visualization technology (3D-RVT) is an important tool in the preoperative assessment of patients undergoing liver resection. However, it is not clear whether this technique can improve short-term and long-term outcomes in patients with hepatocellular carcinoma (HCC) compared with two-dimensional (2D) imaging.
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| [173] |
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| [174] |
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| [175] |
To validate the newly developed artificial intelligence (AI)-assisted simulation by evaluating the speed of three-dimensional (3D) reconstruction and accuracy of segmental volumetry among patients with liver tumors.AI with a deep learning algorithm based on healthy liver computer tomography images has been developed to assist three-dimensional liver reconstruction in virtual hepatectomy.3D reconstruction using hepatic computed tomography scans of 144 patients with liver tumors was performed using two different versions of Synapse 3D (Fujifilm, Tokyo, Japan): the manual method based on the tracking algorithm and the AI-assisted method. Processing time to 3D reconstruction and volumetry of whole liver, tumor-containing and tumor-free segments were compared.The median total liver volume and the volume ratio of a tumor-containing and a tumor-free segment were calculated as 1035 mL, 9.4%, and 9.8% by the AI-assisted reconstruction, whereas 1120 mL, 9.9%, and 9.3% by the manual reconstruction method. The mean absolute deviations were 16.7 mL and 1.0% in the tumor-containing segment and 15.5 mL and 1.0% in the tumor-free segment. The processing time was shorter in the AI-assisted (2.1 vs. 35.0 min; p < 0.001).The virtual hepatectomy, including functional liver volumetric analysis, using the 3D liver models reconstructed by the AI-assisted methods, was reliable for the practical planning of liver tumor resections.© 2022. The Society for Surgery of the Alimentary Tract.
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| [176] |
Liver surgery is the standard of care for primary and many secondary liver tumors. Due to variability and complexity in liver anatomy preoperative imaging is necessary to determine resectability and for planning the surgical strategy. In the last few years, computer-assisted resection planning has been introduced in liver surgery. Aim of this trial was the evaluation of computer-assisted three-dimensional (3D)-navigation for liver surgery.This study was a prospective randomized-controlled pilot trial and patients were randomized in navigated or non-navigated group. Primary end point was the quotient of intraoperative resected volume and planned resection volume. Secondary end points included operation time, resection margin and postoperative complications. 3D reconstructions were performed with MeVis Distant Services (MeVis AG, Bremen, Germany). The navigation system CAS-One Liver (CAScination AG, Bern, Switzerland) was used for intraoperative computer-assisted 3D-navigation.The data of 16 patients with 20 liver tumors were used in this analysis. Of these, 8 liver tumors were resected with the utilization of intraoperative navigation. Two postoperative complications were classified grade IIIa or higher. There was no difference in duration of operation (189 180 min, P=0.970), rate of postoperative complications (n=1 n=1, P=0.696) and length of hospital stay (9 7 days, P=0.368) between the two groups. Minimal resection margin (0.15 0.40 cm, P=0.384) and quotient of planned to intraoperative resection volume (0.94 1.11, P=0.305) were also similar.Intraoperative navigation is a technology that can be safely used during liver resection. Surgical accuracy is not yet superior to the current standard of intraoperative orientation. Further technological advances with suitable deformation algorithms and augmented reality systems will enable a further improvement of the technical feasibility.2023 Annals of Translational Medicine. All rights reserved.
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| [177] |
The aim of this review was to summarize major topics in artificial intelligence (AI), including their applications and limitations in surgery. This paper reviews the key capabilities of AI to help surgeons understand and critically evaluate new AI applications and to contribute to new developments.AI is composed of various subfields that each provide potential solutions to clinical problems. Each of the core subfields of AI reviewed in this piece has also been used in other industries such as the autonomous car, social networks, and deep learning computers.A review of AI papers across computer science, statistics, and medical sources was conducted to identify key concepts and techniques within AI that are driving innovation across industries, including surgery. Limitations and challenges of working with AI were also reviewed.Four main subfields of AI were defined: (1) machine learning, (2) artificial neural networks, (3) natural language processing, and (4) computer vision. Their current and future applications to surgical practice were introduced, including big data analytics and clinical decision support systems. The implications of AI for surgeons and the role of surgeons in advancing the technology to optimize clinical effectiveness were discussed.Surgeons are well positioned to help integrate AI into modern practice. Surgeons should partner with data scientists to capture data across phases of care and to provide clinical context, for AI has the potential to revolutionize the way surgery is taught and practiced with the promise of a future optimized for the highest quality patient care.
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| [178] |
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| [179] |
中国研究型医院学会肝胆胰外科专业委员会. 腹腔镜肝切除术治疗肝细胞癌中国专家共识 (2020 版)[J]. 中华消化外科杂志, 2020, 19(11):1119-1134.DOI:10.3760/cma.j.cn115610-20201029-00682.
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| [180] |
To compare the short- and long-term outcomes of robot-assisted (RALR), laparoscopic (LLR), or open liver resection (OLR) in the treatment of Barcelona Clinic Liver Cancer (BCLC) stage 0-A hepatocellular carcinoma (HCC).
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| [181] |
Background: Robotic hepatectomy represents an appealing treatment modality for resectable hepatocellular carcinoma (HCC). A contemporary review of robotic hepatectomy compared to laparoscopic/open hepatectomy is necessary. Methods: We performed a literature review to identify studies between 2018–2024 comparing robotic to laparoscopic/open hepatectomy for HCC with measurable outcomes. Results: A total of 10 studies were identified, including 943 patients undergoing robotic hepatectomy compared to 1678 patients undergoing laparoscopic/open hepatectomy. Generally, while similar short/long-term survival was noted across all resection modalities, robotic hepatectomy was associated with longer operative time, shorter length of stay, and less post-operative complications. An additional 4 studies were evaluated in the context of HCC, reviewing the prognostic value of robotic hepatectomy margins, robotic hepatectomy in the context of metabolic syndrome, “huge” (>10 cm) HCCs, and robotic hepatectomy vs. microwave ablation. Conclusions: Robotic hepatectomy is a safe alternative to laparoscopic/open hepatectomy for HCC that provides similar oncological/long-term outcomes, while potentially decreasing post-operative complications and length of stay.
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| [182] |
The robotic liver resection (RLR) has been increasingly applied in recent years and its benefits shown in some aspects owing to the technical advancement of robotic surgical system, however, controversies still exist. Based on the foundation of the previous consensus statement, this new consensus document aimed to update clinical recommendations and provide guidance to improve the outcomes of RLR clinical practice. The guideline steering group and guideline expert group were formed by 29 international experts of liver surgery and evidence-based medicine (EBM). Relevant literature was reviewed and analyzed by the evidence evaluation group. According to the WHO Handbook for Guideline Development, the Guidance Principles of Development and Amendment of the Guidelines for Clinical Diagnosis and Treatment in China 2022, a total of 14 recommendations were generated. Among them were 8 recommendations formulated by the GRADE method, and the remaining 6 recommendations were formulated based on literature review and experts’ opinion due to insufficient EBM results. This international experts consensus guideline offered guidance for the safe and effective clinical practice and the research direction of RLR in future.
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| [183] |
夏永祥, 张峰, 李相成, 等. 原发性肝癌 10 966 例外科治疗分析[J]. 中华外科杂志, 2021, 59(1):6-17. DOI:10.3760/cma.j.cn112139-20201110-00791.
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| [184] |
The incidence of hepatocellular carcinoma (HCC) is increasing in the western world over the past decades. As liver resection (LR) represents one of the most efficient treatment options, advantages of anatomic (ALR) versus non‐anatomic liver resection (NALR) show a lack of consistent evidence. Therefore, the aim of this study was to investigate complications and survival rates after both resection types.
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| [185] |
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| [186] |
To compare the efficacy and safety of partial hepatectomy aiming grossly at a narrow (1 cm) and a wide (2 cm) resection margin in patients with macroscopically solitary hepatocellular carcinoma (HCC).For HCC treated with partial hepatectomy, the extent of the margin of liver resection remains controversial despite extensive studies.We conducted a prospective randomized trial in patients with solitary HCC. From January 1999 to February 2003, 169 patients with solitary HCC were stratified according to tumor size and randomized to undergo partial hepatectomy aiming grossly at either a narrow (1 cm) (n = 84) or a wide resection margin (2 cm) (n = 85). Analyses were done on an intention-to-treat basis.The demographic and pathologic data were similar in the 2 groups. The mean +/- SD for the final resection margin of the narrow and the wide margin groups were 0.7 +/- 0.4 cm and 1.9 +/- 0.6 cm, respectively. There was no significant difference in the morbidity and in-hospital mortality between the 2 groups of patients. The 1-, 2-, 3-, and 5-year overall survival rates for the narrow and the wide margin groups were 92.9%, 83.3%, 70.9%, and 49.1% and 96.5%, 91.8%, 86.9%, and 74.9%, respectively. The difference was significant (stratified log-rank test, P = 0.008). Multivariate analysis identified the presence of micrometastases and the treatment allocation were independent risk factors for tumor-related death. At the time of censor, 75 (44.4%) patients had developed tumor recurrence. All recurrences at the margins of liver resection were observed in the narrow margin group. Multiple tumor recurrence was also significantly higher in the narrow margin group (chi test, P = 0.018). Survival after tumor recurrence was significantly better in the wide margin group than the narrow margin group (log-rank test, P = 0.017).For macroscopically solitary HCC, a resection margin aiming grossly at 2 cm efficaciously and safely decreased postoperative recurrence rate and improved survival outcomes when compared with a gross resection margin aiming at 1 cm, especially for HCC < or =2 cm.
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| [187] |
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| [188] |
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| [189] |
To report the surgical and long-term outcomes of major right hepatic resection for large hepatocellular carcinoma (HCC) using the anterior approach compared with the conventional approach.Great difficulty can be encountered during major right hepatic resection for large HCC using the conventional approach. Forceful retraction during mobilization of the tumor might result in serious complications, including dissemination of cancer cells, iatrogenic tumor rupture, and excessive bleeding, leading to unfavorable surgical and long-term outcomes.In patients who had large HCC at the right lobe of liver and underwent major hepatic resection, the technique of anterior approach was used. After hilar control of the inflow blood vessels and without prior mobilization of the right lobe of liver and the tumor, parenchymal transection was performed using an ultrasonic dissector from the anterior surface of the liver until the anterior surface of the inferior vena cava was exposed. All venous tributaries, including the right hepatic vein, were controlled before the right lobe of liver was mobilized. Surgical and long-term outcomes were analyzed retrospectively and compared with patients who underwent surgery using the conventional approach.From 1989 to 1997, the anterior approach was used for major right hepatic resection in 54 patients with HCC of 5 cm or more in diameter. When compared with the 106 patients with similar clinical parameters who underwent hepatic resection using the conventional approach during the same period, the patients in the anterior approach group had significantly less intraoperative blood loss and blood transfusion, a lower hospital death rate, a lower incidence of pulmonary metastases, and a better median disease-free survival and median overall cumulative survival.The anterior approach is the preferred technique for major right hepatic resection for large HCC because it resulted in improved surgical and survival outcomes compared with the conventional approach.
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| [190] |
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| [191] |
<b><i>Background:</i></b> Combined therapy with tyrosine kinase inhibitors (TKIs) and anti-PD-1 antibodies has shown high tumor response rates for patients with unresectable hepatocellular carcinoma (HCC). However, using this treatment strategy to convert initially unresectable HCC to resectable HCC was not reported. <b><i>Methods:</i></b> Consecutive patients with unresectable HCC who received first-line therapy with combined TKI/anti-PD-1 antibodies were analyzed. Tumor response and resectability were evaluated via imaging every 2 months (±2 weeks) using RECIST v1.1. Resectability criteria were (1) R0 resection could be achieved with sufficient remnant liver volume and function; (2) intrahepatic lesions were evaluated as partial responses or stable disease for at least 2 months; (3) no severe or persistent adverse effects occurred; and (4) hepatectomy was not contraindicated. <b><i>Results:</i></b> Sixty-three consecutive patients were enrolled. Of them, 10 (15.9%) underwent R0 resection in 3.2 months (range: 2.4–8.3 months) after the initiation of combination therapy. At baseline, these 10 patients had a median largest tumor diameter of 9.3 cm, 7 had Barcelona Clinic Liver Cancer stage C (vascular invasion) disease, 2 had stage B, and 1 had stage A. Before surgery, 6 patients were evaluated as a partial response, 3 stable disease, and 1 partial response in the intrahepatic lesion but a new metastatic lesion in the right adrenal gland. Six patients (60%) achieved a pathological complete response. One patient died from immune-related adverse effects 2.4 months after hepatectomy. After a median follow-up of 11.2 months (range: 7.8–15.9 months) for other 9 patients, 8 survived without disease recurrence, and 1 experienced tumor recurrence. <b><i>Conclusions:</i></b> Combination of TKI/anti-PD-1 antibodies is a feasible conversion therapy for patients with unresectable HCC to become resectable. This study represents the largest patient cohort on downstaging role of combinational systemic therapy on TKI and PD-1 antibody for HCC.
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| [192] |
Over 70% of the patients with hepatocellular carcinoma (HCC) are diagnosed at an advanced stage and lose the opportunity for radical surgery. Combination therapy of tyrosine kinase inhibitors (TKIs) and anti-programmed cell death protein-1 (PD-1) antibodies has achieved a high tumor response rate in both the first-line and second-line treatment of advanced HCC. However, few studies have prospectively evaluated whether TKIs plus anti-PD-1 antibodies could convert unresectable intermediate-advanced HCC into resectable disease.
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| [193] |
Previous studies showed that 42% to 50% of patients with locally advanced hepatocellular carcinoma (HCC) achieved complete remission (CR) after combined locoregional therapy (LRT) plus immunotherapy (IO). However, data on predictors of CR and long-term clinical outcomes without surgery and after discontinuation of IO are lacking.To assess the long-term clinical outcomes among patients with unresectable HCC who achieved CR after LRT-IO and were placed on a watch-and-wait protocol.This cohort study included patients with unresectable HCC who achieved CR after LRT-IO in 2 prospective studies between January 2018 and December 2022. The time of data cutoff was June 2023. Radiologic CR was defined per modified Response Evaluation Criteria in Solid Tumors. All patients underwent close surveillance after CR without surgical interventions, and IO was discontinued.All patients had received stereotactic body radiotherapy followed by anti-programmed cell death protein 1 or anti-programmed death ligand 1 therapy. Forty-nine patients had received a dose of transarterial chemoembolization before stereotactic body radiotherapy.The primary outcome was the 3-year overall survival (OS) rate. Secondary outcomes included the 3-year time-to-progression rate, 3-year local control rate, and relapse pattern. Factors associated with CR were analyzed using multivariate analyses.A total of 63 patients were enrolled (58 male [92.1%]; median age, 69 years [range, 18-90 years]); 38 patients (60.3%) had macrovascular invasion, and the median tumor diameter was 10 cm (range, 3.8-31.1 cm). The median follow-up time was 34.7 months (95% CI, 6.5-64.6 months). Twenty-nine patients (46.0%) achieved CR. The patients achieving CR had a significantly better 3-year OS rate than patients not achieving CR (75.5% [95% CI, 58.2%-98.3%] vs 28.1% [95% CI, 7.4%-29.4%]; P < .001). Among the 29 patients with CR, the 3-year time-to-progression rate was 58.7% (95% CI, 38.7%-79.1%) and the 3-year local control rate was 90.5% (95% CI, 78.2%-100%). Ten patients (34.5%) developed recurrence; among them, 6 (60.0%) with solitary intrahepatic disease relapse underwent curative surgical treatment. The absence of tumor vascular invasion (odds ratio, 0.30; 95% CI, 0.10-0.89) and the sum of the largest lesion diameters of 8 cm or less (odds ratio, 0.26; 95% CI, 0.07-0.98) were associated with CR.This cohort study of LRT-IO with long-term follow-up data found a durable response in patients with locally advanced unresectable HCC. Long-term survival was attainable in patients with radiologic CR. Further randomized clinical trials are warranted.
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| [194] |
中国研究型医院学会肝胆胰外科专业委员会. 精准肝切除术专家共识[J]. 中华消化外科杂志, 2017, 16(9):883-893. DOI:10.3760/cma.j.issn.1673-9752.2017.09.001.
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| [195] |
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| [196] |
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| [197] |
Selective transarterial chemoembolization (TACE) and portal vein embolization (PVE) could improve the rate of hypertrophy of the future liver remnant (FLR) in patients with chronic liver disease. This study evaluated the feasibility and efficacy of this combined procedure.
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| [198] |
Preoperative portal vein embolization (PVE) induces shrinkage of the embolized lobe and compensatory regeneration in the non-embolized lobe, but does not always induce sufficient regeneration of the future remnant liver (FRL). We previously developed preoperative sequential PVE-hepatic vein embolization (HVE), and here we present our experience of treating 42 patients with sequential PVE-HVE.During 8-year study period, preoperative PVE-HVE was performed on 42 patients with hepatobiliary malignancies.Primary diseases were bile duct cancers [perihilar cholangiocarcinoma (n = 33) and diffuse bile duct cancer (n = 1)], hepatocellular carcinomas (n = 4), and intrahepatic tumors [intrahepatic cholangiocarcinoma (n = 3) and gallbladder cancer liver invasion (n = 1)]. These patients demonstrated insufficient FRL regeneration following PVE, thus HVE was performed to induce further regeneration. No PVE-HVE procedure-associated complications occurred. In the bile duct cancer group, FRL volume was 33.9 ± 2.2 % before PVE, 38.4 ± 1.5 % before HVE, 43.7 ± 2.1 % at surgery, and 73.6 ± 8.3 % at 2 weeks after right hepatectomy. The degree of FRL hypertrophy was 13.3 % after PVE, 28.9 % after PHV-HVE, and 117.1 % at 2 weeks after right hepatectomy. All patients except one recovered uneventfully after surgery, and the 3-year patient survival rate was 45.1 %. In the HCC group, transarterial chemoembolization was initially performed and FRL regeneration following PVE-HVE occurred very slowly. Active FRL regeneration occurred in the liver tumor group, but rapid tumor growth was observed in 1 of 4 patients.The sequential application of HVE following PVE safely and effectively induces further FRL regeneration in non-cirrhotic livers. Further validation using larger patient population and multicenter studies is needed to reliably widen the indications.
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| [199] |
Insufficient volume of the future liver remnant (FLR) is a major cause of unresectability in patients with bilobar colorectal liver metastases (CLM). The objective of this study was to evaluate the safety and efficacy of the novel associating portal embolization and artery ligation (APEAL) technique before extended right hepatectomy during a two-stage procedure for CLM.All patients who had undergone extended right hepatectomy during two-stage surgery for CLM between 2012 and 2014 were identified retrospectively from a prospectively maintained database. In the first stage, right portal vein embolization, partial right hepatic artery ligation and devascularization of segment IVb along the round ligament without parenchymal transection were associated with clearance of the FLR and/or primary tumour resection. Liver volumetry was performed using OsiriX software on postoperative day (POD) 7 and 30.Ten patients underwent the APEAL procedure. During the first stage, APEAL was combined with colorectal resection in seven patients. The median (range) interval between the two stages was 45 (31-71) days. The FLR volume increased from 327 (214-537) cm(3) before surgery to 590 (508-1072) cm(3) on POD 7 and 701 (512-1018) cm(3) on POD 30. This corresponded to a FLR regeneration rate of 104 (42-185) and 134 (53-171) per cent respectively. There were no deaths. The overall morbidity rate was 60 per cent (6 of 10) after each procedure, with severe morbidity occurring in two and three of ten patients after the first and second procedures respectively.APEAL induces fast, safe, reproducible and effective FLR growth when an extended right hepatectomy is scheduled in patients with multiple bilobar CLM.© 2015 BJS Society Ltd Published by John Wiley & Sons Ltd.
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| [200] |
Primary liver and biliary cancers are very aggressive tumors. Surgical treatment is the main option for cure or long term survival. The main purpose of this systematic review is to underline the indications for portal vein embolization (PVE), in patients with inadequate future liver remnant (FLR) and to analyze other parameters such as resection rate, morbidity, mortality, survival after PVE and hepatectomy for primary hepatobiliary tumors. Also the role of trans-arterial chemoembolization (TACE) before PVE, is investigated.A systematic search of the literature was performed in Pub Med and the Cochrane Library from 01.01.1990 to 30.09.2015.Forty articles were selected, including 2144 patients with a median age of 61 years. The median excision rate was 90% for hepatocellular carcinomas (HCCs) and 86% for hilar cholangiocarcinomas (HCs). The main indications for PVE in patients with HCC and presence of liver fibrosis or cirrhosis was FLR <40% when liver function was good (ICGR15 < 10%) and FLR < 50% when liver function was affected (ICGR15:10-20%). The combination of TACE and PVE increased hypertrophy rate and was associated with better overall survival and disease free survival and should be considered in advanced HCC tumors with inadequate FLR. In patients with HCs PVE was performed, after preoperative biliary drainage, when FLR was <40%, in the majority of studies, with very good post-operative outcome. However indications should be refined.PVE before major hepatectomy allows resection in a patient group with advanced primary hepato-biliary tumors and inadequate FLR, with good long term survival.Copyright © 2016 Elsevier Ltd and British Association of Surgical Oncology/European Society of Surgical Oncology. All rights reserved.
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| [201] |
To evaluate a new 2-step technique for obtaining adequate but short-term parenchymal hypertrophy in oncologic patients requiring extended right hepatic resection with limited functional reserve.Patients presenting with primary or metastatic liver tumors often face the dilemma that the remaining liver tissue may not be sufficient. Preoperative portal vein embolization has thus far been established as the standard procedure for achieving resectability.Two-staged hepatectomy was performed in patients who preoperatively appeared to be marginally resectable but had a tumor-free left lateral lobe. Marginal respectability was defined as a left lateral lobe to body weight ratio of less than 0.5. In the first step, surgical exploration, right portal vein ligation (PVL), and in situ splitting (ISS) of the liver parenchyma along the falciform ligament were performed. Computed tomographic volumetry was performed before ISS and before completion surgery.The study included 25 patients with primary liver tumors (hepatocellular carcinoma: n = 3, intrahepatic cholangiocarcinoma: n = 2, extrahepatic cholangiocarcinoma: n = 2, malignant epithelioid hemangioendothelioma: n = 1, gallbladder cancer: n = 1 or metastatic disease [colorectal liver metastasis]: n = 14, ovarian cancer: n = 1, gastric cancer: n = 1). Preoperative CT volumetry of the left lateral lobe showed 310 mL in median (range = 197-444 mL). After a median waiting period of 9 days (range = 5-28 days), the volume of the left lateral lobe had increased to 536 mL (range = 273-881 mL), representing a median volume increase of 74% (range = 21%-192%) (P < 0.001). The median left lateral liver lobe to body weight ratio was increased from 0.38% (range = 0.25%-0.49%) to 0.61% (range = 0.35-0.95). Ten of 25 patients (40%) required biliary reconstruction with hepaticojejunostomy. Rapid perioperative recovery was reflected by normalization of International normalized ratio (INR) (80% of patients), creatinine (84% of patients), nearly normal bilirubin (56% of patients), and albumin (64% of patients) values by day 14 after completion surgery. Perioperative morbidity was classified according to the Dindo-Clavien classification of surgical complications: grade I (12 events), grade II (13 events), grade III (14 events, III a: 6 events, III b: 8 events), grade IV (8 events, IV a: 3 events, IV b: 5 events), and grade V (3 events). Sixteen patients (68%) experienced perioperative complications. Follow-up was 180 days in median (range: 60-776 days) with an estimated overall survival of 86% at 6 months after resection.Two-step hepatic resection performing surgical exploration, PVL, and ISS results in a marked and rapid hypertrophy of functional liver tissue and enables curative resection of marginally resectable liver tumors or metastases in patients that might otherwise be regarded as palliative.
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| [202] |
The aim of the study is to assess the efficacy and safety of associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) in patients with hepatitis B virus-related hepatocellular carcinoma (HCC).ALPSS allows curative resection of conventionally-unresectable liver tumors. However, its role in HCC is largely unknown.Consecutive HCC patients who underwent ALPPS at our center between April 2013 and September 2017 were retrospectively studied. The oncological results were compared with patients receiving transcatheter arterial chemoembolization (TACE), and patients undergoing one-stage resection by using propensity score matching (PSM) analysis.The median tumor diameter was 13 cm (range: 6-22 cm) in patients with a single tumor (n = 28), whereas the median total tumor diameter was 12 cm (range: 9-31 cm) in patients with multiple tumors (n = 17). After stage-1 ALPPS, the median future liver remnant (FLR) increased by 56.8%. The stage-2 ALPPS was completed in 41 patients (91.1%) after a median of 12 days. The 90-day mortality rate was 11.1% (5/45). The overall survival (OS) rates at 1- and 3-year were 64.2% and 60.2%, whereas the disease-free survival (DFS) rates at 1 and 3 years were 47.6% and 43.9%, respectively. On PSM analysis, the long-term survival of patients undergoing ALPPS was significantly better than those receiving TACE (OS, P = 0.004; DFS, P < 0.0001) and similar to those subjected to one-stage liver resection (OS, P = 0.514; DFS, P = 0.849).The long-term survival after ALPPS was significantly better than TACE, and similar to those after one-stage liver resection. ALPPS is a viable treatment option for patients with unresectable HCC in selected patients.
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| [203] |
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| [204] |
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| [205] |
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| [206] |
This study evaluated long-term outcomes of salvage surgery as additional therapy following downstaging of hepatocellular carcinoma (HCC) with transarterial chemoembolization (TACE) in patients with initially unresectable HCC.A retrospective analysis was performed of 831 consecutive patients with unresectable HCC who underwent TACE as initial treatment between June 2004 and December 2014. Of these, 82 patients with downstaged resectable HCC were enrolled in this study: 43 received salvage surgery (S group) and the remaining 39, who refused salvage resection, were the control group (T group). The primary endpoint was overall survival (OS).The median OS in the S and T groups was 49 and 31 months, respectively (p =.027). The 2-, 4-, and 5-year survival rates were 93%, 47%, and 26% in the S group and 74%, 18%, and 10% in the T group, respectively (p =.019). Treatment modality (hazard ratio [HR], 0.337; 95% confidential interval [CI], 0.184-0.616; p <.001) and response to TACE (complete vs. partial; HR, 3.154; 95% CI, 1.709-5.822; p <.001) were independent prognostic factors for survival. The median OS for patients in the complete response and partial response (PR) subgroups was 50 and 49 months, respectively, in the S group and 54 and 24 months, respectively, in the T group (p =.699 and p <.001, respectively). The median OS for HCC patients with macroscopic vascular invasion (MVI) was 58 and 30 months in the S and T groups, respectively (p =.024).Salvage surgery after downstaging of unresectable HCC had a survival benefit only for patients with MVI or a PR to TACE.The results of this study suggest that salvage liver resection after downstaging of unresectable hepatocellular carcinoma in patients with a complete response to transarterial chemoembolization (TACE) has a comparable long-term outcome in this good-prognosis group. Salvage liver resection may provide a better long-term outcome compared with TACE alone, but only in patients with macroscopic vascular invasion or those with a partial response to TACE.©AlphaMed Press.
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| [207] |
To compare the overall survival (OS) and disease progression free survival (PFS) in patients with advanced hepatocellular carcinoma (Ad-HCC) who are undergoing hepatic arterial infusion (HAI) of oxaliplatin, fluorouracil/leucovorin (FOLFOX) treatment vs. sorafenib.This retrospective study was approved by the ethical review committee, and informed consent was obtained from all patients before treatment. HAI of FOLFOX (HAIF) was recommended as an alternative treatment option for patients who refused sorafenib. Of the 412 patients with Ad-HCC (376 men and 36 women) between Jan 2012 to Dec 2015, 232 patients were treated with sorafenib; 180 patients were given HAIF therapy. The median age was 51 years (range, 16-82 years). Propensity-score matched estimates were used to reduce bias when evaluating survival. Survival curves were calculated by performing the Kaplan-Meier method and compared by using the log-rank test and Cox regression models.The median PFS and OS in the HAIF group were significantly longer than those in the sorafenib group (PFS 7.1 vs. 3.3 months [RECIST]/7.4 vs. 3.6 months [mRECIST], respectively; OS 14.5 vs. 7.0 months; p <0.001 for each). In the propensity-score matched cohorts (147 pairs), both PFS and OS in the HAIF group were longer than those in the sorafenib group (p <0.001). At multivariate analysis, HAIF treatment was an independent factor for PFS (hazard ratio [HR] 0.389 [RECIST]/0.402 [mRECIST]; p <0.001 for each) and OS (HR 0.129; p <0.001).HAIF therapy may improve survival compared to sorafenib in patients with Ad-HCC. A prospective randomized trial is ongoing to confirm this finding.We compared the hepatic arterial infusion of FOLFOX (a combination chemotherapy) with sorafenib (a tyrosine kinase inhibitor) in patients with advanced hepatocellular carcinoma, retrospectively. It was found that hepatic arterial infusion of FOLFOX therapy may improve both progression free and overall survival in patients with advanced hepatocellular carcinoma.Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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| [208] |
Sorafenib is the first-line treatment for hepatocellular carcinoma with portal vein invasion; however, it has shown unsatisfactory survival benefit. Sorafenib plus hepatic arterial infusion chemotherapy (HAIC) of oxaliplatin, fluorouracil, and leucovorin (FOLFOX) has shown promising results for these patients in a previous phase 2 study.To investigate the efficacy and safety of sorafenib plus HAIC compared with sorafenib for hepatocellular carcinoma with portal vein invasion.This randomized, open-label clinical trial enrolled 818 screened patients. Of the 818 participants, 247 with hepatocellular carcinoma and portal vein invasion were randomly assigned (1:1) via a computer-generated sequence to receive sorafenib plus HAIC or sorafenib. This trial was conducted at 5 hospitals in China and enrolled patients from April 1, 2016, to October 10, 2017, with a follow-up period of 10 months.Randomization to receive 400 mg sorafenib twice daily (sorafenib group) or 400 mg sorafenib twice daily plus HAIC (SoraHAIC group) (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, fluorouracil bolus 400 mg/m2 on day 1, and fluorouracil infusion 2400 mg/m2 for 46 hours, every 3 weeks).The primary endpoint was overall survival by intention-to-treat analysis. Safety was assessed in patients who received at least 1 dose of study treatment.For 247 patients (median age, 49 years; range, 18-75 years; 223 men and 24 women), median overall survival was 13.37 months (95% CI, 10.27-16.46) in the SoraHAIC group vs 7.13 months (95% CI, 6.28-7.98) in the sorafenib group (hazard ratio [HR], 0.35; 95% CI, 0.26-0.48; P < .001). The SoraHAIC group showed a higher response rate than the sorafenib group (51 [40.8%] vs 3 [2.46%]; P < .001), and a longer median progression-free survival (7.03 [95% CI, 6.05-8.02] vs 2.6 [95% CI, 2.15-3.05] months; P < .001). Grade 3/4 adverse events that were more frequent in the SoraHAIC group than in the sorafenib group included neutropenia (12 [9.68%] vs 3 [2.48%]), thrombocytopenia (16 [12.9%] vs 6 [4.96%]), and vomiting (8 [6.45%] vs 1 [0.83%]).Sorafenib plus HAIC of FOLFOX improved overall survival and had acceptable toxic effects compared with sorafenib in patients with hepatocellular carcinoma and portal vein invasion.ClinicalTrials.gov identifier: NCT02774187.
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| [209] |
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| [210] |
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| [211] |
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| [212] |
To evaluate whether this conversion rate to resectability could be increased when patients are treated with transarterial chemoembolization and hepatic arterial infusion chemotherapy (TACE-HAIC) using oxaliplatin plus fluorouracil/leucovorin.Conventional TACE (c-TACE) is a common regimen for initially unresectable hepatocellular carcinoma (HCC), which converts to curative-intent resection in about 10% of those patients. It is urgent need to investigated better regimen for those patients.The data of 83 initially unresectable HCC patients were examined, including 41 patients in the TACE-HAIC group and 42 patients in the c-TACE group. Their response rate, conversion rate to resection, survival outcome, and adverse events were compared.The conversion rate was significantly better in the TACE-HAIC group than in the c-TACE group (48.8% vs 9.5%; < 0.001). The TACE-HAIC had marginal superiority in overall response rate as compared to c-TACE (14.6% vs 2.4%; = 0.107 [RECIST]; 65.9% vs 16.7%; < 0.001 [mRECIST], respectively). The median progression-free survival was not available and 9.2 months for the TACE-HAIC and cTACE groups, respectively (hazard rate [HR]: 0.38; 95% confidence interval [CI], 0.20-0.70; = 0.003). The median overall survival was not available and 13.5 months for the TACE-HAIC and c-TACE groups, respectively (HR, 0.63; 95% CI, 0.34-1.17; = 0.132). The 2 groups had similar rates of grade 3/4 adverse events (all > 0.05).TACE-HAIC demonstrated a higher conversion rate and progression-free survival benefit than c-TACE and could be considered as a more effective regimen for patients with initially unresectable HCC. Future prospective randomized trials are needed to confirm it.Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.
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| [213] |
To evaluate the effects of dose escalation by intensity-modulated radiotherapy (IMRT) in liver-directed concurrent chemoradiotherapy for locally advanced Barcelona Clinic Liver Cancer stage C hepatocellular carcinoma (BCLC-C HCC).During 2005-2016, 637 patients with BCLC-C HCC received RT with concurrent hepatic arterial 5-fluorouracil. Patients were divided into two groups according to the biologically effective doses for a tumor (α/β = 10 Gy): <72 Gy (536 patients) and ≥72 Gy (101 patients). In each group, 128/536 (24%) and 94/101 patients (93%) used IMRT, respectively.The median follow-up for patients alive at the time of analysis was 36 months (range, 6-159 months). For ≥72 Gy and <72 Gy groups, the median overall survival (OS) was 21 and 13 months, respectively (P = .002). The 1-year local failure-free survival (LFFS) were significantly higher in high-dose group (95% vs. 79%; P < .001). After propensity score matching, high-dose group still had significantly better 1-year OS (62% vs. 51%; P = .03) and 1-year LFFS (95% vs. 78%; P = .008). In the multivariate model, RT dose was an independent predictor of LFFS and OS. The surgical conversion rate was significantly higher in high-dose group (20% vs. 12%, P = .03), with substantially increased median OS among patients who underwent surgery (104 months vs. 11 months; P < .001). There were no significant differences in gastrointestinal bleeding or radiation-induced liver disease.In liver-directed concurrent chemoradiotherapy, radiation dose escalation by IMRT increased LFFS and OS for locally advanced BCLC-C HCC. It also increased the conversion rate to curative resection, which was attributable to increased OS.Copyright © 2018 Elsevier B.V. All rights reserved.
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| [214] |
This study aims to investigate the predictive factors for conversion therapy in patients with unresectable hepatocellular carcinoma (uHCC) and to evaluate the prognosis of conversion cases by comparing them with partial response (PR) and complete response (CR) cases.
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| [215] |
Systemic conversion therapy provides patients with initially unresectable hepatocellular carcinoma (HCC) the chance to salvage radical liver resection and superior survival outcomes, but the optimal conversion strategy is unclear.A systematic literature search was conducted on PubMed, EMBASE, Web of Science, Scopus, and the Cochrane Library between 2007 and 2024 focusing on studies reporting conversion therapy for HCC. The treatment groups were divided into Tyrosine kinase inhibitors (TKI), TKI plus loco-regional therapy (LRT), TKI plus anti-PD-1 therapy (TKI + PD-1), TKI + PD-1 + LRT, immune checkpoint inhibitors (ICI) plus LRT, and Atezolizumab plus bevacizumab (A + T) groups. The conversion to surgery rate (CSR), objective response rate (ORR), grade ≥ 3 treatment-related adverse events (AEs), overall survival (OS) and progression-free survival (PFS) were analyzed.38 studies and 4,042 patients were included. The pooled CSR were 8% (95% CI, 5-12%) in TKI group, 13% (95% CI, 8-19%) in TKI + LRT group, 28% (95% CI, 19-37%) in TKI + PD-1 group, 33% (95% CI, 25-41%) in TKI + PD-1 + LRT group, 23% (95% CI, 1-46%) in ICI + LRT group, and 5% (95% CI, 3-8%) in A + T group, respectively. The pooled HR for OS (0.45, 95% CI, 0.35-0.60) and PFS (0.49, 95% CI, 0.35-0.70) favored survival benefit of conversion surgery. Subgroup analysis revealed that lenvatinib + PD-1 + LRT conferred higher CSR of 35% (95% CI, 26-44%) and increased ORR of 70% (95% CI, 56-83%).The current study indicates that TKI + PD-1 + LRT, especially lenvatinib + PD-1 + LRT, may be the superior conversion therapy with a manageable safety profile for patients with initially unresectable HCC. The successful conversion therapy favors the superior OS and PFS compared with systemic treatment alone.International prospective register of systematic reviews (PROSPERO) (registration code: CRD 42024495289).© 2024. The Author(s).
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| [216] |
Notable-HCC (NCT05185531) is a phase 1b trial, aiming to evaluate the safety and preliminary effectiveness of neoadjuvant PD-1 blockade plus stereotactic body radiotherapy (SBRT) in early-stage resectable hepatocellular carcinoma (HCC). Twenty patients with HCC of BCLC stage 0-A received 3 Gy SBRT and two cycles of tislelizumab, an anti-PD-1 monoclonal antibody before the curative HCC resection. Primary endpoints were the surgery delay, radiographic and pathological tumor response after the neoadjuvant therapy, safety and tolerability. During the neoadjuvant therapy, treatment-related adverse events (TRAEs) of grade 1-2 occurred in all 20 patients (100%), eight patients (40%) had grade 3 TRAEs, no grade 4 to 5 TRAE occurred, and all resolved without corticosteroids treatment. Per mRECIST, the objective response rate was 63.2% (12/19), with 3 complete response; the disease control rate was 100%. Two (10.5%) patients achieved complete pathological response. No surgery delay occurred. The neoadjuvant therapy did not increase the surgical difficulty or the incidence of complications. Secondary endpoints of disease-free survival and overall survival were not mature at the time of the analysis. Our pilot trial shows that neoadjuvant therapy with anti-PD-1 + SBRT is safe and promotes tumor responses in early-stage resectable HCC.© 2024. The Author(s).
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| [217] |
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| [218] |
The aim of this study was to estimate probabilities of achieving the statistical cure from hepatocellular carcinoma (HCC) with hepatic resection (HR) and liver transplantation (LT).Statistical cure occurs when the mortality of a specific population returns to values of that of general population. Resection and transplantation are considered potentially curative therapies for HCC, but their effect on the residual entire life-expectancy has never been investigated.Data from 3286 HCC patients treated with LT (n = 1218) or HR (n = 2068) were used to estimate statistical cure. Disease-free survival (DFS) was the primary survival measure to estimate cure fractions through a nonmixture model. Overall survival (OS) was a secondary measure. In both, patients were matched with general population by age, sex, year, and race/ethnicity. Cure variations after LT were also adjusted for different waiting-list drop-outs.Considering DFS, the cure fraction after LT was 74.1% and after HR was 24.1% (effect size >0.8). LT outperformed HR within all transplant criteria considered (effect size >0.8), especially for multiple tumors (>0.9) and even in presence of a drop-out up to 20% (>0.5). Considering OS, the cure fraction after LT marginally increased to 75.8%, and after that HR increased to 40.5%. The effect size of LT over HR in terms of cure decreased for oligonodular tumors (<0.5), became small for drop-out up to ∼20% (<0.2), and negligible for single tumors <5 cm (∼0.1).As other malignancies, statistical cure can occur for HCC, primarily with LT and secondarily with HR, depending on waiting-list capabilities and efficacy of tumor recurrence therapies after resection.
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| [219] |
Several investigators have advocated for extending the Barcelona Clinic Liver Cancer (BCLC) resection criteria to select patients with BCLC-B and even BCLC-C hepatocellular carcinoma (HCC). The objective of the current study was to define the outcomes and recurrence patterns after resection within and beyond the current resection criteria.Patients who underwent resection for HCC within (i.e., BCLC 0/A) and beyond (i.e. BCLC B/C) the current resection criteria between 2005 and 2017 were identified from an international multi-institutional database. Overall survival (OS), disease-free survival (DFS), as well as patterns of recurrence of patients undergoing HCC resection within and beyond the BCLC guidelines were examined.Among 756 patients, 602 (79.6%) patients were BCLC 0/A and 154 (20.4%) were BCLC B/C. Recurrences were mostly intrahepatic (within BCLC: 74.3% versus beyond BCLC: 70.8%, p = 0.80), with BCLC B/C patients more often having multiple tumors at relapse (69.6% versus 49.4%, p = 0.001) and higher rates of early (< 2 years) recurrence (88.0% versus 75.5%, p = 0.011). During the first postoperative year, annual recurrence was 38.3% and 21.3% among BCLC B/C and BCLC 0/A patients, respectively; 5-year OS among BCLC 0/A and BCLC B/C patients was 76.9% versus 51.6% (p = 0.003). On multivariable analysis, only a-fetoprotein (AFP) > 400 ng/mL (HR = 1.84, 95% CI 1.07-3.15) and R1 resection (HR = 2.36, 95% CI 1.32-4.23) were associated with higher risk of recurrence among BCLC B/C patients.Surgery can provide acceptable outcomes among select patients with BCLC B/C HCC. The data emphasize the need to further refine the BCLC treatment algorithm as well as highlight the need for surveillance protocols with a particular focus on the liver, especially for patients undergoing resection outside the BCLC criteria.
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| [220] |
Resection is the most widely used potentially curative treatment for patients with early hepatocellular carcinoma (HCC). However, recurrence within 2 years occurs in 30-50% of patients, being the major cause of mortality. Herein, we describe 2 models, both based on widely available clinical data, which permit risk of early recurrence to be assessed before and after resection.A total of 3,903 patients undergoing surgical resection with curative intent were recruited from 6 different centres. We built 2 models for early recurrence, 1 using preoperative and 1 using pre and post-operative data, which were internally validated in the Hong Kong cohort. The models were then externally validated in European, Chinese and US cohorts. We developed 2 online calculators to permit easy clinical application.Multivariable analysis identified male gender, large tumour size, multinodular tumour, high albumin-bilirubin (ALBI) grade and high serum alpha-fetoprotein as the key parameters related to early recurrence. Using these variables, a preoperative model (ERASL-pre) gave 3 risk strata for recurrence-free survival (RFS) in the entire cohort - low risk: 2-year RFS 64.8%, intermediate risk: 2-year RFS 42.5% and high risk: 2-year RFS 20.7%. Median survival in each stratum was similar between centres and the discrimination between the 3 strata was enhanced in the post-operative model (ERASL-post) which included 'microvascular invasion'.Statistical models that can predict the risk of early HCC recurrence after resection have been developed, extensively validated and shown to be applicable in the international setting. Such models will be valuable in guiding surveillance follow-up and in the design of post-resection adjuvant therapy trials.The most effective treatment of hepatocellular carcinoma is surgical removal of the tumour but there is often recurrence. In this large international study, we develop a statistical method that allows clinicians to estimate the risk of recurrence in an individual patient. This facility enhances communication with the patient about the likely success of the treatment and will help in designing clinical trials that aim to find drugs that decrease the risk of recurrence.Copyright © 2018. Published by Elsevier B.V.
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| [221] |
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| [222] |
We conducted a retrospective cohort study to investigate factors to early and late phase recurrence of hepatocellular carcinoma (HCC).The study population consisted of 249 patients including 157 with cirrhosis who underwent hepatectomy for HCC. The endpoint was time-to-recurrence. Using a Cox regression model, factors to early and late phase recurrences were investigated censoring recurrence-free patients at the 2-year time point and in patients without recurrence at 2 years.Actuarial probability of overall recurrence at 1, 3, and 5 years were 0.301, 0.623, and 0.790, respectively, with a median follow-up of 624 days. Early recurrence was observed in 123 out of 249 patients; while late recurrence was found in 61 out of 113 patients. Factors to early recurrence were as follows: non-anatomical resection, presence of microscopic vascular invasion, and serum alpha-fetoprotein level >or=32 ng/ml. Those contributing to late phase recurrence were higher grade of hepatitis activity, multiple tumors, and gross tumor classification.Variables associated with metastatic recurrence were factors to early phase recurrence; whereas those related with elevated carcinogenesis contributed to late phase recurrence, thus providing an epidemiological evidence that different mechanisms, i.e. metastasis and de novo, are involved in intrahepatic recurrence after hepatectomy for HCC.
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| [223] |
Detecting residual disease is a critical clinical requirement in the perisurgical management of patients with resectable hepatocellular carcinoma (HCC). Previous studies focused on specific genomic regions exhibiting limited sensitivity and failed to meet the minimal residual disease (MRD) testing threshold. We introduce a next-generation sequencing-based assay, informed by baseline samples, facilitating MRD detection in hepatectomized patients with HCC and offering prognostic predictions.This study involved 88 patients with HCC who underwent surgical resections from January 2016 to May 2016 in Zhongshan Hospital, Fudan University. Tumor and normal tissue samples were collected during surgery, whereas plasma samples were obtained both before surgery and up to 7 days after surgery. Using a next-generation sequencing-based personalized ctDNA assay, we analyzed the MRD in both presurgical and postsurgical blood samples and its correlation with prognosis.With a median follow-up period of 80.7 months, our findings demonstrated significant correlations between presurgical ctDNA tumor fractions, postsurgical plasma MRD status, and both recurrence-free survival and overall survival. Postsurgical MRD status emerged as the most significant risk factor for cancer recurrence (HR = 2.162; 95% confidence interval, 1.09-4.30; P = 0.027) compared with other clinical characteristics in multivariate Cox regression analysis. Notably, MRD status showed potential as a prognostic indicator among clinically low-recurrent-risk patients, such as those with Barcelona Clinic Liver Cancer stages 0 to A or China Liver Cancer Staging stages I to II.Evaluating personalized MRD provided crucial prognostic insights into recurrence-free survival and overall survival. It efficiently identified patients at high risk of recurrence, even among those initially perceived as low-risk cases. See related commentary by Pinato et al., p. 955.©2024 American Association for Cancer Research.
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| [224] |
The role of adjuvant transarterial chemoembolization (TACE) for HCC following curative resection remains controversial. We aimed to determine the effectiveness of postoperative adjuvant TACE in patients with HCC.
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| [225] |
The survival of patients with hepatocellular carcinoma (HCC) recurrence after curative resection is usually poor. We sought to evaluate the safety and efficacy of adjuvant transarterial chemoembolization (TACE) in HBV-related HCC patients with an intermediate (a single tumor larger than 5 cm without microvascular invasion) or high risk (a single tumor with microvascular invasion, or two or three tumors) of recurrence. In this randomized phase 3 trial, 280 eligible patients were assigned to adjuvant TACE (= 140) or no adjuvant treatment (control; = 140) groups. The primary endpoint was recurrence-free survival (RFS); secondary endpoints included overall survival (OS) and safety. Multivariable Cox-proportional hazards model was used to determine the independent impact of TACE on patients' outcomes. Patients who received adjuvant TACE had a significantly longer RFS than those in the control group [56.0% vs. 42.1%, = 0.01; HR, 0.68; 95% confidence interval (CI), 0.49-0.93]. Patients in the adjuvant TACE group had 7.8% higher 3-year OS rate than the control group (85.2% vs. 77.4%; = 0.04; HR, 0.59; 95% CI, 0.36-0.97). The impact of adjuvant TACE on RFS and OS remained significant after controlling for other known prognostic factors (HR, 0.67; = 0.01 for RFS; and HR, 0.59; = 0.04 for OS). There was no grade 3 or 4 toxicity after adjuvant TACE. For patients with HBV-related HCC who had an intermediate or high risk of recurrence after curative hepatectomy, our study showed adjuvant TACE significantly reduced tumor recurrence, improved RFS and OS, and the procedure was well tolerated..©2018 American Association for Cancer Research.
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| [226] |
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| [227] |
Certain patients with hepatocellular carcinoma with portal vein tumor thrombus could benefit from surgical resection, and postoperative adjuvant therapy may lower the incidence of tumor recurrence.To compare the efficacy and safety of sorafenib plus transarterial chemoembolization vs sorafenib alone as postoperative adjuvant therapy for patients with hepatocellular carcinoma with portal vein tumor thrombus.This was a phase 3, multicenter, randomized clinical trial conducted in 5 hospitals in China. A total of 158 patients were enrolled and randomized from October 2019 to March 2022, with a median follow-up of 28.4 months. Portal vein tumor thrombus was graded by the Cheng classification. Eligible patients with hepatocellular carcinoma with Cheng grade I to III portal vein tumor thrombus (ie, involving segmental or sectoral branches, right- or left-side branch, or main trunk of portal vein) were included.Patients were randomly assigned 1:1 to receive transarterial chemoembolization with sorafenib or sorafenib alone as postoperative adjuvant therapy. Sorafenib treatment was started within 3 days after randomization, with an initial dose of 400 mg orally twice a day. In the transarterial chemoembolization with sorafenib group, transarterial chemoembolization was performed 1 day after the first administration of sorafenib.The primary end point was recurrence-free survival. Efficacy was assessed in the intention-to-treat population and safety was assessed in patients who received at least 1 dose of study treatment.Of 158 patients included, the median (IQR) age was 54 (43-61) years, and 140 (88.6%) patients were male. The median (IQR) recurrence-free survival was significantly longer in the transarterial chemoembolization with sorafenib group (16.8 [12.0-NA] vs 12.6 [7.8-18.1] months; hazard ratio [HR], 0.57; 95% CI, 0.39-0.83; P = .002). The median (IQR) overall survival was also significantly longer with transarterial chemoembolization with sorafenib than with sorafenib alone (30.4 [20.6-NA] vs 22.5 [15.4-NA] months; HR, 0.57; 95% CI, 0.36-0.91; P = .02). The most common grade 3/4 adverse event was hand-foot syndrome (23 of 79 patients in the transarterial chemoembolization with sorafenib group [29.1%] vs 24 of 79 patients in the sorafenib alone group [30.4%]). There were no treatment-related deaths in either group. The transarterial chemoembolization with sorafenib group did not show additional toxicity compared with the sorafenib monotherapy group.In this study, the combination of sorafenib and transarterial chemoembolization as postoperative adjuvant therapy in patients with hepatocellular carcinoma with portal vein tumor thrombus resulted in longer recurrence-free survival and overall survival than sorafenib alone and was well tolerated.ClinicalTrials.gov Identifier: NCT04143191.
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| [228] |
Selecting interventions for patients with solitary hepatocellular carcinoma (HCC) remains a challenge. Despite gross classification being proposed as a potential prognostic predictor, its widespread use has been restricted due to inadequate studies with sufficient patient numbers and the lack of established mechanisms. We sought to investigate the prognostic impacts on patients with HCC of different gross subtypes and assess their corresponding molecular landscapes.A prospective cohort of 400 patients who underwent hepatic resection for solitary HCC was reviewed and analysed and gross classification was assessed. Multiomics analyses were performed on tumours and non-tumour tissues from 49 patients to investigate the mechanisms underlying gross classification. Inverse probability of treatment weight (IPTW) was used to control for confounding factors.Overall 3-year survival rates varied significantly among the four gross subtypes (type I: 91%, type II: 80%, type III: 74.6%, type IV: 38.8%). Type IV was found to be independently associated with poor prognosis in both the entire cohort and the IPTW cohort. The four gross subtypes exhibited three distinct transcriptional modules. Particularly, type IV tumours exhibited increased angiogenesis and immune score as well as decreased metabolic pathways, together with highest frequency of TP53 mutations. Patients with type IV HCC may benefit from adjuvant intra-arterial therapy other than the other three subtypes. Accordingly, a modified trichotomous margin morphological gross classification was established.Different gross types of HCC showed significantly different prognosis and molecular characteristics. Gross classification may aid in development of precise individualised diagnosis and treatment strategies for HCC.© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
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| [229] |
To report the efficacy and safety of postoperative adjuvant hepatic arterial infusion chemotherapy (HAIC) with 5-fluorouracil and oxaliplatin (FOLFOX) in hepatocellular carcinoma (HCC) patients with microvascular invasion (MVI).
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| [230] |
No adjuvant therapy has been shown to extend the survival of patients with hepatocellular carcinoma (HCC) receiving curative treatment. We investigated whether injections of activated cytokine-induced killer (CIK) cells (CD3+/CD56+ and CD3+/CD56- T cells and CD3-/CD56+ natural killer cells) prolongs recurrence-free survival of patients after curative therapy for HCC.We performed a multicenter, randomized, open-label, phase 3 trial of the efficacy and safety of adjuvant immunotherapy with activated CIK cells (created by incubation of patients' peripheral blood mononuclear cells with interleukin 2 and an antibody against CD3). The study included 230 patients with HCC treated by surgical resection, radiofrequency ablation, or percutaneous ethanol injection at university-affiliated hospitals in Korea. Patients were assigned randomly to receive immunotherapy (injection of 6.4 × 10(9) autologous CIK cells, 16 times during 60 weeks) or no adjuvant therapy (controls). The primary end point was recurrence-free survival; secondary end points included overall survival, cancer-specific survival, and safety.The median time of recurrence-free survival was 44.0 months in the immunotherapy group and 30.0 months in the control group (hazard ratio with immunotherapy, 0.63; 95% confidence interval [CI], 0.43-0.94; P =.010 by 1-sided log-rank test). Hazard ratios also were lower in the immunotherapy than in the control group for all-cause death (0.21; 95% CI, 0.06-0.75; P =.008) and cancer-related death (0.19; 95% CI, 0.04-0.87; P =.02). A significantly higher proportion of patients in the immunotherapy group than in the control group had an adverse event (62% vs 41%; P =.002), but the proportion of patients with serious adverse events did not differ significantly between groups (7.8% vs 3.5%; P =.15).In patients who underwent curative treatment for HCC, adjuvant immunotherapy with activated CIK cells increased recurrence-free and overall survival. ClinicalTrials.gov number: NCT00699816.Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.
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| [231] |
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| [232] |
There is little evidence that adjuvant therapy after radical surgical resection of hepatocellular carcinoma (HCC) improves recurrence-free survival (RFS) or overall survival (OS). We conducted a multicentre, randomised, controlled, phase IV trial evaluating the benefit of an aqueous extract of Murr (Huaier granule) to address this unmet need.A total of 1044 patients were randomised in 2:1 ratio to receive either Huaier or no further treatment (controls) for a maximum of 96 weeks. The primary endpoint was RFS. Secondary endpoints included OS and tumour extrahepatic recurrence rate (ERR). The Huaier (n=686) and control groups (n=316) had a mean RFS of 75.5 weeks and 68.5 weeks, respectively (HR 0.67; 95% CI 0.55 to 0.81). The difference in the RFS rate between Huaier and control groups was 62.39% and 49.05% (95% CI 6.74 to 19.94; p=0.0001); this led to an OS rate in the Huaier and control groups of 95.19% and 91.46%, respectively (95% CI 0.26 to 7.21; p=0.0207). The tumour ERR between Huaier and control groups was 8.60% and 13.61% (95% CI -12.59 to -2.50; p=0.0018), respectively.This is the first nationwide multicentre study, involving 39 centres and 1044 patients, to prove the effectiveness of Huaier granule as adjuvant therapy for HCC after curative liver resection. It demonstrated a significant prolongation of RFS and reduced extrahepatic recurrence in Huaier group.NCT01770431; Post-results.© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
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Despite antiviral treatment has been shown to reduce hepatocellular carcinoma (HCC) recurrence after curative treatment for hepatitis B virus (HBV)-related HCC in patients with high preoperative HBV-DNA levels, it is still unclear whether antiviral therapy is useful in reducing recurrence in patients with low preoperative HBV-DNA levels.In this randomized controlled trial, 200 patients who underwent curative resection for HCC with low baseline HBV-DNA levels were randomly assigned to receive preemptive antiviral therapy or not. The primary endpoints were recurrence-free survival. This study was censored on March 31, 2015 when all surviving patients had a minimum follow-up of 60 months. The analysis was done on an intention-to-treat basis.The baseline clinical, laboratory, and tumor characteristics of the 2 groups were comparable. The 1-, 3-, and 5-year recurrence-free survival rates for the antiviral group and the control group were 85.9%, 55.2%, and 52.0% and 80.6%, 40.9%, and 32.3%, respectively. The corresponding overall survival rates for the 2 groups were 94.0%, 75.7%, and 64.1% and 90.0%, 62.4%, and 43.7%, respectively. The recurrence-free survival and overall survival for the antiviral group were significantly better than the control group (P = 0.016, P = 0.004, respectively). After adjusting for confounding prognostic factors in a Cox model, the relative risks of recurrence and death for antiviral treatment were 0.601 [95% confidence interval (CI), 0.409-0.884; P = 0.010] and 0.509 (95% CI, 0.333-0.778; P = 0.002), respectively. Antiviral therapy was an independent protective factor of late tumor recurrence (hazard ratio [HR] = 0.316, 95% CI 0.157-0.637; P = 0.001) but not of early tumor recurrence (HR = 0.782, 95% CI, 0.493-1.240; P = 0.296).In patients with low preoperative HBV-DNA levels, antiviral therapy significantly reduced HCC recurrence after R0 hepatic resection.
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| [234] |
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| [235] |
The purpose of this clinical practice update is to evaluate the evidence describing the interaction between direct-acting antiviral (DAA) therapy for hepatitis and hepatocellular carcinoma (HCC) with regard to HCC incidence, HCC recurrence, and DAA efficacy, and to summarize best practice advice regarding HCC surveillance and timing of DAA therapy.The recommendations outlined in this expert review are based on available published evidence, including observational studies and systematic reviews, and incorporates expert opinion where applicable. BEST PRACTICE ADVICE 1: DAA treatment is associated with a reduction in the risk of incident HCC. The relative risk reduction is similar in patients with and without cirrhosis. BEST PRACTICE ADVICE 2: Patients with advanced liver fibrosis (F3) or cirrhosis should receive surveillance imaging before initiating DAA treatment. BEST PRACTICE ADVICE 3: Patients with advanced liver fibrosis (F3) or cirrhosis at the time of DAA treatment represent the highest-risk group for HCC after DAA-induced sustained virologic response. These patients should stay in HCC surveillance. BEST PRACTICE ADVICE 4: HCC surveillance should be performed using ultrasound with or without α-fetoprotein every 6 months. Current data do not support shorter surveillance intervals or the use of alternative surveillance modalities. BEST PRACTICE ADVICE 5: Future studies may show a reduction in HCC risk over time after DAA-induced sustained virologic response. However, in the interim, HCC surveillance should continue indefinitely if patients are otherwise eligible for potentially curative therapy. BEST PRACTICE ADVICE 6: The presence of active HCC is associated with a small but statistically significant decrease in sustained virologic response with DAA therapy. BEST PRACTICE ADVICE 7: Patients with HCC who are eligible for potentially curative therapy with liver resection or ablation should defer DAA therapy until after HCC treatment is completed. BEST PRACTICE ADVICE 8: Timing of DAA therapy for patients with HCC who are listed for liver transplantation should be determined with consideration of median wait times, availability of hepatitis C virus-positive organs, and degree of liver dysfunction. BEST PRACTICE ADVICE 9: There are insufficient data evaluating benefits and cost-effectiveness of DAA therapy in patients with active intermediate or advanced HCC. Decisions regarding DAA treatment in these patients should be considered in light of HCC tumor burden, degree of liver dysfunction, life expectancy, and patient preferences. BEST PRACTICE ADVICE 10: There are no conclusive data that DAA therapy is associated with increased or decreased risk, differential time to recurrence, or aggressiveness of recurrent HCC in patients with complete response to HCC therapy. BEST PRACTICE ADVICE 11: DAA therapy should not be withheld from patients with complete response to HCC therapy; however, DAA therapy can be deferred 4-6 months to confirm response to HCC therapy. BEST PRACTICE ADVICE 12: Patients with complete response to HCC therapy who are treated with DAAs have a continued risk of HCC recurrence and require HCC surveillance, which should be conducted indefinitely with dynamic contrast-enhanced computed tomography or magnetic resonance imaging every 3-6 months. Current data do not support more frequent surveillance in these patients. This Clinical Practice Update was produced by the AGA Institute.Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.
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| [236] |
Hepatocellular carcinoma (HCC), particularly when accompanied by microvascular invasion (MVI), has a markedly high risk of recurrence after liver resection. Adjuvant immunotherapy is considered a promising avenue. This multicenter, open-label, randomized, controlled, phase 2 trial was conducted at six hospitals in China to assess the efficacy and safety of adjuvant sintilimab, a programmed cell death protein 1 inhibitor, in these patients. Eligible patients with HCC with MVI were randomized (1:1) into the sintilimab or active surveillance group. The sintilimab group received intravenous injections every 3 weeks for a total of eight cycles. The primary endpoint was recurrence-free survival (RFS) in the intention-to-treat population. Key secondary endpoints included overall survival (OS) and safety. From September 1, 2020, to April 23, 2022, a total of 198 eligible patients were randomly allocated to receive adjuvant sintilimab (n = 99) or undergo active surveillance (n = 99). After a median follow-up of 23.3 months, the trial met the prespecified endpoints. Sintilimab significantly prolonged RFS compared to active surveillance (median RFS, 27.7 versus 15.5 months; hazard ratio 0.534, 95% confidence interval 0.360-0.792; P = 0.002). Further follow-up is needed to confirm the difference in OS. In the sintilimab group, 12.4% of patients experienced grade 3 or 4 treatment-related adverse events, the most common of which were elevated alanine aminotransferase levels (5.2%) and anemia (4.1%). These findings support the potential of immune checkpoint inhibitors as effective adjuvant therapy for these high-risk patients. Chinese Clinical Trial Registry identifier: ChiCTR2000037655.© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.
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| [237] |
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| [238] |
Liver transplantation for hepatocellular carcinoma (HCC) is the best treatment option for patients with early-stage tumours and accounts for ∼20-40% of all liver transplantations performed at most centres worldwide. The Milan criteria are the most common criteria to select patients with HCC for transplantation but they can be seen as too restrictive. Several proposals have been made for a moderate expansion of the criteria, which result in good outcomes but with an increase in the risk of tumour recurrence. In this Review, we provide a comprehensive overview of the outcomes after liver transplantation for HCC, focusing on tumour recurrence in terms of surveillance, prevention and treatment. Additionally, novel surgical techniques have been developed to increase the available pool of organs for liver transplantation (such as living donor liver transplantation, donation after circulatory death and split livers), but the effect of these techniques on patients with HCC is still under debate. Thus, we will describe these techniques and expose the benefits and disadvantages of each surgical approach. Finally, we will comment on the limitations of the current priority policies for liver transplantation and the need to further refine them to better serve the population.
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| [239] |
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| [240] |
Liver transplantation (LT) has been the treatment of choice for patients with hepatocellular carcinoma (HCC). This study was designed to summarize our experience in LT for HCC patients and establish a new set of criteria for patient selection and prognosis prediction.
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| [241] |
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| [242] |
邵卓, 杨广顺, 杨宁, 等. 三亚共识在原发性肝癌肝移植治疗中的运用[J]. 中国实用外科杂志, 2008, 28(6):466-469. DOI: 10.3321/j.issn:1005-2208.2008.06.018.
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| [243] |
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| [244] |
Alpha-fetoprotein (AFP) predicts hepatocellular carcinoma (HCC) recurrence after liver transplant (LT) but remains an imperfect biomarker. The role of DCP (des-gamma-carboxyprothrombin) and AFP-L3 (AFP bound to Lens culinaris agglutinin) in predicting HCC recurrence remains incompletely characterized. AFP-L3 and DCP could identify patients at high risk of post-transplant HCC recurrence and serve as liver transplant exclusion criteria to defer transplant until patients receive additional risk-reducing pre-transplant local regional therapy.This prospective cohort study included consecutive HCC patients who underwent LT (within or down-staged to Milan criteria) between 2017 and 2022. Pre-transplant AFP, AFP-L3, and DCP measurements were obtained. The primary endpoint was the ability of biomarkers to predict HCC recurrence-free survival.This cohort included 285 patients with a median age of 67 (IQR 63-71). At LT, median biomarker values were AFP 5.0 ng/mL (IQR 3.0-12.1), AFP-L3 6.7% (0.5-13.2), and DCP 1.0 ng/mL (0.3-2.8). Most (94.7%) patients received pre-LT local regional therapy (LRT). After a median post-LT follow-up of 3.1 years, HCC recurrence was observed in 18 (6.3%) patients. AFP-L3 and DCP outperformed AFP with C-statistics of 0.81 and 0.86 respectively, compared with 0.74 for AFP. A dual-biomarker combination of AFP-L3 ≥15% and DCP ≥7.5 predicted 61.1% of HCC recurrences whereas among 265 patients not meeting this threshold, only 7 (2.6%) recurred. The Kaplan-Meier recurrence-free survival at 3 years post-LT was 43.7% for patients with dual-positive biomarkers compared to 97.0% for all others (p<0.001).Dual-positivity for AFP-L3 ≥15% and DCP ≥7.5 strongly predicted post-LT HCC recurrence. This model could refine LT selection criteria and identify high-risk HCC patients to receive additional LRT with LT on hold until biomarker reduction is achieved.Copyright © 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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| [245] |
In patients with HCC awaiting liver transplantation (LT), there is a need to identify biomarkers that are superior to AFP in predicting prognosis. AFP-L3 and des-gamma-carboxyprothrombin (DCP) play a role in HCC detection, but their ability to predict waitlist dropout is unknown. In this prospective single-center study commenced in July 2017, 267 HCC patients had all 3 biomarkers obtained at LT listing. Among them, 96.2% received local-regional therapy, and 18.8% had an initial tumor stage beyond Milan criteria requiring tumor downstaging. At listing, median AFP was 7.0 ng/mL (IQR 3.4–21.5), median AFP-L3 was 7.1% (IQR 0.5–12.5), and median DCP was 1.0 ng/mL (IQR 0.2–3.8). After a median follow-up of 19.3 months, 63 (23.6%) experienced waitlist dropout, while 145 (54.3%) received LT, and 59 (22.1%) were still awaiting LT. Using Cox proportional hazards analysis, AFP-L3≥35% and DCP≥7.5 ng/mL were associated with increased waitlist dropout, whereas AFP at all tested cutoffs, including ≥20,≥ 100, and≥250 ng/mL was not. In a multivariable model, AFP-L3≥35% (HR 2.25, p=0.04) and DCP≥7.5 ng/mL (HR 2.20, p=0.02) remained associated with waitlist dropout as did time from HCC diagnosis to listing ≥ 1 year and increasing MELD-Na score. Kaplan-Meier probability of waitlist dropout within 2 years was 21.8% in those with AFP-L3<35% and DCP<7.5 ng/mL, 59.9% with either AFP-L3 or DCP elevated, and 100% for those with both elevated (p<0.001). In this prospective study, listing AFP-L3% and DCP were superior to AFP in predicting waitlist dropout with the combination of AFP-L3≥35% and DCP≥7.5 ng/mL associated with a 100% risk of waitlist dropout, thus clearly adding prognostic value to AFP alone.
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| [246] |
Patients with hepatocellular carcinoma (HCC) who are listed for liver transplantation (LT) are often treated while on the waiting list with locoregional therapy (LRT), which is aimed at either preventing progression of HCC or reducing the measurable disease burden of HCC in order to receive increased allocation priority. We aimed to synthesize evidence regarding the effectiveness of LRT in the management of patients with HCC who were on the LT waitlist. We conducted a comprehensive search of multiple databases from 1996 to April 25, 2016, for studies that enrolled adults with cirrhosis awaiting LT and treated with bridging or down-staging therapies before LT. Therapies included transcatheter arterial chemoembolization, transarterial radioembolization, ablation, and radiotherapy. We included both comparative and noncomparative studies. There were no randomized controlled trials identified. For adults with T1 HCC and waiting for LT, there were only two nonrandomized comparative studies, both with a high risk of bias, which reported the outcome of interest. In one series, the rate of dropout from all causes at 6 months in T1 HCC patients who underwent LRT was 5.3%, while in the other series of T1 HCC patients who did not receive LRT, the dropout rate at median follow-up of 2.4 years and the progression rate to T2 HCC were 30% and 88%, respectively. For adults with T2 HCC awaiting LT, transplant with any bridging therapy showed a nonsignificant reduction in the risk of waitlist dropout due to progression (relative risk [RR], 0.32; 95% confidence interval [CI], 0.06-1.85; I = 0%) and of waitlist dropout from all causes (RR, 0.38; 95% CI, 0.060-2.370; I = 85.7%) compared to no therapy based on three comparative studies. The quality of evidence is very low due to high risk of bias, imprecision, and inconsistency. There were five comparative studies which reported on posttransplant survival rates and 10 comparative studies which reported on posttransplant recurrence, and there was no significant difference seen in either of these endpoints. For adults initially with stage T3 HCC who received LRT, there were three studies reporting on transplant with any down-staging therapy versus no downstaging, and this showed a significant increase in 1-year (two studies, RR, 1.11; 95% CI, 1.01-1.23) and 5-year (1 study, RR, 1.17; 95% CI, 1.03-1.32) post-LT survival rates for patients who received LRT. The quality of evidence is very low due to serious risk of bias and imprecision.In patients with HCC listed for LT, the use of LRT is associated with a nonsignificant trend toward improved waitlist and posttransplant outcomes, though there is a high risk of selection bias in the available evidence. (Hepatology 2018;67:381-400).© 2017 by the American Association for the Study of Liver Diseases.
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| [247] |
There is no consensus regarding selection criteria on liver transplantation (LT) for hepatocellular carcinoma (HCC), especially for living donor liver transplantation, although emerging evidence has been found for the effectiveness of bridging or downstaging.We evaluated the long-term outcomes of patients who underwent LT with or without bridging or downstaging for HCC.This retrospective study included 896 LT recipients with HCC between June 2005 and May 2015. Recurrence-free survival (RFS), overall survival (OS), and their associated factors were evaluated.The 5-year RFS in the full cohort of 896 patients was 82.4%, and the OS was 85.3%. In patients with initial Organ Procurement and Transplantation Network (OPTN) T1 and T2, the 5-year RFS and OS did not significantly differ between LT groups with and without bridging (all ≥ 0.05). The 5-year RFS and OS of OPTN T3 patients with successful downstaging were not significantly different from those of patients with OPTN T2 with primary LT (= 0.070 and = 0.185), but were significantly higher than in patients with OPTN T3 with downstaging failure and initial OPTN T1 or T2 with progression (all < 0.001). In the multivariate analysis, last alpha-fetoprotein before LT ≥70 ng/mL (hazard ratio [HR]: 1.77, = 0.001; HR: 1.72, = 0.004), pretransplant HCC status exceeding the Milan criteria (HR: 5.12, < 0.001; HR: 3.31, < 0.001), and positron emission tomography positivity (HR: 2.57, < 0.001; HR: 2.57, < 0.001) were independent predictors for worse RFS and OS.The impact of bridging therapy on survival outcomes is limited in patients with early-stage HCC, whereas OPTN T1 or T2 with progression provides worse prognosis. OPTN T3 should undergo LT after successful downstaging, and OPTN T3 with successful downstaging allows for acceptable long-term posttransplant outcomes.Copyright © 2020 by S. Karger AG, Basel.
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| [248] |
Indications for liver transplantation for hepatocellular carcinoma are evolving and so-called expanded criteria remain debated. Locoregional therapies are able to downstage hepatocellular carcinoma from beyond to within the Milan criteria. We aimed to investigate the efficacy of liver transplantation after successful hepatocellular carcinoma downstaging.We did an open-label, multicentre, randomised, controlled trial designed in two phases, 2b and 3, at nine Italian tertiary care and transplantation centres. Patients aged 18-65 years with hepatocellular carcinoma beyond the Milan criteria, absence of macrovascular invasion or extrahepatic spread, 5-year estimated post-transplantation survival of at least 50%, and good liver function (Child-Pugh A-B7) were recruited and underwent tumour downstaging with locoregional, surgical, or systemic therapies according to multidisciplinary decision. After an observation period of 3 months, during which sorafenib was allowed, patients with partial or complete responses according to modified Response Evaluation Criteria in Solid Tumors were randomly assigned (1:1) by an interactive web-response system to liver transplantation or non-transplantation therapies (control group). A block randomisation (block size of 2), stratified by centre and compliance to sorafenib treatment, was applied. Liver transplantation was done with whole or split organs procured from brain-dead donors. The control group received sequences of locoregional and systemic treatment at the time of demonstrated tumour progression. The primary outcomes were 5-year tumour event-free survival for phase 2b and overall survival for phase 3. Analyses were by intention to treat. Organ allocation policy changed during the course of the study and restricted patient accrual to 4 years. This trial is registered with ClinicalTrials.gov, NCT01387503.Between March 1, 2011, and March 31, 2015, 74 patients were enrolled. Median duration of downstaging was 6 months (IQR 4-11). 29 patients dropped out before randomisation and 45 were randomly assigned: 23 to the transplantation group versus 22 to the control group. At data cutoff on July 31, 2019, median follow-up was 71 months (IQR 60-85). 5-year tumour event-free survival was 76·8% (95% CI 60·8-96·9) in the transplantation group versus 18·3% (7·1-47·0) in the control group (hazard ratio [HR] 0·20, 95% CI 0·07-0·57; p=0·003). 5-year overall survival was 77·5% (95% CI 61·9-97·1) in the transplantation group versus 31·2% (16·6-58·5) in the control group (HR 0·32, 95% CI 0·11-0·92; p=0·035). The most common registered grade 3-4 serious adverse events were hepatitis C virus recurrence (three [13%] of 23 patients) and acute transplant rejection (two [9%]) in the transplantation group, and post-embolisation syndrome (two [9%] of 22 patients) in the control group. Treatment-related deaths occurred in four patients: two (8%) of 23 patients in the transplantation group (myocardial infarction and multi-organ failure) versus two (9%) of 22 patients in the control group (liver decompensation).Although results must be interpreted with caution owing to the early closing of the trial, after effective and sustained downstaging of eligible hepatocellular carcinomas beyond the Milan criteria, liver transplantation improved tumour event-free survival and overall survival compared with non-transplantation therapies Post-downstaging tumour response could contribute to the expansion of hepatocellular carcinoma transplantation criteria.Italian Ministry of Health.Copyright © 2020 Elsevier Ltd. All rights reserved.
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| [249] |
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| [250] |
National guidelines on transplant selection have adopted successful downstaging to within Milan criteria (MC) as a viable option for the treatment of hepatocellular carcinoma (HCC) before liver transplant (LT). Recurrence of HCC after LT carries a poor prognosis, and treatment modalities remain challenging.To establish the 10-year outcomes of patients with HCC after LT in a large, multicenter US study based on individual data; provide robust data on the long-term role of downstaging; and evaluate the association of treatment modalities with postrecurrence survival.In this cohort study, a retrospective, multicenter analysis of prospectively collected data was conducted for 2645 adults who had undergone LT for HCC at 5 US academic centers between January 2001 and December 2015. The analysis was performed from May 2019 through June 2021. Outcomes of 341 patients whose disease was downstaged to within MC were compared with those in 2122 patients whose disease was always within MC and 182 patients whose disease was not downstaged. The associations of tumor and treatment factors on postrecurrence survival were analyzed using Cox proportional hazards regression and multivariable logistic regression models.The primary outcome was overall survival for the whole cohort and according to downstaging status. Secondary outcomes were time to recurrence, recurrence-free survival, and recurrence after specific post-LT therapies.Of the 2645 patients studied, the median age was 59.9 years (IQR, 54.7-64.7 years). The majority of the patients were men (2028 [76.7%] vs 617 [23.3%] women). The 10-year post-LT survival and recurrence rates were, respectively, 52.1% and 20.6% among those whose disease was downstaged; 61.5% and 13.3% in those always within MC; and 43.3% and 41.1% in those whose disease was not downstaged. Independent variables associated with downstaging failure were tumor size greater than 7 cm at diagnosis (OR, 2.62; 95% CI, 1.20-5.75; P = .02), more than 3 tumors at diagnosis (OR, 2.34; 95% CI, 1.22-4.50; P = .01), and α-fetoprotein response of at least 20 ng/mL with less than 50% improvement from maximum α-fetoprotein before LT (OR, 1.99; 95% CI, 1.14-3.46; P = .02). Surgically treated patients with recurrent HCC differed in clinicopathologic characteristics and had improved 5-year postrecurrence survival rates (31.6% vs 7.3%; P < .001).In a large, multicenter cohort of patients with HCC successfully downstaged to within MC, 10-year post-LT outcomes were excellent, validating national downstaging policies and showing a clear utility benefit for LT prioritization decision making. Surgical management of HCC recurrence after LT was associated with improved survival in well-selected patients and should be pursued, if feasible.
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| [251] |
United Network of Organ Sharing (UNOS) has adopted uniform criteria for down-staging (UNOS-DS) of hepatocellular carcinoma (HCC) prior to liver transplantation (LT), but down-staging success rate and intention-to-treat outcomes across broad geographic regions are unknown.In this first multi-regional study (7 centers, 4 UNOS regions), consecutive patients with HCC undergoing down-staging based on UNOS-DS criteria were prospectively evaluated from 2016-2019 (n=209).Probability of successful down-staging to Milan criteria and dropout at 2 years from initial down-staging procedure was 87.7% and 37.3%, respectively. Pre-treatment AFP-L3 >10% (HR 3.7, p=0.02) was associated with increased dropout risk. When comparing chemoembolization (n=132) and Y-90 radioembolization (n=62) as initial down-staging treatment, there were no differences in mRECIST response, probability of or time to successful down-staging, waitlist dropout or LT. Probability of LT at 3 years was 46.6% after a median of 17.2 months. In the explant, 17.5% had vascular invasion and 42.8% exceeded Milan criteria (under-staging). The only factor associated with under-staging was the sum of the number of lesions plus largest tumor diameter on last pre-LT imaging, and odds of under-staging increased by 35% per 1 unit increase in this sum. Post-LT survival at 2 years was 95% and HCC recurrence occurred in 7.9%.In this first prospective multi-regional study based on UNOS-DS criteria, we observed successful down-staging rate of >80%, and similar efficacy of chemoembolization and Y-90 radioembolization as initial down-staging treatment. A high rate of tumor under-staging was observed despite excellent 2-year post-LT survival of 95%. Additional LRT to reduce viable tumor burden may reduce tumor under-staging.Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.
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| [252] |
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| [253] |
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| [254] |
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| [255] |
Several factors are associated with increased hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT), but no reliable risk score has been established to determine the individual risk for HCC recurrence.We aimed to develop and validate a Risk Estimation of Tumor Recurrence After Transplant (RETREAT) score for patients with HCC meeting Milan criteria by imaging.Predictors of recurrence were tested in a development cohort of 721 patients who underwent LT between 2002 and 2012 at 3 academic transplant centers (University of California-San Francisco; Mayo Clinic, Rochester; and Mayo Clinic, Jacksonville) to create the RETREAT score. This was subsequently validated in a cohort of 341 patients also meeting Milan criteria by imaging who underwent LT at the University of Toronto transplant center using the C concordance statistic and net reclassification index.Characteristics associated with post-LT HCC recurrence.A total of 1061 patients participated in the study; 77.8% (825) were men, and the median (IQR) age was 58.2 (53.3-63.9) years in the development cohort and 56.4 (51.7-61.0) years in the validation cohort (P < .001). In the development cohort of 721 patients (542 men), median α-fetoprotein (AFP) level at the time of LT was 8.3 ng/mL; 9.4% had microvascular invasion (n = 68), and 22.1% were beyond Milan criteria on explant (n = 159) owing to understaging by pretransplantation imaging. Cumulative probabilities of HCC recurrence at 1 and 5 years were 5.7% and 12.8%, respectively. On multivariable Cox proportional hazards regression, 3 variables were independently associated with HCC recurrence: microvascular invasion, AFP at time of LT, and the sum of the largest viable tumor diameter and number of viable tumors on explant. The RETREAT score was created using these 3 variables, with scores ranging from 0 to 5 or higher that were highly predictive of HCC recurrence (C statistic, 0.77). RETREAT was able to stratify 5-year post-LT recurrence risk ranging from less than 3% with a score of 0 to greater than 75% with a score of 5 or higher. The validation cohort (n = 340; 283 men) had significantly higher microvascular invasion (23.8% [n = 81], P < .001), explant beyond Milan criteria (37.3% [n = 159], P < .001), and HCC recurrence at 5 years (17.9% [n = 159], P = .03). RETREAT showed good model discrimination (C statistic, 0.82; 95% CI, 0.77-0.86) and superior recurrence risk classification compared with explant Milan criteria (net reclassification index, 0.40; P = .001) in the validation cohort.We have developed and validated a simple and novel prognostic score that may improve post-LT HCC surveillance strategies and help identify patients who may benefit from future adjuvant therapies.
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| [256] |
HCC recurrence following liver transplantation (LT) is highly morbid and occurs despite strict patient selection criteria. Individualized prediction of post-LT HCC recurrence risk remains an important need. Clinico-radiologic and pathologic data of 4981 patients with HCC undergoing LT from the US Multicenter HCC Transplant Consortium (UMHTC) were analyzed to develop a REcurrent Liver cAncer Prediction ScorE (RELAPSE). Multivariable Fine and Gray competing risk analysis and machine learning algorithms (Random Survival Forest and Classification and Regression Tree models) identified variables to model HCC recurrence. RELAPSE was externally validated in 1160 HCC LT recipients from the European Hepatocellular Cancer Liver Transplant study group. Of 4981 UMHTC patients with HCC undergoing LT, 71.9% were within Milan criteria, 16.1% were initially beyond Milan criteria with 9.4% downstaged before LT, and 12.0% had incidental HCC on explant pathology. Overall and recurrence-free survival at 1, 3, and 5 years was 89.7%, 78.6%, and 69.8% and 86.8%, 74.9%, and 66.7%, respectively, with a 5-year incidence of HCC recurrence of 12.5% (median 16 months) and non-HCC mortality of 20.8%. A multivariable model identified maximum alpha-fetoprotein (HR = 1.35 per-log SD, 95% CI,1.22–1.50, p < 0.001), neutrophil-lymphocyte ratio (HR = 1.16 per-log SD, 95% CI,1.04–1.28, p < 0.006), pathologic maximum tumor diameter (HR = 1.53 per-log SD, 95% CI, 1.35–1.73, p < 0.001), microvascular (HR = 2.37, 95%–CI, 1.87–2.99, p < 0.001) and macrovascular (HR = 3.38, 95% CI, 2.41–4.75, p < 0.001) invasion, and tumor differentiation (moderate HR = 1.75, 95% CI, 1.29–2.37, p < 0.001; poor HR = 2.62, 95% CI, 1.54–3.32, p < 0.001) as independent variables predicting post-LT HCC recurrence (C-statistic = 0.78). Machine learning algorithms incorporating additional covariates improved prediction of recurrence (Random Survival Forest C-statistic = 0.81). Despite significant differences in European Hepatocellular Cancer Liver Transplant recipient radiologic, treatment, and pathologic characteristics, external validation of RELAPSE demonstrated consistent 2- and 5-year recurrence risk discrimination (AUCs 0.77 and 0.75, respectively). We developed and externally validated a RELAPSE score that accurately discriminates post-LT HCC recurrence risk and may allow for individualized post-LT surveillance, immunosuppression modification, and selection of high-risk patients for adjuvant therapies.
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| [257] |
\n Steroid use after liver transplantation (LT) has been associated with diabetes, hypertension, hyperlipidemia, obesity, and hepatitis C (HCV) recurrence. We performed meta-analysis and meta-regression of 30 publications representing 19 randomized trials that compared steroid-free with steroid-based immunosuppression (IS). There were no differences in death, graft loss, and infection. Steroid-free recipients demonstrated a trend toward reduced hypertension [relative risk (RR) 0.84,\n \n P\n \n = 0.08], and statistically significant decreases in cholesterol (standard mean difference −0.41,\n \n P\n \n < 0.001) and cytomegalovirus (RR 0.52,\n \n P\n \n = 0.001). In studies where steroids were replaced by another IS agent, the risks of diabetes (RR 0.29,\n \n P\n \n < 0.001), rejection (RR 0.68,\n \n P\n \n = 0.03), and severe rejection (RR 0.37,\n \n P\n \n = 0.001) were markedly lower in steroid-free arms. In studies in which steroids were not replaced, rejection rates were higher in steroid-free arms (RR 1.31,\n \n P\n \n = 0.02) and reduction of diabetes was attenuated (RR 0.74,\n \n P\n \n = 0.2). HCV recurrence was lower with steroid avoidance and, although no individual trial reached statistical significance, meta-analysis demonstrated this important effect (RR 0.90,\n \n P\n \n = 0.03). However, we emphasize the heterogeneity of trials performed to date and, as such, do not recommend basing clinical guidelines on our conclusions. We believe that a large, multicenter trial will better define the role of steroid-free regimens in LT.\n
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| [258] |
Recurrence of hepatocellular carcinoma (HCC) is a major complication after liver transplantation (LT). The initial immunosuppression protocol may influence HCC recurrence, but the optimal regimen is still unknown.219 HCC consecutive patients under Milan criteria, who received an LT at 2 European centres between 2000 and 2010, were included. Median follow-up was 51 months (IQR 26-93). Demographic characteristics, HCC features, and immunosuppression protocol within the first month after LT were evaluated against HCC recurrence by using Cox regression.In the explanted liver, 110 patients (50%) had multinodular HCC, and largest nodule diameter was 3±2.1cm. Macrovascular invasion was incidentally detected in 11 patients (5%), and microvascular invasion was present in 41 patients (18.7%). HCC recurrence rates were 13.3% at 3 years and 17.6% at 5 years. HCC recurrence was not influenced by the use/non-use of steroids and antimetabolites (p=0.69 and p=0.70 respectively), and was similar with tacrolimus or cyclosporine (p=0.25). Higher exposure to calcineurin inhibitors within the first month after LT (mean tacrolimus trough concentrations >10ng/ml or cyclosporine trough concentrations >300ng/ml), but not thereafter, was associated with increased risk of HCC recurrence (27.7% vs. 14.7% at 5 years; p=0.007). The independent predictors of HCC recurrence by multivariate analysis were: high exposure to calcineurin inhibitors defined as above (RR=2.82; p=0.005), diameter of the largest nodule (RR=1.31; p<0.001), microvascular invasion (RR=2.98; p=0.003) and macrovascular invasion (RR=4.57; p=0.003).Immunosuppression protocols with early CNI minimization should be preferred in LT patients with HCC in order to minimize tumour recurrence.Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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| [259] |
The aim of this study was to evaluate the survival benefit of sirolimus in patients undergoing liver transplantation (LT) for hepatocellular carcinoma (HCC) (exploratory analysis of the SiLVER-trial).
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| [260] |
Liver transplantation is the best treatment option for cirrhotic patients with early-stage hepatocellular carcinoma, but it faces the problem of scarcity of donors and the risk of tumor recurrence, which affects between 15% and 20% of the cases, despite the use of restrictive criteria. The risk of recurrence depends on a number of factors, related to the tumor, the patient, and the treatment, which are discussed in this review. Some of these factors are already well established, such as the histopathological characteristics of the tumor, Alpha-fetoprotein (AFP) levels, and waiting time. Other factors related to the biological behavior of the tumor and treatment should be recognized because they can be used in the refinement of the selection criteria of transplant candidates and in an attempt to reduce recurrence. This review also discusses the clinical presentation of recurrence and its prognosis, contributing to the identification of a subgroup of patients who may have better survival, if they are timely identified and treated. Development of recurrence after the first year, with AFP levels ≤ 100 ng/mL, and single site capable of locoregional therapy are associated with better survival after recurrence.
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| [261] |
To evaluate predictors of mortality and impact of treatment in patients developing recurrent hepatocellular carcinoma (HCC) following liver transplantation (LT).Despite well-described clinicopathologic predictors of posttransplant HCC recurrence, data on prognosis following recurrence are scarce.Multivariate predictors of mortality following HCC recurrence were identified to develop a risk score model to stratify prognostic subgroups among 106 patients developing posttransplant recurrence from 1984 to 2014, including analysis of recurrence treatment modality on survival.Of 857 patients undergoing LT, 106 (12.4%) developed posttransplant HCC recurrence (median 15.8 months following LT) with a median post-recurrence survival of 10.6 months. Patients receiving surgical therapy (n = 25) had a median survival of 27.8 months, significantly superior to patients receiving nonsurgical therapy (10.6 months) and best supportive care (3.7 months, P < 0.001). Multivariate predictors of mortality following recurrence included model for end-stage liver disease at LT >23, time to recurrence, >3 recurrent nodules, maximum recurrence size, bone recurrence, alphafetoprotein at recurrence, donor serum sodium, and pretransplant recipient neutrophil-lymphocyte ratio. A risk score model based on multivariate predictors accurately stratified recurrent HCC patients into prognostic subgroups, with low-risk patients (<10 points) demonstrating excellent median survival of 70.6 months, significantly superior to the medium-risk (12.2 months, 10-16 points) and high-risk (3.4 months, >16 points) groups (C-statistic 0.75, P < 0.001).In the largest single-center report of recurrent HCC following LT, surgical treatment in well-selected patients is associated with significantly improved survival and should be pursued. A risk score model accurately stratifies prognostic subgroups, and may help guide treatment strategies.
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| [262] |
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| [263] |
Regorafenib is one option for second-line treatment of hepatocellular carcinoma (HCC), improving overall survival (OS) of sorafenib-tolerant patients who develop progression. We aim to evaluate the safety and outcomes of regorafenib as second-line treatment for HCC recurrence after liver transplantation (LT). This is a retrospective, multicenter, international study including regorafenib-treated LT patients (2015-2018), with analysis of baseline characteristics and evolutionary events during sorafenib/regorafenib treatment. Twenty-eight LT patients (57 years, 7% cirrhotics, 54% performance status 1) were included. Median time from LT to regorafenib initiation was 3.9 (1.1-18.5) years; median time on sorafenib was 11.3 (0.7-76.4) months and 14 (1-591) days from sorafenib discontinuation to regorafenib. During regorafenib (6.3 months), all patients had at least one adverse event (AE), the most common grade 3/4 AEs were fatigue (n = 7) and dermatological reaction (n = 5). While no liver rejection was observed, plasma levels of immunosuppressive drugs increased in five. Twenty-four patients developed progression (38% extrahepatic growth, 33% new extrahepatic lesions/vascular invasion). Median OS from regorafenib initiation was 12.9 (95% CI, 6.7-19.1) and 38.4 months (95% CI, 18.5-58.4) for the sorafenib initiation. This is the first study showing safety of regorafenib after LT, thus providing the rational of considering regorafenib in the clinical decision-making in sorafenib-tolerant patients with HCC recurrence after LT.© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.
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| [264] |
Currently, no surveillance guidelines for hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) exist. In this retrospective, multicenter study, we have investigated the role of surveillance imaging on postrecurrence outcomes.Patients with recurrent HCC after LT from 2002 to 2016 were reviewed from 3 transplant centers (University of California San Francisco, Mayo Clinic Florida, and University of Toronto). For this study, we proposed the term cumulative exposure to surveillance (CETS) as a way to define the cumulative sum of all the protected intervals that each surveillance test provides. In our analysis, CETS has been treated as a continuous variable in months.Two hundred twenty-three patients from 3 centers had recurrent HCC post-LT. The median follow-up was 31.3 months, and median time to recurrence was 13.3 months. Increasing CETS was associated with improved postrecurrence survival (hazard ratio, 0.94; P < 0.01) as was treatment of recurrence with resection or ablation (hazard ratio, 0.31; P < 0.001). An receiver operating characteristic curve (area under the curve, 0.64) for CETS covariate showed that 252 days of coverage (or 3 surveillance scans) within the first 24 months provided the highest probability for aggressive postrecurrence treatment.In this review of 223 patients with post-LT HCC recurrence, we found that increasing CETS does lead to improved postrecurrence survival as well as a higher probability for aggressive recurrence treatment. We found that 252 days of monitoring (ie, 3 surveillance scans) in the first 24 months was associated with the ability to offer potentially curative treatment.
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| [265] |
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| [266] |
The safety of immunotherapy in patients undergoing transplant remains unclear due to rejection risks. This study assessed the safety and efficacy of programmed death-1 (PD-1) inhibitors in patients with recurrent tumors who had undergone liver transplantation, emphasizing the value of using graft programmed death-ligand 1 expression as a predictor of rejection to guide patient selection. This single-center, open-label, prospective, single-arm study was conducted from July 2019 to May 2024 at Zhongshan Hospital, Fudan University (Shanghai, China). Eligible participants included patients with recurrent or metastatic liver cancer who had undergone liver transplantation and were unresponsive to locoregional or systemic therapies. The primary endpoints were the incidence and clinical outcomes of acute rejection. Secondary endpoints were overall survival and objective response rate. Twenty consecutive patients received PD-1 inhibitor therapy. Of these, 18 had HCC, and 2 had intrahepatic cholangiocarcinoma. Liver graft biopsies confirmed negative programmed death-ligand 1 expression in all participants before PD-1 inhibitor therapy. Three patients (15%) experienced acute rejection, with a 95% CI of 3.2%–37.9%. The 1-year and 2-year survival probabilities after PD-1 inhibitor treatment were 0.55 (95% CI: 0.33–0.77) and 0.24 (95% CI: 0.05–0.43), respectively. The median survival time after tumor recurrence was 24.6 months, exceeding the historically reported median survival time of 16.3 months. These exploratory findings suggest that, in selected recipients of liver transplant, PD-1 inhibitors may be associated with reduced rejection risk and potential survival benefit, although further validation is needed.
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| [267] |
The therapeutic value of repeat hepatic resection (rHR) or radiofrequency ablation (RFA) for recurrent hepatocellular carcinoma (HCC) is unknown. This study aimed to investigate the safety and efficacy of rHR or RFA.This was a retrospective multicentre study of patients with recurrent HCC within the Milan criteria who underwent rHR or RFA at nine university hospitals in China and Italy between January 2003 and January 2018. Survival after rHR or RFA was examined in unadjusted analyses and after propensity score matching (1 : 1).Of 847 patients included, 307 and 540 underwent rHR and RFA respectively. Median overall survival was 73.5 and 67.0 months after rHR and RFA respectively (hazard ratio 1.01 (95 per cent c.i. 0.81 to 1.26)). Median recurrence-free survival was longer after rHR versus RFA (23.6 versus 15.2 months; hazard ratio 0.76 (95 per cent c.i. 0.65 to 0.89)). These results were confirmed after propensity score matching. RFA was associated with lower morbidity of grade 3 and above (0.6 versus 6.2 per cent; P < 0.001) and shorter hospital stay (8.0 versus 3.0 days, P < 0.001) than rHR.rHR was associated with longer recurrence-free survival but not overall survival compared with RFA.© The Author(s) 2021. Published by Oxford University Press on behalf of BJS Society Ltd. All rights reserved. For permissions, please email: journals.permissions@oup.com.
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| [268] |
The study objective was to compare the effectiveness of microwave ablation (MWA) and laparoscopic liver resection (LLR) on solitary 3-5-cm HCC over time.From 2008 to 2019, 1289 patients from 12 hospitals were enrolled in this retrospective study. Diagnosis of all lesions were based on histopathology. Propensity score matching was used to balance all baseline variables between the two groups in 2008-2019 (n = 335 in each group) and 2014-2019 (n = 257 in each group) cohorts, respectively. For cohort 2008-2019, during a median follow-up of 35.8 months, there were no differences in overall survival (OS) between MWA and LLR (HR: 0.88, 95% CI 0.65-1.19, p = 0.420), and MWA was inferior to LLR regarding disease-free survival (DFS) (HR 1.36, 95% CI 1.05-1.75, p = 0.017). For cohort 2014-2019, there was comparable OS (HR 0.85, 95% CI 0.56-1.30, p = 0.460) and approached statistical significance for DFS (HR 1.33, 95% CI 0.98-1.82, p = 0.071) between MWA and LLR. Subgroup analyses showed comparable OS in 3.1-4.0-cm HCCs (HR 0.88, 95% CI 0.53-1.47, p = 0.630) and 4.1-5.0-cm HCCs (HR 0.77, 95% CI 0.37-1.60, p = 0.483) between two modalities. For both cohorts, MWA shared comparable major complications (both p > 0.05), shorter hospitalization, and lower cost to LLR (all p < 0.001).MWA might be a first-line alternative to LLR for solitary 3-5-cm HCC in selected patients with technical advances, especially for patients unsuitable for LLR.© 2022 American Association for the Study of Liver Diseases.
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| [269] |
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| [270] |
To compare the long-term outcomes of surgical resection and radiofrequency ablation for the treatment of small hepatocellular carcinoma (HCC).Radiofrequency ablation (RFA) is a promising, emerging therapy for small HCC. Whether it is as effective as surgical resection (RES) for long-term outcomes is still indefinite.Two hundred thirty HCC patients who met the Milan criteria and were suitable to be treated by either RES or RFA entered into a randomized controlled trial. The patients were regularly followed up after treatment for 5 years (except for those who died). The primary end point was overall survival; the secondary end points were recurrence-free survival, overall recurrence, and early-stage recurrence.The 1-, 2-, 3-, 4- and 5-year overall survival rates for the RFA group and the RES group were 86.96%, 76.52%, 69.57%, 66.09%, 54.78% and 98.26%, 96.52%, 92.17%, 82.60%, 75.65%, respectively. The corresponding recurrence-free survival rates for the 2 groups were 81.74%, 59.13%, 46.08%, 33.91%, 28.69% and 85.22%, 73.92%, 60.87%, 54.78%, 51.30%, respectively. Overall survival and recurrence-free survival were significantly lower in the RFA group than in the RES group (P = 0.001 and P = 0.017). The 1-, 2-, 3-, 4-, and 5-year overall recurrence rates were 16.52%, 38.26%, 49.57%, 59.13%, and 63.48% for the RFA group and 12.17%, 22.60%, 33.91%, 39.13%, and 41.74% for the RES group. The overall recurrence was higher in the RFA group than in the RES group (P = 0.024).Surgical resection may provide better survival and lower recurrence rates than RFA for patients with HCC to the Milan criteria.
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| [271] |
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| [272] |
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| [273] |
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| [274] |
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| [275] |
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| [276] |
To evaluate the efficacy and safety of surgical resection plus radiofrequency ablation (SR-RFA) for multifocal hepatocellular carcinoma (HCC) with 2 or 3 nodules compared with surgical resection (SR). We retrospectively evaluated 824 consecutive HCC patients (SR, n = 754; SR-RFA, n = 70) from January 2009 to December 2015 and performed propensity score matching (PSM) to adjust for patient imbalances at a ratio of 1:4. At baseline, patients in the SR-RFA group had a smaller tumour size and worse liver function (including more ascites, a higher total bilirubin level, and a longer prothrombin time) than patients in the SR group. However, the two groups had similar overall survival (OS) and recurrence-free survival (RFS) rates (= 0.209 and = 0.332). The local recurrence rate of the SR-RFA group was significantly higher than that of the SR group (25.71% and 14.32%, = 0.011). More patients in the SR-RFA group had postoperative complications (= 0.003). In the propensity model, there was no intergroup difference in OS or RFS (= 0.229 and = 0.311, respectively). SR-RFA provides a similar long-term survival to that on SR in HCC patients with 2 or 3 nodules, and its application should be carefully considered.
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| [277] |
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| [278] |
If liver transplantation is not feasible, partial resection is considered the treatment of choice for hepatocellular carcinoma (HCC) in patients with cirrhosis. However, in some centers the first-line treatment for small, single, operable HCC is now radiofrequency ablation (RFA). In the current study, 218 patients with single HCC <or= 2.0 cm (very early or T1 stage) underwent RFA. We assessed 2 primary end points that could be easily compared with those reported for resective surgery: (1) the rate of sustained, local, complete response and (2) the rate of treatment-related complications. The secondary end point was 5-year survival in the 100 patients whose tumors had been considered potentially operable. After a median follow-up of 31 months, sustained complete response was observed in 216 patients (97.2%). In the remaining 6, percutaneous ethanol injection, selective intraarterial chemoembolization, or resection were used as salvage therapy. Perioperative mortality, major complication, and 5-year survival rates were 0%, 1.8%, and 68.5%, respectively.Compared with resection, RFA is less invasive and associated with lower complication rate and lower costs. RFA is also just as effective for ensuring local control of stage T1 HCC, and it is associated with similar survival rates (as recently demonstrated by 2 randomized trials). These data indicate that RFA can be considered the treatment of choice for patients with single HCC <or= 2.0 cm, even when surgical resection is possible. Other approaches can be used as salvage therapy for the few cases in which RFA is unsuccessful or unfeasible.
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| [279] |
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| [280] |
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| [281] |
We aimed to compare the therapeutic outcomes of radiofrequency ablation (RFA) and microwave ablation (MWA) as first-line therapies in patients with small single perivascular hepatocellular carcinoma (HCC).A total of 144 eligible patients with small (≤ 3 cm) single perivascular (proximity to hepatic and portal veins) HCC who underwent RFA (N = 70) or MWA (N = 74) as first-line treatment were included. The overall survival (OS), disease-free survival (DFS), and local tumor progression (LTP) rates between the two ablation modalities were compared. The inverse probability of treatment weighting (IPTW) method was used to reduce selection bias. Subgroup analysis was performed according to the type of hepatic vessels.After a median follow-up time of 38.2 months, there were no significant differences in OS (5-year OS: RFA 77.7% vs. MWA 74.6%; p = 0.600) and DFS (5-year DFS: RFA 24.7% vs. MWA 40.4%; p = 0.570). However, a significantly higher LTP rate was observed in the RFA group than the MWA group (5-year LTP: RFA 24.3% vs. MWA 8.4%; p = 0.030). IPTW-adjusted analyses revealed similar results. The treatment modality (RFA vs. MWA: HR 7.861, 95% CI 1.642-37.635, p = 0.010) was an independent prognostic factor for LTP. We observed a significant interaction effect of ablation modality and type of peritumoral vessel on LTP (p = 0.034). For patients with periportal HCC, the LTP rate was significantly higher in the RFA group than in the MWA group (p = 0.045). However, this difference was not observed in patients with perivenous HCC (p = 0.116).In patients with a small single periportal HCC, MWA exhibited better tumor control than RFA.• Microwave ablation exhibited better local tumor control than radiofrequency ablation for small single periportal hepatocellular carcinoma. • There was a significant interaction between the treatment effect of ablation modality and type of peritumoral vessel on local tumor progression. • The type of peritumoral vessel is vital in choosing ablation modalities for hepatocellular carcinoma.
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| [282] |
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| [283] |
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| [284] |
Although microwave ablation (MWA) is a promising technique for hepatocellular carcinoma (HCC) treatment, its 10-year efficacy is unknown.The objective of the study was to assess whether the advances in MWA for HCC translated into a real-world survival benefit.This retrospective study included 2,354 patients with Barcelona Clinic Liver Cancer (BCLC) stage 0 to B from 5 hospitals, with at least 2 years of follow-up for all the patients. Recurrence and survival were analyzed using the Kaplan-Meier method with time-period stratification.A total of 5,326 HCCs (mean diameter, 2.9 cm ± 1.2) underwent 4,051 sessions of MWA with a median follow-up of 61.3 (0.6-169.5 range) months during 3 periods (2007-2010, 2011-2014, and 2015-2018). Technical success was achieved in 5,194 (97.5%) tumors with significant improvement over time, especially for >3.0-cm HCC (< 0.001). Local tumor progression (LTP) showed no period-dependent advance, with >3.0-cm HCC and perivascular location being the risk factors for LTP. The median intrahepatic metastasis time was 27.6 (95% confidence interval [CI]: 25.2-28.8) months, with 5- and 10-year occurrence rates of 68.8% and 79.4%, respectively. The 5- and 10-year overall survivals were 63.9% and 41.1%, respectively, and BCLC stage 0, A, and all B patients showed an observable survival improvement over time (< 0.001). The median disease-free survival time increased from 19.4 (95% CI: 16.5-22.6) months in 2007-2010 to 28.1 (95% CI: 25.9-32.3) months in 2015-2018. The improved survival for early recurrent (≤2 years) patients was period-dependent, as verified by Cox regression analyses. The major complications rate per procedure was 3.0% (122/4,051).These real-world data show that MWA provided an upward trend in survival for HCC patients with BCLC stage 0-B over a 12-year follow-up period. An encouraging clear survival benefit in early recurrent patients was also observed.Copyright © 2022 by The Author(s). Published by S. Karger AG, Basel.
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| [285] |
亚洲冷冻治疗学会, 中国医药教育协会介入微创治疗专业委员会, 山东省医师协会肿瘤介入医师分会. 影像引导肝癌的冷冻消融治疗专家共识(2020 版)[J]. 中国医刊, 2020, 55(5):489-492. DOI: 10.3969/j.issn.1008-1070.2020.05.008.
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| [286] |
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| [287] |
At present, the main clinical application of local ablation therapy, such as radiofrequency ablation (RFA), is to heat the tissue to a certain temperature. However, high temperature will cause thermal damage. Irreversible electroporation (IRE) is a novel minimally invasive local ablation technology for tumors. By high-frequency pulse, the tumor cell membrane can be irretrievably perforated, resulting in the destruction of the intracellular environment, which can preserve important structures in the treatment area. However, there are no randomized controlled clinical trials comparing the efficacy of IRE with traditional local ablation in the treatment of liver cancer.This study aims to conduct a randomized controlled clinical trial comparing the efficacy of IRE with RFA in the treatment of liver cancer.We will conduct a multicenter, randomized, parallel-controlled non-inferiority clinical trial to compare the efficacy and safety of IRE and RFA for hepatocellular carcinoma (HCC). One hundred and ninety patients with HCC from five academic medical centers will be enrolled. The patients will be randomized into treatment arm (IRE) and control arm (RFA). The primary outcome is the progress -free survival (PFS) and the key secondary outcome is the Overall survival (OS).Forty-eight patients had been recruited from 5 centers, of which, 33 patients (median age, 59.1 years) with 38 tumors had completed the 1-month follow-up and 21 patients have complete the 3-month follow up, with 2.3 months median follow up period. The mean largest tumor diameter is 3.9 cm. No end point was observed for PFS or OS in both groups, and the complete ablation rate was 100% in both groups. The lesions in the IRE group showed obvious shrinkage 1 month after procedure. One major adverse event (AE) was occurred in the control group.This is the first randomized controlled clinical trial to compare the clinical effects of IRE and RFA. The preliminary results suggest that both RFA and IRE are effective in the treatment of HCC, which can provide strong evidence for the use of IRE in HCC and provide more options for the treatment of patients with HCC.ClinicalTrials. gov, identifier NCT05451160.© 2024. The Author(s).
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| [288] |
The aim of this study was to compare the outcomes of radiofrequency thermal ablation (RFTA), percutaneous ethanol injection (PEI), and percutaneous acetic acid injection (PAI) in the treatment of hepatocellular carcinoma (HCC).A total of 187 patients with HCCs of 3 cm or less were randomly assigned to RFTA (n = 62), PEI (n = 62), or PAI (n = 63). Tumour recurrence and survival rates were assessed.One, two, and three year local recurrence rates were 10%, 14%, and 14% in the RFTA group, 16%, 34%, and 34% in the PEI group, and 14%, 31%, and 31% in the PAI group (RFTA v PEI, p = 0.012; RFTA v PAI, p = 0.017). One, two, and three year survival rates were 93%, 81%, and 74% in the RFTA group, 88%, 66%, and 51% in the PEI group, and 90%, 67%, and 53% in the PAI group (RFTA v PEI, p = 0.031; RFTA v PAI, p = 0.038). One, two, and three year cancer free survival rates were 74%, 60%, and 43% in the RFTA group, 70%, 41%, and 21% in the PEI group, and 71%, 43%, and 23% in the PAI group (RFTA v PEI, p = 0.038; RFTA v PAI, p = 0.041). Tumour size, tumour differentiation, and treatment methods (RFTA v PEI and PAI) were significant factors for local recurrence, overall survival, and cancer free survival. Major complications occurred in 4.8% of patients (two with haemothorax, one gastric perforation) in the RFTA group and in none in two other groups (RFTA v PEI and PAI, p = 0.035).RFTA was superior to PEI and PAI with respect to local recurrence, overall survival, and cancer free survival rates, but RFTA also caused more major complications.
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| [289] |
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| [290] |
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| [291] |
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| [292] |
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| [293] |
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| [294] |
To investigate the changes in liver volume and function after microwave ablation (MWA) of hepatocellular carcinomas (HCCs).
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| [295] |
There is currently a lack of convincing evidence for microwave ablation (MWA) and laparoscopic liver resection (LLR) for patients ≥60 years old with 3–5 cm hepatocellular carcinoma.
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| [296] |
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| [297] |
中国抗癌协会肿瘤介入专家委员会. 经导管动脉灌注化疗药物应用原则:中国肿瘤介入专家共识[J]. 介入放射学杂志, 2017, 26(11):963-970. DOI:10.3969/j.issn.1008-794X.2017.11.001.
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| [298] |
Transarterial chemoembolization (TACE) using lipiodol-based regimens, including the administration of an anticancer-in-oil emulsion followed by embolic agents, is widely used in the treatment of hepatocellular carcinoma (HCC). This approach has been supported by meta-analyses of randomized, controlled trials (RCTs) performed more than a decade ago. We performed a systematic review to understand current efficacy and safety data of lipiodol TACE in treatment of HCC. A search of the literature published between January 1, 1980 and June 30, 2013 was performed using MEDLINE and EMBASE databases. All potentially relevant publications were reviewed and articles were selected based on predefined inclusion and exclusion criteria. Of a total of 1,564 articles reviewed, 101 articles, including a total of 10,108 patients treated with lipiodol TACE, were selected for the efficacy analysis. Objective response rate was 52.5% (95% confidence interval [CI]: 43.6-61.5). Overall survival (OS) was 70.3% at 1 year, 51.8% at 2 years, 40.4% at 3 years, and 32.4% at 5 years. Median OS was 19.4 months (95% CI: 16.2-22.6). A total of 217 articles presenting precise description on numbers of adverse events (AEs) were selected for the safety review: In these studies, a total of 21,461 AEs were reported in 15,351 patients. Liver enzyme abnormalities were the most commonly observed AE, followed by the symptoms associated with postembolization syndrome. Overall mortality rate was 0.6% and the most common cause of death was related to acute liver insufficiency.In a systematic literature review, survival figures of HCC patients undergoing lipiodol TACE appear to be in line with those reported in previous RCTs, and no new or unexpected safety concerns were identified. (Hepatology 2016;64:106-116).© 2016 by the American Association for the Study of Liver Diseases.
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| [299] |
Lipiodol chemoembolization is a widely used method of treatment in patients with unresectable hepatocellular carcinoma, but its efficacy is still debated. The aim of our study was to assess the efficacy of lipiodol chemoembolization in patients with unresectable hepatocellular carcinoma.Seventy-three patients with unresectable hepatocellular carcinoma, but without severe liver disease or portal vein occlusion, were randomly assigned to receive either repeated lipiodol chemoembolization (lipiodol, cisplatin (2 mg/kg), lecithin, and gelatin sponge injected into the hepatic artery) plus tamoxifen (40 mg) or tamoxifen alone. The main end-point was survival.The 37 patients in the lipiodol chemoembolization group received 104 courses (median 3 per patient). By 1 September 1996, 58 patients had died: 30 in the lipiodol chemoembolization group and 28 in the tamoxifen group. There was no difference in survival between the two groups (p=0.77). The relative risk of death in the lipiodol chemoembolization plus tamoxifen group as compared to the tamoxifen group was 0.92 (95% confidence interval 0.55 to 1.56). At 1 year, survival was 51% and 55%, respectively. An objective tumoral response was more frequently observed in the lipiodol chemoembolization group than in the tamoxifen group (24 versus 5.5%, respectively, p=0.046). Lipiodol chemoembolization caused two deaths and induced signs of liver failure in 51% of the patients assigned to this treatment.In our randomized study, lipiodol chemoembolization did not improve the survival of patients with unresectable hepatocellular carcinoma treated with tamoxifen.
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| [300] |
This randomized, controlled trial assessed the efficacy of transarterial Lipiodol (Lipiodol Ultrafluide, Laboratoire Guerbet, Aulnay-Sous-Bois, France) chemoembolization in patients with unresectable hepatocellular carcinoma. From March 1996 to October 1997, 80 out of 279 Asian patients with newly diagnosed unresectable hepatocellular carcinoma fulfilled the entry criteria and randomly were assigned to treatment with chemoembolization using a variable dose of an emulsion of cisplatin in Lipiodol and gelatin-sponge particles injected through the hepatic artery (chemoembolization group, 40 patients) or symptomatic treatment (control group, 40 patients). One patient assigned to the control group secondarily was excluded because of unrecognized systemic metastasis. Chemoembolization was repeated every 2 to 3 months unless there was evidence of contraindications or progressive disease. Survival was the main end point. The chemoembolization group received a total of 192 courses of chemoembolization with a median of 4.5 (range, 1-15) courses per patient. Chemoembolization resulted in a marked tumor response, and the actuarial survival was significantly better in the chemoembolization group (1 year, 57%; 2 years, 31%; 3 years, 26%) than in the control group (1 year, 32%; 2 years, 11%; 3 years, 3%; P =.002). When adjustments for baseline variables that were prognostic on univariate analysis were made with a multivariate Cox model, the survival benefit of chemoembolization remained significant (relative risk of death, 0.49; 95% CI, 0.29-0.81; P =.006). Although death from liver failure was more frequent in patients who received chemoembolization, the liver functions of the survivors were not significantly different. In conclusion, in Asian patients with unresectable hepatocellular carcinoma, transarterial Lipiodol chemoembolization significantly improves survival and is an effective form of treatment.
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| [301] |
There is no standard treatment for unresectable hepatocellular carcinoma. Arterial embolisation is widely used, but evidence of survival benefits is lacking.We did a randomised controlled trial in patients with unresectable hepatocellular carcinoma not suitable for curative treatment, of Child-Pugh class A or B and Okuda stage I or II, to assess the survival benefits of regularly repeated arterial embolisation (gelatin sponge) or chemoembolisation (gelatin sponge plus doxorubicin) compared with conservative treatment. 903 patients were assessed, and 112 (12%) patients were finally included in the study. The primary endpoint was survival. Analyses were by intention to treat.The trial was stopped when the ninth sequential inspection showed that chemoembolisation had survival benefits compared with conservative treatment (hazard ratio of death 0.47 [95% CI 0.25-0.91], p=0.025). 25 of 37 patients assigned embolisation, 21 of 40 assigned chemoembolisation, and 25 of 35 assigned conservative treatment died. Survival probabilities at 1 year and 2 years were 75% and 50% for embolisation; 82% and 63% for chemoembolisation, and 63% and 27% for control (chemoembolisation vs control p=0.009). Chemoembolisation induced objective responses sustained for at least 6 months in 35% (14)of cases, and was associated with a significantly lower rate of portal-vein invasion than conservative treatment. Treatment allocation was the only variable independently related to survival (odds ratio 0.45 [95% CI 0.25-0.81], p=0.02).Chemoembolisation improved survival of stringently selected patients with unresectable hepatocellular carcinoma.
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| [302] |
To review the available evidence of chemoembolization for unresectable hepatocellular carcinoma (HCC).Computerized bibliographic searches with MEDLINE and CANCERLIT databases from 1980 through 2000 were supplemented with manual searches, with the keywords "hepatocellular carcinoma," "liver cell carcinoma," "randomized controlled trial [RCT]," and "chemoembolization." Studies were included if patients with unresectable HCC were enrolled and if they were RCTs in which chemoembolization was compared with nonactive treatment (five RCTs) or if different transarterial modalities of therapy (13 RCTs) were compared. Data were extracted from each RCT according to the intention-to-treat method. Five of the RCTs with a nonactive treatment arm were combined by using the random-effects model, whereas all 18 RCTs were pooled from meta-regression analysis.Chemoembolization significantly reduced the overall 2-year mortality rate (odds ratio, 0.54; 95% CI: 0.33, 0.89; P =.015) compared with nonactive treatment. Analysis of comparative RCTs helped to predict that overall mortality was significantly lower in patients treated with transarterial embolization (TAE) than in those treated with transarterial chemotherapy (odds ratio, 0.72; 95% CI: 0.53, 0.98; P =.039) and that there is no evidence that transarterial chemoembolization is more effective than TAE (odds ratio, 1.007; 95% CI: 0.79, 1.27; P =.95), which suggests that the addition of an anticancer drug did not improve the therapeutic benefit.In patients with unresectable HCC, chemoembolization significantly improved the overall 2-year survival compared with nonactive treatment, but the magnitude of the benefit is relatively small.
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| [303] |
There is no standard treatment for patients with unresectable hepatocellular carcinoma (HCC). Survival benefits derived from medical interventions are controversial. The aim of this systematic review was to assess the evidence of the impact of medical treatments on survival. Randomized controlled trials (RCTs) that were published as full papers assessing survival for primary treatments of HCC were included. MEDLINE, the Cochrane Library, CANCERLIT, and a manual search from 1978 to May 2002 were used. The primary end point was survival, and the secondary end point was response to treatment. Estimates of effect were calculated according to the random effects model. Sensitivity analysis included methodological quality. We identified 61 randomized trials, but only 14 met the criteria to perform a meta-analysis assessing arterial embolization (7 trials, 545 patients) or tamoxifen (7 trials, 898 patients). Arterial embolization improved 2-year survival compared with control (odds ratio [OR], 0.53; 95% confidence interval [CI], 0.32-0.89; P =.017). Sensitivity analysis showed a significant benefit of chemoembolization with cisplatin or doxorubicin (OR, 0.42; 95% CI, 0.20-0.88) but none with embolization alone (OR, 0.59; 95% CI, 0.29-1.20). Overall, treatment induced objective responses in 35% of patients (range, 16%-61%). Tamoxifen showed no antitumoral effect and no survival benefits (OR, 0.64; 95% CI, 0.36-1.13; P =.13), and only low-quality scale trials suggested 1-year improvement in survival. In conclusion, chemoembolization improves survival of patients with unresectable HCC and may become the standard treatment. Treatment with tamoxifen does not modify the survival of patients with advanced disease.
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| [304] |
中国医师协会介入医师分会临床诊疗指南专委会. 中国肝细胞癌经动脉化疗栓塞 (TACE) 治疗临床实践指南 (2023 年版)[J]. 中华医学杂志, 2023, 103(34):2674-2694. DOI:10.3760/cma.j.cn112137-20230630-01114.
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中国医师协会介入医师分会临床诊疗指南专委会. 中国肝细胞癌经动脉化疗栓塞(TACE)治疗临床实践指南(2021 年版)[J]. 中华内科杂志, 2021, 60(7):599-614.DOI:10.3760/cma.j.cn112137-20210425-00991.
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郭志, 滕皋军, 邹英华, 等. 载药微球治疗原发性和转移性肝癌的技术操作推荐[J]. 中华放射学杂志, 2019, 53(5):336-340. DOI:10.3760/cma.j.issn.1005-1201.2019.05.002.
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| [307] |
Liver cancer is among the 10 most common tumors globally. In China, liver cancer ranks 4 for prevalence and 3 for mortality among all malignant tumors. With respect to the treatment of primary liver cancer, there are a number of therapies currently available, including surgical resection, liver transplantation, ablation, transarterial chemoembolization (TACE), systemic chemotherapy, radiation therapy, targeted drug therapy and immunotherapy. Clinical practice and research have shown that, compared with conventional TACE (cTACE), drug-eluting bead TACE (DEB-TACE) can achieve a higher response rate and longer survival time in patients with primary liver cancer. Compared with that of cTACE, DEB-TACE has more favorable basic conditions for achieving uniformity, which could facilitate the standardization of operation techniques. China is the country with the highest incidence of primary liver cancer, accounting for more than 50% of the global patients, and its etiology and epidemiology in Chinese patients differ from those in Europeans and Americans. Therefore, experts in China have drafted these technical recommendations for the standard operation of drug-eluting beads for the treatment of liver cancer on the basis of accumulated abundant clinical experience and evidence-based medical data.2021 Annals of Translational Medicine. All rights reserved.
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| [308] |
Drug-eluting embolic transarterial chemoembolization (DEE-TACE) is an advance in TACE technique. However, at present there is insufficient evidence to support that DEE-TACE is superior to conventional TACE (cTACE) for hepatocellular carcinoma (HCC). The aim of this meta-analysis is to evaluate the efficacy and safety of TACE with CalliSpheres® microspheres (CSM-TACE) compared with cTACE in patients with HCC.
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| [309] |
Conventional transarterial chemoembolization with ethiodized oil and gelatin sponge (GS) particles is a standard technique for hepatocellular carcinoma. Ethiodized oil can temporarily block tumor sinusoids, portal venules, hepatic sinusoids, and arterial microcommunications. By adding GS embolization, strong ischemic effects not only on the tumor but also on the surrounding liver parenchyma can be achieved. Superselective conventional transarterial chemoembolization is mainly indicated for patients with Child-Pugh scores of 5-8, tumors ≤ 7 cm, and ≤ 5 lesions. According to a Japanese nationwide survey, the 5-year survival rate of patients with Child-Pugh class A and a single tumor was 52%. Copyright © 2016 SIR. Published by Elsevier Inc. All rights reserved.
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| [310] |
To compare patient survival after transarterial chemoembolization with and without intraprocedural C-arm computed tomography (CT) in patients with unresectable hepatocellular carcinoma.We retrospectively reviewed the records of 130 patients with unresectable hepatocellular carcinoma who underwent lipiodol-based chemoembolization using a C-arm cone-beam system. We compared patients who underwent chemoembolization with angiography alone (69 patients; April 2005-July 2007) to those who underwent C-arm CT-assisted chemoembolization (61 patients; July 2007-April 2010). Overall and local progression-free survivals were compared using the Kaplan-Meier estimator with log-rank testing. Univariate and multivariate analyses were performed using the Cox proportional hazards model.Overall survival rates of patients who underwent chemoembolization with and without C-arm CT assistance were 94% and 79%, 81% and 65%, and 71% and 44% at 1, 2, and 3 years, respectively. Local progression-free survival rates of these patients were 43% and 27%, 31% and 10%, and 26% and 5% at 1, 2, and 3 years, respectively. Patients receiving C-arm CT-assisted chemoembolization had significantly higher overall (P=0.005) and local progression-free (P=0.003) survival rates than those receiving chemoembolization with angiography alone. Multivariate analysis showed that C-arm CT assistance was an independent factor associated with longer overall survival (hazard ratio, 0.40; P=0.033) and local progression-free survival (hazard ratio, 0.25; P=0.003).C-arm CT usage in addition to angiography during transarterial chemoembolization prolongs survival in patients with unresectable hepatocellular carcinoma.Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
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| [311] |
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| [312] |
To retrospectively evaluate the relationship between local tumor recurrence and iodized oil deposition in the portal vein by using ultraselective transcatheter arterial chemoembolization (TACE) for small hepatocellular carcinoma.One-hundred twenty-three tumors smaller than 5 cm in diameter (mean diameter, 1.9 cm; median diameter, 1.6 cm) were treated with TACE by using a 2-F tip microcatheter at a distal portion of the subsegmental artery of the liver. Portal vein visualization at spot radiography during TACE was divided into three grades, as follows: 0 = not visualized, 1 = limited near the tumor, and 2 = whole or extended to the embolized area. Local recurrence rates of each grade group were compared. The recurrent pattern was divided into intratumoral and peritumoral recurrence. Complications were also analyzed.Of the 123 tumors, 53 (43.1%) were classified as grade 2, 52 (42.3%) were classified as grade 1, and 18 (14.6%) tumors were classified as grade 0. Overall local recurrence rates at 12, 24, and 36 months were 25.6%, 34.7%, and 34.7%, respectively. The local recurrence rates for the grades 2, 1, and 0 groups were 7.9%, 24.8%, and 85.7%, respectively, at 12 months and 17.7%, 38.9%, and 85.7% at 24 months. Recurrence rates in the grade 2 group were significantly lower than those in the grades 1 and 0 groups (P =.0485 and P <.0001, respectively). Intratumoral recurrence was observed in 21 tumors, most of which were in the grade 0 group. Peritumoral recurrence was noted in 16 tumors, most of which were in the grade 2 group. There were no major complications.Ultraselective TACE was safe and effective in a significant number of tumors. In particular, local recurrence was significantly lower when a greater degree of portal vein visualization was demonstrated during TACE.
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| [313] |
Several publications show that superselective conventional TransArterial ChemoEmbolization (cTACE), meaning cTACE performed selectively with a microcatheter positioned as close as possible to the tumor, improves outcomes, maximizing the anti-tumoral effect and minimizing the collateral damages of the surrounding liver parenchyma. Recent recommendations coming from the European Association for the Study of the Liver (EASL) and European Society of Medical Oncology (ESMO) highlighted that TACE must be used in Hepatocellular Carcinoma (HCC) "selectively targetable" and "accessible to supraselective catheterization." The goal of the manuscript is to better define such population and to standardize superselective cTACE (ss-cTACE) technique. An expert panel with extensive clinical-procedural experience in TACE, have come together in a virtual meeting to generate recommendations and express their consensus. Experts recommend that anytime cTACE is proposed, it should be ss-cTACE, preferably with a 1.5-2.0 Fr microcatheter. Ideally, ss-cTACE should be proposed to patients with less than five lesions and a maximum number of two segments involved, with largest tumor smaller than 5 cm. Angio Cone-Beam Computed Tomography (CBCT) should be used to detect enhancing tumors, tumor feeders and guide tumor targeting. Whole tumor volume should be covered to obtain the best response. Adding peritumoral margins is encouraged but not mandatory. The treatment should involve a water-in-oil emulsion, whose quality is assessable with the "drop test." Additional particulate embolization should be systematically performed, as per definition of cTACE procedure. Non-contrast CBCT or Multi-Detector Computed Tomography (MDCT) combined with angiography has been considered the gold standard for imaging during TACE, and should be used to assess tumor coverage during the procedure. Experts convene that superselectivity decreases incidence of adverse effects and improves tolerance. Experts recommend contrast-enhanced Computed Tomography (CT) as initial imaging on first follow-up after ss-cTACE, and Magnetic Resonance Imaging (MRI) if remaining tumor viability cannot be confidently assessed on CT. If no response is obtained after two ss-cTACE sessions within six months, patient must be considered unsuitable for TACE and proposed for alternative therapy. Patients are best served by multidisciplinary decision-making, and Interventional Radiologists should take an active role in patient selection, treatment allocation, and post-procedural care.© 2022. The Author(s).
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| [314] |
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| [315] |
We analyzed the magnetic resonance imaging (MRI) responses by world health organization (WHO), response evaluation criteria in solid tumor (RECIST), European Association for the Study of Liver (EASL), and modified RECIST (mRECIST) guidelines and correlated with survival after doxorubicin (Adriamycin; Pharmacia & Upjohn, Peapac, NJ). drug-eluting beads transarterial chemoembolization (DEB TACE) in patients with unresectable hepatocellular carcinoma (HCC).The early target and overall imaging responses were studied in 120 consecutive patients treated with DEB TACE for unresectable HCC, using RECIST, WHO, EASL, and mRECIST guidelines on contrast-enhanced dynamic liver MRI. The median period between the DEB TACE and assessment scan was 33.50 days. Survival analyses were carried out with the Kaplan-Meier method and the Cox proportional model.WHO and RECIST1.1 had poor correlation with survival. mRECIST and EASL had significant correlation with survival with target lesion response rates of 63.3% and 48.3% and with overall response rates of 52.5% and 39.2%, respectively. The responders of EASL and mRECIST had significant median survival (P ≤ 0.0001). Moreover, mRECIST was better than EASL in predicting survival, because the survival difference between responders and non-responders of overall response was statistically significant (P = 0.013) for mRECIST, but not for EASL (P = 0.064).EASL and mRECIST responses measured on MRI at an early time point after DEB TACE predicted survival. mRECIST response demonstrated higher survival correlation than EASL.
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| [316] |
Objective response rate (ORR) under mRECIST criteria after transarterial chemoembolization (TACE) is a well-perceived surrogate endpoint of overall survival (OS). However, its optimal time point remains controversial and may be influenced by tumor burden. We aim to investigate the surrogacy of initial/best ORR in relation to tumor burden.A total of 1549 eligible treatment-naïve patients with unresectable hepatocellular carcinoma (HCC), Child-Pugh score ≤ 7, and performance status score ≤ 1 undergoing TACE between January 2010 and May 2016 from 17 academic hospitals were retrospectively analyzed. Based on "six-and-twelve" criteria, tumor burden was graded as low, intermediate, and high if the sum of the maximum tumor diameter and tumor number was ≤ 6, > 6 but ≤ 12, and > 12, respectively.Both initial and best ORRs interacted with tumor burden. Initial and best ORRs could equivalently predict and correlate with OS in low (adjusted HR, 2.55 and 2.95, respectively, both p < 0.001; R = 0.84, p = 0.035, and R = 0.97, p = 0.002, respectively) and intermediate strata (adjusted HR, 1.81 and 2.22, respectively, both p < 0.001; R = 0.74, p = 0.023, and R = 0.9, p = 0.002, respectively). For high strata, only best ORR exhibited qualified surrogacy (adjusted HR, 2.61, p < 0.001; R = 0.70, p = 0.035), whereas initial ORR was not significant (adjusted HR, 1.08, p = 0.357; R = 0.22, p = 0.54).ORR as surrogacy of OS is associated with tumor burden. For patients with low/intermediate tumor burden, initial ORR should be preferred in its early availability upon similar sensitivity, whereas for patients with high tumor burden, best ORR has optimal sensitivity. Timing of OR assessment should be tailored according to tumor burden.• This is the first study utilizing individual patient data to comprehensively analyze the surrogacy of ORR with a long follow-up period. • Optimal timing of ORR assessment for predicting survival should be tailored according to tumor burden. • For patients with low and intermediate tumor burden, initial ORR is optimal for its timeliness upon similar sensitivity with best ORR. For patients with high tumor burden, best ORR has optimal sensitivity.© 2022. The Author(s), under exclusive licence to European Society of Radiology.
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| [317] |
European Association for the Study of the Liver (EASL) and modified Response Evaluation Criteria in Solid Tumours (mRECIST) guidelines, which measure changes in arterialised hepatocellular carcinoma (HCC), differ in terms of number of target lesions (all versus ≤2) and calculation method (bidimensional versus unidimensional). We compared prognostic values of mRECIST for predicting overall survival (OS) with reference to EASL criteria in treatment-naïve HCC undergoing trans-arterial chemoembolisation (TACE).The ability to predict OS during longitudinal follow-up was expressed as C-index, and a sample size of 292 patients was required to validate its equivalence between each criteria. Treatment responses were assessed using both guidelines 4weeks after the first TACE, using dynamic computed tomography or magnetic resonance imaging. Kaplan-Meier and Cox regression analyses were used to explore differences in OS between responders (complete or partial) and non-responders (stable or progressive disease), defined by each method.C-index for EASL and mRECIST guidelines was 0.753 and 0.759, respectively, demonstrating equivalence between two methods. Differences in median OS between responders and non-responders were statistically significant for both EASL (30.1 versus 18.7 months, p<0.001) and mRECIST (33.8 versus 17.1 months, p<0.001) guidelines. In addition to radiological response, α-fetoprotein (p<0.001), tumour number (p<0.001) and tumour size (p=0.048) were significant predictors of OS. In multivariate analysis, radiological criteria, tumour number and α-fetoprotein were identified as independent predictors (all p<0.05).mRECIST, a simpler method, provided prognostic values for predicting OS equivalent to EASL criteria in patients with HCC undergoing TACE as an initial treatment modality.Copyright © 2012 Elsevier Ltd. All rights reserved.
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| [318] |
It is not clear whether survival times of patients with hepatocellular carcinoma (HCC) are associated with their response to therapy. We analyzed the association between tumor response and survival times of patients with HCC who were treated with locoregional therapies (LRTs) (chemoembolization and radioembolization).Patients received LRTs over a 9-year period (n = 463). Patients with metastases, portal venous thrombosis, or who had received transplants were excluded; 159 patients with Child-Pugh B7 or lower were analyzed. Response (based on European Association for the Study of the Liver [EASL] and World Health Organization [WHO] criteria) was associated with survival times using the landmark, risk-of-death, and Mantel-Byar methodologies. In a subanalysis, survival times of responders were compared with those of patients with stable disease and progressive disease.Based on 6-month data, in landmark analysis, responders survived longer than nonresponders (based on EASL but not WHO criteria: P =.002 and.0694). The risk of death was also lower for responders (based on EASL but not WHO criteria: P =.0463 and.707). Landmark analysis of 12-month data showed that responders survived longer than nonresponders (P <.0001 and.004, based on EASL and WHO criteria, respectively). The risk of death was lower for responders (P =.0132 and.010, based on EASL and WHO criteria, respectively). By the Mantel-Byar method, responders had longer survival than nonresponders, based on EASL criteria (P <.0001; P =.596 with WHO criteria). In the subanalysis, responders lived longer than patients with stable disease or progressive disease.Radiographic response to LRTs predicts survival time. EASL criteria for response more consistently predicted survival times than WHO criteria. The goal of LRT should be to achieve a radiologic response, rather than to stabilize disease.Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.
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| [319] |
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| [320] |
Aim of the study was to assess the clinical impact of conventional transarterial chemoembolization (cTACE) repeated "on demand" on HCC outcome. Outcome measures were: response rate to first and repeated cTACE, recurrence rates and overall survival.The outcome of 151 consecutive HCC patients submitted to a first cTACE from January 2004 to December 2005 was retrospectively analyzed.Complete radiological response (CR) was observed in 72/151 (48%), 34/60 (52%) and 12/22 (55%) patients after first, second and third cTACE, respectively. Recurrence rates at 6 and 12months were 37% and 61% after the first cTACE, and 40% and 59% after the second cTACE, respectively. Patients not achieving CR or with a recurrence after CR not treated with curative therapies were 94 and 84 after first and second cTACE, respectively. Of these, 60/94 (64%) and 22/84 (26%) were submitted to a second and third cTACE, respectively. Median overall survival was 32.0months but 25.0months excluding transplanted patients. Factors at the time of first cTACE associated with overall shorter survival at multivariate analysis were higher bilirubin, higher AFP and not achieving CR.CR and recurrence rates after first and second cTACE were similar. About 64% of patients were submitted to second cTACE, while only few patients (26%) were submitted to third cTACE using an "on demand" policy. These figures may be also useful for planning trials for the evaluation of the efficacy of repeated TACE vs. TACE combined with adjuvant treatments or vs. systemic treatments.Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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| [321] |
Treatment strategy for hepatocellular carcinoma (HCC) and Vp4 [main trunk] portal vein tumor thrombosis (PVTT) remains limited due to posttreatment liver failure. We aimed to assess the efficacy of irradiation stent placement with 125I plus transcatheter arterial chemoembolization (TACE) (ISP-TACE) compared to sorafenib plus TACE (Sora-TACE) in these patients.
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| [322] |
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| [323] |
To assess feasibility, safety, and preliminary efficacy of an irradiation portal vein stent for portal vein tumor thrombosis (PVTT) in patients with hepatocellular carcinoma (HCC).Between October 2012 and September 2015, 25 of 40 patients (mean age of 55.5 y) with PVTT caused by HCC were recruited for treatment with an irradiation portal vein stent (self-expandable stent loaded with iodine-125 seeds) at a single hospital. Liver function was classified as Child-Pugh class A in 15 patients (60%) and class B in 10 patients (40%). The Eastern Cooperative Oncology Group performance status score was 0 in 3 patients (12%), 1 in 13 patients (52%), and 2 in 9 patients (36%). Transarterial chemoembolization was performed after stent placement. Outcomes were measured in terms of technical success, complications, stent patency, and overall survival.The technical success rate was 92.0% (23/25). No complications grade 3 or higher according to Common Terminology Criteria for Adverse Events were observed. Median stent patency period was 8.0 months (range, 0.6-30.0 months). Between 7 and 955 days after stent placement, 65 cycles of transarterial chemoembolization were performed with a mean of 2.8 cycles per patient. Median survival was 12.5 months (range, 0.6-35.7 months).Placement of an irradiation portal vein stent appears feasible and safe and may prolong the patency of the portal vein. It is a promising technique for combining recanalization of an occluded portal vein and brachytherapy.Copyright © 2017 SIR. Published by Elsevier Inc. All rights reserved.
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| [324] |
胡鸿涛, 黎海亮, 郭晨阳, 等. 125I 粒子植入联合动脉化学栓塞治疗原发性肝癌合并门静脉癌栓[J]. 中华放射学杂志, 2012, 46(6):552-556. DOI:10.3760/cma.j.issn.1005-1201.2012.06.016.
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| [326] |
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| [327] |
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| [328] |
Thermal ablation is widely regarded as definitive therapy for early-stage hepatocellular carcinoma, but its efficacy decreases in tumors greater than 3 cm. Extensive clinical studies have supported improved outcomes provided through combining transarterial embolic therapy with ablation in the treatment of larger tumors. This article will provide a survey of the science and data for combination therapy in both thermal and nonthermal ablation modalities, as well as describe emerging applications.
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| [329] |
To improve the efficacy of radiofrequency ablation (RFA) for the treatment of intermediate-sized hepatocellular carcinomas (HCCs), the authors compared RFA combined with transcatheter arterial chemoembolization (TACE) to RFA alone.The authors randomly assigned 37 patients with solitary HCCs (diameter, 3.1-5.0 cm in the greatest dimension) to 2 groups: the TACE-RFA group, in which the patients received TACE followed by RFA on the same day, and the RFA group, in which the patients received only RFA.Technical success was achieved after 1.4±0.5 RFA sessions in the RFA group and after 1.1±0.2 RFA sessions in the TACE-RFA group (P<.01). The mean diameters of the longer and shorter axes of the RFA-induced ablated areas were 50±8.0 mm and 41±7.1 mm, respectively, in the RFA group and 58±13.2 mm and 50±11.3 mm, respectively, in the TACE-RFA group; the mean diameters of the shorter axes were significantly different (P=.012). The rates of local tumor progression at the end of the third year in the RFA and TACE-RFA groups were 39% and 6%, respectively (P=.012). The 3-year survival rates of the patients in the RFA and TACE-RFA groups were 80% and 93%, respectively (P=.369).In patients with intermediate-sized HCCs, RFA combined with TACE is more effective than RFA alone for extending the ablated area in fewer treatment sessions and for decreasing the local tumor progression rate.Copyright © 2010 American Cancer Society.
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| [330] |
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| [331] |
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中华医学会放射肿瘤学分会, 中国生物医学工程学会精确放疗分会肝癌学组与消化系统肿瘤专家委员会, 中国研究型医院学会放射肿瘤学分会肝癌学组. 2016 年原发性肝癌放疗共识[J]. 中华放射肿瘤学杂志, 2016, 25(11):1141-1150.DOI: 10.3760/cma.j.issn.1004-4221.2016.11.001.
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| [334] |
Background Transarterial chemoembolization (TACE) is an effective downstaging procedure for hepatocellular carcinoma (HCC). However, knowledge of the effectiveness of radiofrequency ablation (RFA) after downstaging of HCC is currently lacking. Purpose To evaluate the clinical outcomes of RFA after downstaging of HCC by using TACE. Materials and Methods This retrospective study investigated a cohort of patients who underwent RFA with curative intent after downstaging with TACE to meet Milan criteria (one lesion up to 5 cm or no more than three lesions ≤3 cm without vascular invasion or extrahepatic metastasis) from January 2012 to July 2017. A control group of patients initially meeting the Milan criteria also underwent RFA as first-line treatment in the same period. Overall survival (OS), disease-free survival (DFS), and major complication rates were compared by using the log-rank test. To reduce potential bias, a propensity score analysis was also performed. Results There were 72 patients (median age, 56.5 years; range, 30-78 years; 67 men) in the downstaging group and 357 patients meeting the Milan criteria (median age, 58.0 years; range, 25-87 years; 313 men) included in this study. After propensity score matching, the 1-, 3-, and 5-year OS rates were 99%, 80%, and 66%, respectively, for the patients in the downstaging group and 94%, 84%, and 69%, respectively, for the patients in the Milan criteria group. The 1-, 3-, and 5-year DFS rate were 73%, 34%, and 24% for the downstaging group and 74%, 43%, and 37% for the Milan criteria group. There were no differences in the OS, DFS, or major complication rates between the two groups (=.74, =.39, =.73, respectively). Conclusion The long-term patient survival and major complication rates of radiofrequency ablation following transarterial chemoembolization downstaging for hepatocellular carcinoma were similar to that of patients initially meeting the Milan criteria. © RSNA, 2019 See also the editorial by vanSonnenberg and Mueller in this issue.
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| [335] |
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| [336] |
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| [337] |
Microvascular invasion has been widely accepted as a major risk factor of hepatocellular carcinoma prognoses after surgery. It is still controversial whether postoperative adjuvant transarterial chemoembolization could improve the survival of hepatocellular carcinoma patients with microvascular invasion.To evaluate the effect of postoperative adjuvant transarterial chemoembolization for postoperative hepatocellular carcinoma patients with microvascular invasion.PubMed, Web of Science, and Embase databases were searched for eligible studies, and the one-, three-, and five-year recurrence rates and overall survival rates were extracted for meta-analysis.A total of eight studies were included in this study. The results showed that the one-, three-, and five-year recurrence rate of the postoperative adjuvant transarterial chemoembolization group were better than those of the hepatectomy alone group, with a pooled risk ratio (RR) of 0.66 (95% confidence interval [CI] 0.58-0.75, < 0.00001), 0.82 (95% CI 0.76-0.88, < 0.00001), and 0.89 (95% CI 0.82-0.97, = 0.007), respectively. The overall survival rates with one-, three-, and five-year pooled RR were 0.34 (95% CI 0.25-0.47, < 0.00001), 0.69 (95% CI 0.60-0.79, < 0.00001), and 0.78 (95% CI 0.69-0.89, = 0.0001), respectively. No serious side effects have been reported, indicating that postoperative intervention is safe.For hepatocellular carcinoma patients with microvascular invasion confirmed by postoperative pathology, postoperative adjuvant transarterial chemoembolization is a safe treatment, which could reduce the tumor recurrence rate and improve the patient's overall survival.
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| [338] |
The role of adjuvant transarterial chemoembolization (TACE) for patients with resectable hepatocellular carcinoma (HCC) undergoing hepatectomy is currently unclear. We performed a systematic review of the literature using the MEDLINE, Embase, and Cochrane Library databases. Random-effects meta-analysis was carried out to compare the overall survival (OS) and recurrence-free survival (RFS) of patients with resectable HCC undergoing hepatectomy followed by adjuvant TACE vs. hepatectomy alone in randomized controlled trials (RCTs). The risk of bias was assessed using the Risk of Bias 2.0 tool. Meta-regression analyses were performed to explore the effect of hepatitis B viral status, microvascular invasion, type of resection (anatomic vs. parenchymal-sparing), and tumor size on the outcomes. Ten eligible RCTs, reporting on 1216 patients in total, were identified. The combination of hepatectomy and adjuvant TACE was associated with superior OS (hazard ratio (HR): 0.66, 95% confidence interval (CI): 0.52 to 0.85; p < 0.001) and RFS (HR: 0.70, 95% CI: 0.56 to 0.88; p < 0.001) compared to hepatectomy alone. There were significant concerns regarding the risk of bias in most of the included studies. Overall, adjuvant TACE may be associated with an oncologic benefit in select HCC patients. However, the applicability of these findings may be limited to Eastern Asian populations, due to the geographically restricted sample. High-quality multinational RCTs, as well as predictive tools to optimize patient selection, are necessary before adjuvant TACE can be routinely implemented into standard practice. PROSPERO Registration ID: CRD42021245758.
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| [339] |
To evaluate the safety and efficacy of drug-eluting bead transarterial chemoembolization (DEB-TACE) combined with oxaliplatin plus fluorouracil and leucovorin (FOLFOX)-based hepatic arterial infusion chemotherapy (D-TACE-HAIC) for unresectable large (5.1-10 cm) or huge (>10 cm) hepatocellular carcinoma (HCC).This retrospective study evaluated consecutive patients with unresectable large or huge HCC who underwent D-TACE-HAIC (D-TACE-HAIC group) or DEB-TACE (DEB-TACE group) from January 2017 to December 2020. At imaging, tumor infiltrating appearance was classified into smooth tumor margin, non-smooth tumor margin, and macrovascular invasion. Adverse events, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were compared between the two groups.A total of 133 patients (mean age, 53 years ± 12; 117 men) were included: 69 underwent D-TACE-HAIC and 64 underwent DEB-TACE. The patients who underwent D-TACE-HAIC had higher ORR (71.0% vs 53.1%; = 0.033), longer PFS (median, 9.3 vs 6.3 months; = 0.005), and better OS (median, 19.0 vs 14.0 months; = 0.008) than those who underwent DEB-TACE. In subgroup analysis, patients with non-smooth tumor margin (median, 20.8 vs 13.0 months; = 0.031) or macrovascular invasion (median, 15.0 vs 11.0 months; = 0.015) had significantly longer OS in D-TACE-HAIC group than in DEB-TACE group; but in patients with smooth tumor margin, OS between the two groups was similar (median, 37.0 vs 35.0 months; = 0.458). DEB-TACE, non-smooth tumor margin, and macrovascular invasion were independent prognostic factors for poor OS in uni- and multivariable analyses. The incidence of grade 3/4 adverse events was not statistically different between the two groups (37.7% vs 28.1%; = 0.242).D-TACE-HAIC was tolerable and led to better OS than DEB-TACE in patients with large or huge HCC, especially in those with non-smooth tumor margin or macrovascular invasion.© 2021 Huang et al.
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| [340] |
Previous prognostic scores for transarterial chemoembolization (TACE) were mainly derived from real-world settings, which are beyond guideline recommendations. A robust model for outcome prediction and risk stratification of recommended TACE candidates is lacking. We aimed to develop an easy-to-use tool specifically for these patients.Between January 2010 and May 2016, 1,604 treatment-naïve patients with unresectable hepatocellular carcinoma (HCC), Child-Pugh A5-B7 and performance status 0 undergoing TACE were included from 24 tertiary centres. Patients were randomly divided into training (n = 807) and validation (n = 797) cohorts. A prognostic model was developed and subsequently validated. Predictive performance and discrimination were further evaluated and compared with other prognostic models.The final presentation of the model was "linear predictor = largest tumour diameter (cm) + tumour number", which consistently outperformed other currently available models in both training and validation datasets as well as in different subgroups. The thirtieth percentile and the third quartile of the linear predictor, namely 6 and 12, were further selected as cut-off values, leading to the "six-and-twelve" score which could divide patients into 3 strata with the sum of tumour size and number ≤6, >6 but ≤12, and >12 presenting significantly different median survival of 49.1 (95% CI 43.7-59.4) months, 32.0 (95% CI 29.9-37.5) months, and 15.8 (95% CI 14.1-17.7) months, respectively.The six-and-twelve score may prove an easy-to-use tool to stratify recommended TACE candidates (Barcelona Clinic Liver Cancer stage-A/B) and predict individual survival with favourable performance and discrimination. Moreover, the score could stratify these patients in clinical practice as well as help design clinical trials with comparable criteria involving these patients. Further external validation of the score is required.There is currently no prognostic model specifically developed for recommended or ideal transarterial chemoembolization (TACE) candidates with hepatocellular carcinoma, despite these patients being frequently identified as the best target population in pivotal randomized controlled trials. The six-and-twelve score provides patient survival prediction, especially in ideal candidates of TACE, outperforming other currently available models in both training and validation sets, as well as different subgroups. With cut-off values of 6 and 12, the score can stratify ideal TACE candidates into 3 strata with significantly different outcomes and may shed light on risk stratification of these patients in clinical practice as well as in clinical trials.Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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| [341] |
The benefits of combining transarterial chemoembolization (TACE) and sorafenib (TACE-S) over TACE alone for treatment of unresectable hepatocellular carcinoma (HCC) remain controversial. Yet, such populations are heterogeneous in terms of baseline characteristics.To investigate the predictors of survival benefits from added sorafenib and identify the potential candidates for TACE-S.This multicenter observational study was conducted in 17 Chinese tertiary hospitals for patients with unresectable, liver-confined HCC. Eligible patients with performance status score of ≤1 and Child-Pugh score of ≤7 were treated with TACE or TACE-S. Interactions between treatment and baseline variables were evaluated to find indicators for survival benefits, based on which the patients were stratified. Multivariate models adjusted for baseline characteristics or propensity score were used to compare overall survival (OS) and time to tumor progression (TTP).From January 2009 to December 2015, 1,719 consecutive patients received TACE (= 1,406) or TACE-S (= 313). Although TACE-S compared with TACE improved TTP (adjusted hazard ratio [HR] 0.75, = 0.008), no difference in OS was observed (adjusted HR 0.87, = 0.090). Nevertheless, the tumor burden (sum of maximum diameter of largest tumor [cm] and tumor number) and albumin-bilirubin (ALBI) score independently predicted the survival benefits from added sorafenib (interaction < 0.001). For patients with either moderate tumor burden (7-13) or low ALBI score (no more than -2.8) defined as candidates, TACE-S prolonged OS (adjusted HR 0.73, = 0.003) and TTP (adjusted HR 0.72, = 0.014) compared to TACE alone, whereas its superiority disappeared in non-candidates.Not all unresectable HCC patients but those with moderate tumor burden or low ALBI score achieve survival benefits from TACE-S compared with TACE alone. Future randomized controlled trials focusing on the subset are warranted.Copyright © 2020 by S. Karger AG, Basel.
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| [342] |
Lenvatinib is the first-line treatment for advanced hepatocellular carcinoma (HCC). We aimed to compare the clinical outcomes of lenvatinib plus drug-eluting beads transarterial chemoembolization (DEB-TACE) versus lenvatinib alone in real-world practice.This retrospective analysis included 142 consecutive patients who received lenvatinib plus DEB-TACE and 69 patients who received lenvatinib alone as first-line treatment from 15 Chinese academic centers from November 2018 to November 2019. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR) were evaluated by modified Response Evaluation Criteria in Solid Tumors criteria, and safety profiles were compared between the two groups.The median OS and PFS were significantly longer in the combined therapy group than in the monotherapy group in whole cohort (median OS, 15.9 vs. 8.6 months, = 0.0022; median PFS, 8.6 vs. 4.4 months, < 0.001) and after propensity score matching analysis (median OS, 13.8 vs. 7.8 months, = 0.03; median PFS, 7.8 vs. 4.5 months, = 0.009). Moreover, the treatment option was an independent prognostic factor for OS and PFS with adjustment based upon baseline characteristics (adjusted hazard ratio [HR]: 0.53, 95% confidence interval [CI]: 0.36-0.78, = 0.001, and adjusted HR: 0.42, 95% CI: 0.30-0.60, < 0.001, respectively) and propensity score (adjusted HR: 0.52, 95% CI: 0.36-0.76, = 0.001, and adjusted HR: 0.46, 95% CI: 0.33-0.64, < 0.001, respectively). Moreover, a greater ORR was observed in the combined group (ORR: 46.48% vs. 13.05%, < 0.001). Furthermore, the most common adverse events (AEs) were elevated aspartate aminotransferase (54.9%) and fatigue (46.4%) in the lenvatinib plus DEB-TACE group and lenvatinib group, respectively. Most AEs were mild-to-moderate and manageable.With well-tolerated safety, lenvatinib plus DEB-TACE was more effective than lenvatinib monotherapy in improving OS, PFS, and ORR. Thus, it may be a promising treatment for advanced HCC. Future prospective studies confirming these findings are warranted.Copyright © 2022 by The Author(s). Published by S. Karger AG, Basel.
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| [343] |
Numerous studies have demonstrated limited survival benefits of transarterial chemoembolization (TACE) alone in the treatment of intermediate-stage hepatocellular carcinoma (HCC) beyond up-to-seven criteria. The advent of immunotherapy, particularly immune checkpoint inhibitors (ICIs), has opened new avenues for HCC treatment. However, TACE combined with ICIs has not been investigated for patients with intermediate-stage HCC beyond the up-to-seven criteria. The study aims to evaluate the efficacy and safety of this treatment strategy for such patients.
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| [344] |
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| [345] |
This study aimed to investigate the efficacy and safety of transarterial chemoembolization (TACE) plus camrelizumab, a monoclonal antibody targeting programmed death-1, and apatinib for patients with intermediate and advanced hepatocellular carcinoma (HCC) in a real-world setting.
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| [346] |
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| [347] |
Transarterial chemoembolisation (TACE) is standard care for unresectable, non-metastatic hepatocellular carcinoma. We aimed to evaluate the addition of lenvatinib and pembrolizumab to TACE versus dual placebo plus TACE in patients with unresectable, non-metastatic hepatocellular carcinoma.In this multicentre, randomised, double-blind, phase 3 study (LEAP-012), patients were recruited from 137 global sites in 33 countries or regions. Eligible patients were age 18 years or older with unresectable, non-metastatic hepatocellular carcinoma not amenable to curative treatment, but with tumours amenable to TACE, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and Child-Pugh class A disease. Eligible participants were randomly assigned (1:1), stratified by study site, α-fetoprotein level, ECOG performance status, albumin-bilirubin grade, and tumour burden, by a central interactive response system, to receive TACE and either oral lenvatinib (bodyweight ≥60 kg: 12 mg; bodyweight <60 kg: 8 mg; once daily) plus intravenous pembrolizumab (400 mg once every 6 weeks for up to 2 years) or matched dual placebo (oral and intravenous). Primary endpoints were progression-free survival (threshold one-sided p=0·025), per Response Evaluation Criteria in Solid Tumours version 1.1 (modified for the current study to allow for up to five target tumours in the liver and requiring new intrahepatic tumours to meet LI-RADS 5 criteria to be considered progressive disease) by blinded independent central review, and overall survival (threshold one-sided p=0·0012) in the intention-to-treat (ITT) population (ie, all participants randomly assigned to treatment). Safety was assessed in the as-treated population (ie, all participants who were randomly assigned and received at least one dose of any study treatment). Here, we report results from the first interim analysis (final analysis for progression-free survival). This study is registered with ClinicalTrials.gov, NCT04246177, and is active but not recruiting.Between May 22, 2020, and Jan 11, 2023, 847 patients were screened, of whom 480 (57%) were enrolled and randomly assigned to receive TACE plus lenvatinib plus pembrolizumab (n=237) or TACE plus dual placebo (n=243; ITT population). Median age was 66 years (IQR 58-73), 82 (17%) of 480 participants were female, 398 (83%) were male, 98 (20%) were White, 347 (72%) were Asian, four (1%) were Black or African American, and five (1%) were American Indian or Alaska Native. Median follow-up as of data cutoff (Jan 30, 2024) was 25·6 months (IQR 19·5-32·4). Median progression-free survival was 14·6 months (95% CI 12·6-16·7; 132 events [20 deaths and 112 progressions]) with lenvatinib plus pembrolizumab and 10·0 months (8·1-12·2; 154 events [eight deaths and 146 progressions]) with placebo (hazard ratio [HR] 0·66 [95% CI 0·51-0·84]; one-sided p=0·0002). 69 (29%) of 237 in the lenvatinib plus pembrolizumab group and 82 (34%) of 243 from the placebo group died, with a 24-month overall survival rate of 75% (95% CI 68-80) in the lenvatinib plus pembrolizumab group and 69% (62-74) in the placebo group (HR 0·80 [95% CI 0·57-1·11]; one-sided p=0·087). Grade 3 or worse treatment-related adverse events occurred in 169 (71%) of 237 participants in the lenvatinib plus pembrolizumab group and in 76 (32%) of 241 in the placebo group, the most common of which were hypertension (57 [24%] vs 18 [7%]) and platelet count decreased (27 [11%] vs 15 [6%]). Deaths due to treatment-related adverse events occurred in four (2%) participants in the lenvatinib plus pembrolizumab group (n=1 each due to hepatic failure, gastrointestinal haemorrhage, myositis, and immune-mediated hepatitis) and one (<1%) in the placebo group (due to brain stem haemorrhage).TACE plus lenvatinib plus pembrolizumab showed significant, clinically meaningful improvement in progression-free survival in patients with unresectable, non-metastatic hepatocellular carcinoma compared with TACE plus placebo. The numerical improvement in overall survival is encouraging, but longer follow-up is necessary.Merck Sharp & Dohme, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA, and Eisai, Nutley, NJ, USA.Copyright © 2025 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.
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| [348] |
Transarterial chemoembolisation (TACE) is standard of care for patients with unresectable hepatocellular carcinoma that is amenable to embolisation; however, median progression-free survival is still approximately 7 months. We aimed to assess whether adding durvalumab, with or without bevacizumab, might improve progression-free survival.In this multiregional, randomised, double-blind, placebo-controlled, phase 3 study (EMERALD-1), adults aged 18 years or older with unresectable hepatocellular carcinoma amenable to embolisation, an Eastern Cooperative Oncology Group performance status of 0 or 1 at enrolment, and at least one measurable intrahepatic lesion per modified Response Evaluation Criteria in Solid Tumours (RECIST) were enrolled at 157 medical sites including research centres and general and specialist hospitals in 18 countries. Eligible patients were randomly assigned (1:1:1), stratified by TACE method, region, and portal vein invasion, using an interactive voice response or web response system, to TACE plus either durvalumab plus bevacizumab (1500 mg intravenous durvalumab once every 4 weeks, then 1120 mg durvalumab plus 15 mg/kg intravenous bevacizumab once every 3 weeks), durvalumab plus placebo (same regimen using placebo instead of bevacizumab), or placebo alone (same regimen using placebo instead of durvalumab and instead of bevacizumab). Participants, investigators, and those assessing outcomes were masked to treatment assignment until data analysis. The primary endpoint was progression-free survival, by blinded independent central review (BICR), and per RECIST version 1.1, with durvalumab plus bevacizumab versus placebo alone in the intention-to-treat population (ITT; ie, all participants assigned to treatment). Key secondary endpoints were progression-free survival by BICR per RECIST version 1.1 with durvalumab plus placebo versus placebo alone, overall survival, and time to deterioration in select patient-reported outcomes. Participants continue to be followed up for overall survival, and overall survival and patient-reported outcomes will be reported in a later publication. Safety was assessed in the safety analysis set, which included all participants assigned to treatment who received any study treatment (ie, any durvalumab, bevacizumab, or placebo) by treatment received. This study is registered with ClinicalTrials.gov, NCT03778957, and is closed to accrual.Between Nov 30, 2018, and July 19, 2021, 887 patients were screened, of whom 616 were randomly assigned to durvalumab plus bevacizumab (n=204), durvalumab plus placebo (n=207), or placebo alone (n=205; ITT population). Median age was 65·0 years (IQR 59·0-72·0), 135 (22%) of 616 participants were female, 481 (78%) were male, 375 (61%) were Asian, 176 (29%) were White, 22 (4%) were American Indian or Alaska Native, nine (1%) were Black or African American, one (<1%) was native Hawaiian or other Pacific Islander, and 33 (5%) were other races. As of data cutoff (Sept 11, 2023) median follow-up for progression-free survival was 27·9 months (95% CI 27·4-30·4), median progression-free survival was 15·0 months (95% CI 11·1-18·9) with durvalumab plus bevacizumab, 10·0 months (9·0-12·7) with durvalumab, and 8·2 months (6·9-11·1) with placebo. Progression-free survival hazard ratio was 0·77 (95% CI 0·61-0·98; two-sided p=0·032) for durvalumab plus bevacizumab versus placebo, and 0·94 (0·75-1·19; two-sided p=0·64) for durvalumab plus placebo versus placebo. The most common maximum grade 3-4 adverse events were hypertension in participants who received durvalumab and bevacizumab (nine [6%] of 154 participants), anaemia in participants who received durvalumab and placebo (ten [4%] of 232 participants), and post-embolisation syndrome in participants who received placebo alone (eight [4%] of 200 participants). Study treatment-related adverse events that led to death occurred in none of 154 participants who received durvalumab and bevacizumab, three (1%) of 232 who received durvalumab and placebo (n=1 for arterial haemorrhage, liver injury, and multiple organ dysfunction syndrome), and three (2%) of 200 who received placebo alone (n=1 for oesophageal varices haemorrhage, upper gastrointestinal haemorrhage, and dermatomyositis).Durvalumab plus bevacizumab plus TACE has the potential to set a new standard of care. With additional follow-up of the EMERALD-1 study, future analyses, including the final overall survival data and patient-reported outcomes, will help to further characterise the potential clinical benefits of durvalumab plus bevacizumab plus TACE in hepatocellular carcinoma amenable to embolisation.AstraZeneca.Copyright © 2025 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.
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| [349] |
Reactivation of hepatitis B virus (HBV) replication is a well-known complication in cancer patients receiving chemotherapy. The aims of this study were to determine the incidence of HBV reactivation in hepatocellular carcinoma (HCC) patients undergoing transarterial chemo-lipiodolization, and to clarify factors contributing to HBV reactivation.From April 2001 to September 2002, 146 HBsAg positive patients newly diagnosed as HCC were enrolled in the study. Among these, 83 patients underwent transarterial chemo-lipiodolization using epirubicin and/or cisplatin, and 63 received other treatments.In total, HBV reactivation occurred in 30 (20.5%) patients (28 with chemo-lipiodolization and 2 with other treatments), and of the 30 patients, 19 (13.0%) (18 with chemo-lipiodolization and 1 with other treatments) developed hepatitis. Chemo-lipiodolization was significantly correlated with a higher incidence of hepatitis attributed to HBV reactivation than other treatments (21.7% vs. 1.6%, P<0.001), irrespective of HBeAg or HBV DNA. Among 83 patients undergoing chemo-lipiodolization, HBV reactivation occurred in 28 (33.7%) patients, and HBeAg seropositivity was the only independent predictor of HBV reactivation (P=0.013). Three (10.7%) of them died of hepatic decompensation resulting from HBV reactivation.Transarterial chemo-lipiodolization can reactivate HBV, and HBeAg-positive HCC patients receiving chemo-lipiodolization should be closely monitored for HBV reactivation.
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中华医学会感染病学分会, 中华医学会肝病学分会. 慢性乙型肝炎防治指南 (2019 年版)[J]. 临床肝胆病杂志, 2019, 35(12):2648-2669.DOI:10.3969/j.issn.1001-5256.2019.12.007.
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中国抗癌协会肝癌专业委员会. 肝动脉灌注化疗治疗肝细胞癌中国专家共识 (2021 版)[J]. 中华消化外科杂志, 2021, 20(7):754-759.DOI:10.3760/cma.j.cn115610-20210618-00288.
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Hepatic arterial infusion chemotherapy (HAIC) with oxaliplatin and 5-fluorouracil was effective in unresectable hepatocellular carcinoma (HCC). The program of FOLFOX-HAIC in HCC was performed for 1 day (HAIC 1d) or 2 days (HAIC 2d). We hereby retrospectively compared the efficacy and safety between these two treatment regimens and explored the predictive power of thymidylate synthase (TYMS), an enzyme involved in the DNA synthesis process and metabolism of fluorouracil.This study included patients with a primary diagnosis of unresectable HCC. These patients received HAIC for 1 day or 2 days. The overall survival (OS), progression-free survival (PFS), tumor response, and adverse events were compared. The propensity score matching (PSM) was used to reduce bias. Peripheral blood samples before the treatments were collected and used to measure the concentration of TYMS through enzyme-linked immunosorbent assay (ELISA). ELISA was performed according to the manufacturers' guidelines.We included 368 patients for this study: 248 in the HAIC 1d group and 120 in the HAIC 2d group. There was no significant difference of OS between the two groups (14.5 for HAIC 1d vs 15.3 months for HAIC 2d, p=0.46). Compared with the HAIC 1d group, the HAIC 2d group did not prolong the PFS (7.3 vs 7.5 months, p=0.91) or elevate the tumor response (42.5% vs 39.1%, p=0.53) per RECIST 1.1. In the PSM cohort, the efficacy between the two groups was similar. The total frequencies of grade 3-4 events were higher with the HAIC 2d group than with the HAIC 1d group, especially in the PSM cohort (p=0.043). Additionally, patients with TYMS low level might benefit longer OS from the HAIC 2d group (18.7 vs 13.6 months, p=0.014).There was not much of a difference in efficacy between the two groups, but the HAIC for 1 day might be safer, which needed further research. The level of TYMS might be the predictive biomarkers.© 2022. The Author(s).
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中国抗癌协会肝癌专业委员会转化治疗协作组. 肝癌转化治疗中国专家共识 (2021 版)[J]. 中华消化外科杂志, 2021, 20(6):600-616.DOI:10.3760/cma.j.cn115610-20210512-00223.
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| [358] |
This study aimed to assess the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) combined with lenvatinib and immunotherapy and explore its potential as a conversion treatment for unresectable hepatocellular carcinoma (uHCC).
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徐立, 陈敏山, 胡自力. 肝动脉灌注化疗在肝癌转化治疗中的作用[J]. 中国实用外科杂志, 2021, 41(3):272-275. DOI: 10.19538/j.cjps.issn1005-2208.2021.03.07.
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陈敏山, 元云飞, 郭荣平, 等. 肝动脉灌注化疗在肝癌转化治疗中的应用:中山大学肿瘤防治中心的经验总结[J]. 中国医学前沿杂志 : 电子版, 2021, 13(3):70-76. DOI:10.12037/YXQY.2021.03-11.
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| [361] |
The long-term survival of patients with hepatocellular carcinoma (HCC) with portal vein tumour thrombus (PVTT) is poor. Systemic therapy, transcatheter arterial chemoembolization (TACE), and hepatic artery infusion chemotherapy are widely used in HCC patients with PVTT. This study aims to explore the efficacy of combining systemic therapy with transarterial-based therapy in HCC patients with PVTT.
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| [362] |
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| [363] |
Radioembolization is the selective application of radionuclide-loaded microspheres into liver arteries for the therapy of liver tumours and metastases. In this review, we focused on therapy planning and dosimetry, as well as the main indications of 90Y-glass and resin microspheres and 166Ho-microspheres.
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| [364] |
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中国抗癌协会肿瘤介入学专业委员会, 国家卫生健康委能力建设和继续教育中心介入医学专家委员会. 钇 90 微球管理专家共识[J]. 中国介入影像与治疗学, 2021, 18(6):321-325. DOI:10.13929/j.issn.1672-8475.2021.06.001.
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中国医师协会介入医师分会临床诊疗指南专委会, 中国研究型医院学会肝胆胰外科专业委员会. 钇-90 微球选择性内放射治疗肝脏恶性肿瘤规范化操作专家共识 (2024 版)[J]. 中华消化外科杂志, 2024, 23(2):165-178.DOI:10.3760/cma.j.cn115610-20231025-00164.
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| [368] |
Selective internal radiotherapy (SIRT) is a minimal invasive tumor therapy for hepatocellular carcinoma (HCC), biliary tract cancer (BTC), and liver metastasis of extrahepatic tumors. Comprehensive data on past and current trends of SIRT as well as outcome parameters such as in-hospital mortality and adverse events in Germany are missing.We evaluated current clinical developments and outcomes of SIRT in Germany based on standardized hospital discharge data, provided by the German Federal Statistical Office from 2012 to 2019.A total of 11,014 SIRT procedures were included in the analysis. The most common indication was hepatic metastases (54.3%; HCC: 39.7%; BTC: 6%) with a trend in favor of HCC and BTC over time. Most SIRTs were performed with yttrium-90 (99.6%) but the proportion of holmium-166 SIRTs increased in recent years. There were significant differences in the mean length of hospital stay between Y (3.67 ± 2 days) and Ho (2.9 ± 1.3 days) based SIRTs. Overall in-hospital mortality was 0.14%. The mean number of SIRTs/hospital was 22.9 (SD ± 30.4). The 20 highest case volume centers performed 25.6% of all SIRTs.Our study gives a detailed insight into indications, patient-related factors, and the incidence of adverse events as well as the overall in-hospital mortality in a large SIRT collective in Germany. SIRT is a safe procedure with low overall in-hospital mortality and a well-definable spectrum of adverse events. We report differences in the regional distribution of performed SIRTs and changes in the indications and used radioisotopes over the years.SIRT is a safe procedure with very low overall mortality and a well-definable spectrum of adverse events, particularly gastrointestinal. Complications are usually treatable or self-limiting. Acute liver failure is a potentially fatal but exceptionally rare complication. Ho has promising beneficial bio-physical characteristics and Ho-based SIRT should be further evaluated against Y-based SIRT as the current standard of care.Copyright: © 2023 Author(s).
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| [369] |
Locoregional therapies, including yttrium-90 (Y) radioembolization, play an important role in the treatment of unresectable hepatocellular carcinoma (HCC). The aim of the LEGACY study was to evaluate objective response rate (ORR) and duration of response (DoR) in patients with solitary unresectable HCC treated with Y glass microspheres. LEGACY is a multi-center, single-arm, retrospective study conducted at 3 sites that included all eligible, consecutive HCC patients treated with radioembolization between 2014-2017. Eligibility criteria included: solitary HCC ≤8 cm, Child-Pugh A cirrhosis, and ECOG performance status 0-1. Primary endpoints were ORR and DoR based on mRECIST in the treated area (localized mRECIST) as evaluated by blinded, independent, central review (BICR). Radioembolization was performed with intent of ablative-level dosimetry in a selective fashion when possible. Overall survival (OS) was evaluated using Kaplan-Meier (KM) and multivariate Cox proportional hazards. Among the 162 patients included, 60.5% were ECOG 0; the median tumor size was 2.7 cm (range: 1-8) according to BICR. Radioembolization served as neoadjuvant therapy for transplantation or resection in 21.0% (34/162) and 6.8% (11/162) of patients, respectively, and as primary treatment for all others. Median follow-up time was 29.9 months by reverse KM. ORR (best response) was 88.3% (CI:82.4-92.4), with 62.2%(CI:54.1-69.8) exhibiting a DoR ≥6 months. Three-year OS was 86.6% for all patients and 92.8% for those neoadjuvant patients resected or transplanted. Conclusion: In this multi-center study of radioembolization, clinical meaningful response rates and prolonged DoR were observed in the treatment of unresectable, solitary HCC ≤8 cm.This article is protected by copyright. All rights reserved.
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| [370] |
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| [371] |
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| [372] |
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| [373] |
Synergistic effect of radiotherapy and immunotherapy for the treatment of hepatocellular carcinoma (HCC) has been reported. This phase I/IIa pilot trial evaluated preliminary efficacy and safety of combination of radioembolization with yttrium-90 microspheres (Y90-radioembolization) and durvalumab in patients with locally advanced unresectable HCC.
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| [374] |
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| [375] |
Stereotactic body radiotherapy (SBRT) is a promising ablative modality for hepatocellular carcinoma (HCC) especially for those with small-sized or early-stage tumors. This study aimed to synthesize available data to evaluate efficacy and explore related predictors of SBRT for small liver-confined HCC (≤ 3 lesions with longest diameter ≤ 6 cm).A systematic search were performed of the PubMed and Cochrane Library databases. Primary endpoints were overall survival (OS) and local control (LC) of small HCC treated with SBRT, meanwhile, to evaluate clinical parameters associated with treatment outcome by two methods including subgroup comparisons and pooled HR meta-analysis. The secondary endpoint was treatment toxicity.After a comprehensive database review, 14 observational studies with 1238 HCC patients received SBRT were included. Pooled 1-year and 3-year OS rates were 93.0% (95% confidence interval [CI] 88.0-96.0%) and 72.0% (95% CI 62.0-79.0%), respectively. Pooled 1-year and 3-year LC rates were 96.0% (95% CI 91.0-98.0%) and 91.0% (95% CI 85.0-95.0%), respectively. Subgroup comparisons regarding Child-Pugh class (stratified by CP-A percentage 100%, 75-100%, 50-75%) showed there were statistically significant differences for both 1-year and 3-year OS rate (p < 0.01), while that regarding number of lesions, pretreatment situation, age (median/mean age of 65), macrovascular invasion, tumor size, and radiation dose (median BED of 100 Gy), there were no differences. In subgroup comparisons for LC rate, it showed number of lesions (1 lesion vs. 2-3 lesions) was significantly associated with 1-year LC rate (p = 0.04), though not associated with 3-year LC rate (p = 0.72). In subgroup comparisons categorized by other factors including pretreatment situation, age, CP-A percentage, macrovascular invasion, tumor size, and radiation dose, there were no significant differences for 1- or 3-year LC rate. To further explore the association between CP class and OS, the second method was applied by combining HR and 95% CIs. Results indicated CP-A was predictive of better OS (p = 0.001) with pooled HR 0.31 (95% CIs 0.11-0.88), which was consistent with subgroup comparison results. Concerning adverse effect of SBRT, pooled rates of grade ≥ 3 hepatic complications and RILD were 4.0% (95% CI 2.0-8.0%) and 14.7% (95% CI 7.4-24.7%), respectively.The study showed that SBRT was a potent local treatment for small liver-confined HCC conferring excellent OS and LC persisting up to 3 years, even though parts of included patients were pretreated or with macrovascular invasion. CP-A class was a significant predictor of optimal OS, while number of lesions might affect short term tumor control (1-year LC). Tumor size and radiation dose were not vital factors impacting treatment outcome for such small-sized HCC patients. Because of the low quality of observational studies and heterogeneous groups of patients treated with SBRT, further clinical trials should be prospectively investigated in large sample sizes.
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| [376] |
To assess the efficacy and safety of stereotactic body radiation therapy using an abdominal compression technique and modified fractionation regimen (5-10 fractions) in patients with small-sized hepatocellular carcinoma.
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| [377] |
Hepatocellular carcinoma (HCC) is increasing in incidence and mortality. Although the prognosis remains poor, long-term survival has improved from 3% in 1970 to an 18% 5-year survival rate today. This is likely because of the introduction of well tolerated, oral antiviral therapies for hepatitis C. Curative options for patients with HCC are often limited by underlying liver dysfunction/cirrhosis and medical comorbidities. Less than one-third of patients are candidates for surgery, which is the current gold standard for cure. Nonsurgical treatments include embolotherapies, percutaneous ablation, and ablative radiation. Technological advances in radiation delivery in the past several decades now allow for safe and effective ablative doses to the liver. Conformal techniques allow for both dose escalation to target volumes and normal tissue sparing. Multiple retrospective and prospective studies have demonstrated that hypofractionated image-guided radiation therapy, used as monotherapy or in combination with other liver-directed therapies, can provide excellent local control that is cost effective. Therefore, as the HCC treatment paradigm continues to evolve, ablative radiation treatment has moved from a palliative treatment to both a "bridge to transplant" and a definitive treatment.© 2018 American Cancer Society.
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| [378] |
Potentially curative treatments for early-stage hepatocellular carcinoma (HCC) have drawbacks and contraindications. Recently, radiotherapy has achieved good outcomes. We compared the outcomes of radiotherapy and radiofrequency ablation (RFA) for early-stage HCC. Consecutive patients with ≤3 early-stage HCC lesions and tumor diameters ≤3 cm treated with RFA or radiotherapy were reviewed. RFA was the first choice for HCC unsuitable for surgery. Otherwise, stereotactic body radiotherapy in five fractions was mainly performed. For HCC adjacent to the gastrointestinal tract, radiotherapy with mild hypofractionation was performed. Propensity score matching was performed to reduce the selection bias between the RFA and radiotherapy groups. Between 2012 and 2016, a total of 231 patients with 474 tumors and 143 patients with 221 tumors were eligible and were treated with RFA and radiotherapy, respectively. In an unmatched comparison, the 3-year local recurrence rate was significantly lower for radiotherapy than for RFA (5.3%; 95% confidence interval [CI], 2.7-9.2; versus 12.9%, 95% CI, 9.9-16.2) (P < 0.01). A propensity score matching analysis of 106 patients in each group successfully matched the two treatment groups with regard to Barcelona Clinic Liver Cancer staging, T stage, and tumor size but not the adjacency of the tumor to risk organs or first or salvage treatment. The 3-year overall survival rates for RFA and radiotherapy patients were comparable (69.1%; 95% CI, 58.2-77.7; and 70.4%; 95% CI, 58.5-79.4, respectively; P = 0.86). Conclusion: Radiotherapy has excellent local control and comparable overall survival in patients with well-compensated liver function, exhibiting advantageous characteristics and compensating for the deficiencies of other treatment modalities; radiotherapy appears to be an acceptable alternative treatment option for patients who are not candidates for RFA.© 2019 by the American Association for the Study of Liver Diseases.
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| [379] |
Although several prospective studies have reported the efficacy of stereotactic body radiotherapy (SBRT) for hepatocellular carcinoma (HCC), treatment-related toxicity varies and has not been determined. Therefore, the authors evaluated the safety and efficacy of SBRT for patients with HCC in a hepatitis B virus-endemic area.This multicenter phase 2 trial enrolled patients with unresectable HCC. Patients received SBRT with 45 to 60 Gy in 3 fractions. To evaluate gastroduodenal toxicity, esophagogastroduodenoscopy (EGD) was performed before and 2 months after SBRT. The primary endpoint was treatment-related severe toxicity at 1 year after SBRT. The secondary endpoints were the 2-year local control, progression-free survival, and overall survival rates.In total, 74 patients were enrolled between January 2012 and April 2015, and 65 eligible patients were analyzed. One patient experienced radiation-induced liver disease with acute grade ≥3 toxicity 1 month after SBRT. In addition, 1 patient had a grade 3 esophageal ulcer with stenosis 5 months after SBRT. The actuarial rate of treatment-related severe toxicity at 1 year was 3%. The pre-SBRT and post-SBRT EGD findings were not significantly different among the 57 evaluable patients who underwent EGD. The 2-year and 3-year local control rates were 97% and 95%, respectively. The progression-free and overall survival rates were 48% and 84% at 2 years, respectively, and 36% and 76% at 3 years, respectively.With a median follow-up of 41 months, this prospective multicenter study demonstrated that SBRT for patients with HCC is well tolerated and is an effective treatment modality.© 2019 American Cancer Society.
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| [380] |
Few studies have been conducted to compare the efficacies of stereotactic body radiation therapy (SBRT) and radiofrequency ablation (RFA). Thus, in this multinational study, we compared the effectiveness of SBRT and RFA in patients with unresectable HCC.The retrospective study cohort included 2,064 patients treated in 7 hospitals: 1,568 and 496 in the RFA and SBRT groups, respectively. More than half of the patients (56.5%) developed recurrent tumors, mainly after transarterial chemoembolization (44.8%). Propensity score matching was performed to adjust for clinical factors (n = 313 in each group).At baseline, the SBRT group had unfavorable clinical features compared to the RFA group, including BCLC stage (B-C 65% vs. 16%), tumor size (median 3.0 cm vs. 1.9 cm), and frequent history of liver-directed treatment (81% vs. 49%, all p <0.001). With a median follow-up of 27.7 months, the 3-year cumulative local recurrence rates in the SBRT and RFA groups were 21.2% and 27.9%, respectively (p <0.001). After adjusting for clinical factors, SBRT was related to a significantly lower risk of local recurrence than RFA in both the entire (hazard ratio [HR] 0.45, p <0.001) and matched (HR 0.36, p <0.001) cohorts. In subgroup analysis, SBRT was associated with superior local control in small tumors (≤3 cm) irrespective of location, large tumors located in the subphrenic region, and those that progressed after transarterial chemoembolization. Acute grade ≥3 toxicities occurred in 1.6% and 2.6% of the SBRT and RFA patients, respectively (p = 0.268).SBRT could be an effective alternative to RFA for unresectable HCC, particularly for larger tumors (>3 cm) in a subphrenic location and tumors that have progressed after transarterial chemoembolization.It is currently not known what the best treatment option is for patients with unresectable hepatocellular carcinoma. Here, we show that stereotactic body radiation therapy provides better local control than radiofrequency ablation, with comparable toxicities. Stereotactic body radiation therapy appears to be an effective alternative to radiofrequency ablation that should be considered when there is a higher risk of local recurrence or toxicity after radiofrequency ablation.Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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| [381] |
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| [382] |
Data guiding selection of nonsurgical treatment of hepatocellular carcinoma (HCC) are lacking. We therefore compared outcomes between stereotactic body radiotherapy (SBRT) and radiofrequency ablation (RFA) for HCC.From 2004 to 2012, 224 patients with inoperable, nonmetastatic HCC underwent RFA (n = 161) to 249 tumors or image-guided SBRT (n = 63) to 83 tumors. We applied inverse probability of treatment weighting to adjust for imbalances in treatment assignment. Freedom from local progression (FFLP) and toxicity were retrospectively analyzed.RFA and SBRT groups were similar with respect to number of lesions treated per patient, type of underlying liver disease, and tumor size (median, 1.8 v 2.2 cm in maximum diameter; P =.14). However, the SBRT group had lower pretreatment Child-Pugh scores (P =.003), higher pretreatment alpha-fetoprotein levels (P =.04), and a greater number of prior liver-directed treatments (P <.001). One- and 2-year FFLP for tumors treated with RFA were 83.6% and 80.2% v 97.4% and 83.8% for SBRT. Increasing tumor size predicted for FFLP in patients treated with RFA (hazard ratio [HR], 1.54 per cm; P =.006), but not with SBRT (HR, 1.21 per cm; P =.617). For tumors ≥ 2 cm, there was decreased FFLP for RFA compared with SBRT (HR, 3.35; P =.025). Acute grade 3+ complications occurred after 11% and 5% of RFA and SBRT treatments, respectively (P =.31). Overall survival 1 and 2 years after treatment was 70% and 53% after RFA and 74% and 46% after SBRT.Both RFA and SBRT are effective local treatment options for inoperable HCC. Although these data are retrospective, SBRT appears to be a reasonable first-line treatment of inoperable, larger HCC.© 2015 by American Society of Clinical Oncology.
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| [383] |
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| [384] |
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| [385] |
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| [386] |
Background: Hepatocellular carcinoma (HCC) is the most frequent liver malignancy and a leading cause of cancer death in the world. In unresectable HCC patients, transcatheter arterial (chemo-) embolization (TAE/TACE) has shown a disease response in 15–55% of cases. Though multiple TAE/TACE courses can be administered in principle, Stereotactic Body Radiotherapy (SBRT) has emerged as an alternative option in the case of local relapse following multiple TAE/TACE courses. Methods: This is a single-center, prospective, randomized, controlled, parallel-group superiority trial of SBRT versus standard TAE/TACE for the curative treatment of the intermediate stage of HCC after an incomplete response following TAE/TACE (NCT02323360). The primary endpoint is 1-year local control (LC): 18 events were needed to assess a 45% difference (HR: 0.18) in favor of SBRT. The secondary endpoints are 1-year Progression-Free Survival (PFS), Distant Recurrence-Free Survival (DRFS), Overall Survival (OS) and the incidence of acute and late complications. Results: At the time of the final analysis, 40 patients were enrolled, 19 (49%) in the TAE/TACE arm and 21 (51%) in the SBRT arm. The trial was prematurely closed due to slow accrual. The 1- and 2-year LC rates were 57% and 36%. The use of SBRT resulted in superior LC as compared to TAE/TACE rechallenge (median not reached versus 8 months, p = 0.0002). PFS was 29% and 16% at 1 and 2 years, respectively. OS was 86% and 62% at 1 year and 2 years, respectively. In the TAE arm, PFS was 13% and 6% at 1 and 2 years, respectively. In the SBRT arm, at 1 and 2 years, PFS was 37% and 21%, respectively. OS at 1 and 2 years was 75% and 64% in the SBRT arm and 95% and 57% in the TACE arm, respectively. No grade >3 toxicity was recorded. Conclusions: SBRT is an effective treatment option in patients affected by inoperable HCC experiencing an incomplete response following ≥1 cycle of TAE/TAC.
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| [387] |
Background/Aims: Stereotactic body radiation therapy (SBRT) is used as an alternative ablative treatment in patients with hepatocellular carcinoma (HCC) not suitable for curative treatments. The purpose of this prospective study was to evaluate the long-term efficacy of SBRT for small (≤5 cm) HCCs.Methods: A phase II, single-arm clinical trial on SBRT for small HCCs was conducted at an academic tertiary care center. The planned SBRT dose was 45 Gy with a fraction size of 15-Gy over 3 consecutive days. The primary endpoint was 2-year local control rate. Radiologic responses were assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) and the modified RECIST criteria.Results: Between 2013 and 2016, 50 patients (53 lesions) were enrolled, with a median follow-up period of 47.8 months (range, 2.9–70.6). Patients’ age ranged from 41 to 74 years, and 80% were male. Median tumor size was 1.3 cm (range, 0.7–3.1). The 2- and 5-year local control rates were 100% and 97.1%, respectively. The 5-year overall survival rate was 77.6%. Six months after SBRT, radiologic responses were evident in 44 lesions (83%) according to the RECIST criteria and 49 (92.4%) according to the modified RECIST criteria. None of the patients showed grade ≥3 adverse events.Conclusions: SBRT showed excellent results as an ablative treatment for patients with small HCCs while showing minimal toxicities. SBRT can be a good alternative for both curative and salvage intents in patients with HCCs that are unsuitable for curative treatments.
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| [388] |
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| [389] |
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| [390] |
Patients with hepatocellular carcinoma showing macroscopic vascular invasion have a poor prognosis. Sorafenib is the sole treatment option for these patients, with unsatisfactory response and survival benefit. Combined treatment with transarterial chemoembolization (TACE) plus external beam radiotherapy (RT) has shown promising results for these patients in observational studies.To evaluate the efficacy and safety of TACE plus RT compared with sorafenib for patients with hepatocellular carcinoma and macroscopic vascular invasion.In this randomized, open-label clinical trial conducted at an academic tertiary care center between July 1, 2013, and October 31, 2016, 90 treatment-naive patients with liver-confined hepatocellular carcinoma showing macroscopic vascular invasion were randomly assigned to receive sorafenib (400 mg twice daily; 45 participants [the sorafenib group]) or TACE (every 6 weeks) plus RT (within 3 weeks after the first TACE, maximum 45 Gy with the fraction size of 2.5 to 3 Gy; 45 participants [the TACE-RT group]).The primary end point was the 12-week progression-free survival rate by intention-to-treat analysis. Radiologic response was assessed by independent review according to the Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1). Treatment crossover was permitted after confirming disease progression.Of the 90 patients (median age, 55 years; range, 33-82 years), 77 were men and 13 were women. All patients had portal vein invasion of hepatocellular carcinoma and Child-Pugh class A liver function. The median maximal tumor diameter was 9.7 cm. Most patients (71 [78.9%]) had multiple lesions. At week 12, the progression-free survival rate was significantly higher in the TACE-RT group than the sorafenib group (86.7% vs 34.3%; P < .001). The TACE-RT group showed a significantly higher radiologic response rate than the sorafenib group at 24 weeks (15 [33.3%] vs 1 [2.2%]; P < .001), a significantly longer median time to progression (31.0 vs 11.7 weeks; P < .001), and significantly longer overall survival (55.0 vs 43.0 weeks; P = .04). Curative surgical resection was conducted for 5 patients (11.1%) in the TACE-RT group owing to downstaging. No patients in the TACE-RT group discontinued treatment owing to hepatic decompensation.For patients with advanced hepatocellular carcinoma showing macroscopic vascular invasion, first-line treatment with TACE plus RT was well tolerated and provided an improved progression-free survival, objective response rate, time to progression, and overall survival compared with sorafenib treatment.clinicaltrials.gov Identifier: NCT01901692.
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| [391] |
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| [392] |
Stereotactic body radiotherapy (SBRT) has shown promising results in the control of macroscopic vascular invasion in patients with hepatocellular carcinoma (HCC); however, its efficacy in comparison to sorafenib when combined with transarterial chemoembolization (TACE) remains to be determined. Between 2009 and 2017, 77 HCC patients with macroscopic vascular invasion receiving TACE–SBRT or TACE–sorafenib combination therapies were enrolled. The best treatment responses, overall survival (OS), and progression-free survival (PFS) of the two treatment arms were compared. Of the patients enrolled, 26 patients (33.8%) received TACE–SBRT treatment, and 51 (66.2%) received TACE–sorafenib treatment. The patients in the TACE–SBRT group were more frequently classified as elder in age (p = 0.012), having recurrent disease (p = 0.026), and showing lower rates of multiple hepatic lesions (p = 0.005) than patients in TACE–sorafenib group. After propensity score matching (PSM), 26 pairs of well-matched HCC patients were selected; patients in the TACE–SBRT group showed better overall response rates in trend compared to those in the TACE–sorafenib group. The hazard ratio (HR) of OS to PFS for the TACE–SBRT approach and the TACE–sorafenib approach was 0.36 (95% CI, 0.17–0.75; p = 0.007) and 0.35 (95% CI, 0.20–0.62; p < 0.001), respectively. For HCC patients with macrovascular invasion, TACE plus SBRT could provide improved OS and PFS compared to TACE–sorafenib therapy.
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| [393] |
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| [394] |
To investigate the impact of postoperative intensity modulated radiation therapy (IMRT) in patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT) after partial hepatectomy +/- thrombectomy.From July 2013 to June 2016, consecutive patients with HCC and PVTT who underwent partial hepatectomy were randomly assigned to 2 groups: a control group and an adjuvant IMRT group. Survival outcomes in the 2 groups were studied.The 52 patients in this study were equally randomized into 2 groups with comparable clinicopathological data. The median disease-free survival (DFS) and overall survival (OS) were 9.1 ± 1.6 months, 18.9 ± 1.8 months for the adjuvant RT group and 4.1 ± 0.5 months, 10.8 ± 1.3 months for the control group, respectively. The 1-, 2- and 3-years overall survival rates were significantly better in the adjuvant IMRT group (76.9%, 19.2%, and 11.5%; respectively) than the control group (26.9%, 11.5% and 0%, respectively; p = 0.005).Postoperative IMRT significantly improved the overall survival outcomes in patients with HCC and PVTT after partial hepatectomy +/- thrombectomy.Copyright © 2019 Elsevier B.V. All rights reserved.
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| [395] |
The optimal locoregional treatment for hepatocellular carcinoma (HCC) patients with portal vein tumor thrombus (PVTT) is unclear. This study aimed to investigate the efficacy of Gamma knife radiosurgery (GKR) versus transcatheter arterial chemoembolization (TACE) in HCC patients with PVTT.
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| [396] |
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| [397] |
Stereotactic ablative radiotherapy (SABR) has demonstrated curative potential with survival benefits in patients with oligometastatic disease (OMD). However, limited evidence exists regarding its use in oligometastatic hepatocellular carcinoma (HCC). We aimed to prospectively investigate the efficacy and safety of SABR in patients with oligometastatic HCC.We enrolled patients with controlled primary HCC and one to five metastatic lesions amenable to SABR. The primary endpoint was treatment efficacy defined as overall survival (OS) and progression-free survival (PFS). The secondary endpoints included time to local progression, objective response rate, disease control rate, toxicities, and quality of life (QOL), assessed using the EORTC QLQ-C30 before, and 0, 1, and 3 months after SABR.Overall, 40 consecutive patients received SABR on 62 lesions between 2021 and 2022. The most common locations for OMD were the lungs (48.4%), lymph nodes (22.6%), and bone (17.7%). After a median follow-up of 15.5 months, the 2-year OS was 80%. Median PFS was 5.3 months, with 1- and 2-year rates of 21.2% and 0%, respectively. A shorter time to OMD from the controlled primary independently correlated with PFS (p=0.039, hazard ratio 2.127) alongside age, Child-Pugh class, and α-fetoprotein (p=0.002, 0.004, 0.019). The 2-year time to local progression, objective response rate, and disease control rate were 91.1%, 75.8%, and 98.4%, respectively. Overall, 10% of the patients experienced acute toxicity, and 7.5% experienced late toxicity, with no grade 3+ toxicity. All QOL scores remained stable, whereas the patients without systemic treatments had improved insomnia and social functioning scores.SABR is an effective and feasible option for oligometastatic HCC, excellently controls local tumors, and improves survival without adversely affecting QOL.NCT05173610.Copyright © 2024. Published by Elsevier B.V.
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| [398] |
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| [399] |
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| [400] |
To evaluate the feasibility and response of liver radiotherapy (RT) in improving symptoms and quality of life in patients with hepatocellular carcinoma (HCC) or liver metastases (LM).Eligible patients had HCC or LM, unsuitable for or refractory to standard therapies, with an index symptom of pain, abdominal discomfort, nausea, or fatigue. The Brief Pain Inventory (BPI), Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep), and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) were completed by patients at baseline and each follow-up. The primary outcome was the percentage of patients with a clinically significant change at 1 month in the BPI subscale of symptom on average in the past 24 hours. Secondary outcomes were improvement in other BPI subscales and at other time points, FACT-Hep and EORTC QLQ-C30 at each follow-up, and toxicity at 1 week.Forty-one patients (30 men and 11 women) with HCC (n = 21) or LM (n = 20) were accrued. At 1 month, 48% had an improvement in symptom on average in the past 24 hours. Fifty-two percent of patients had improvement in symptom at its worst, 37% at its least, and 33% now. Improvements in the FACT-G and hepatobiliary subscale were seen in 23% and 29% of patients, respectively, at 1 month. There were also improvements in EORTC QLQ-C30 functional (range, 11% to 21%) and symptom (range, 11% to 50%) domains. One patient developed grade 3 nausea at 1 week.Improvements in symptoms were observed at 1 month in a substantial proportion of patients. A phase III study of palliative liver RT is planned. [Corrected]
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| [401] |
There is no prospective data on stereotactic body radiation therapy (SBRT) as a bridge to liver transplantation for hepatocellular carcinoma (HCC). This study aimed to evaluate the efficacy and safety of SBRT as bridging therapy, with comparison to transarterial chemoembolization (TACE) and high intensity focused ultrasound (HIFU).Patients were prospectively enrolled for SBRT under a standardized protocol from July 2015, and compared to a retrospective cohort of patients who underwent TACE or HIFU from 2010. The primary endpoint was tumor control rate at 1-year after bridging therapy. Secondary endpoints included cumulative incidence of dropout, toxicity and post-transplant survival. During the study period, 150 patients were evaluated (SBRT n=40, TACE n=59, HIFU n=51). The tumor control rate at 1-year was significantly higher after SBRT compared to TACE and HIFU(92.3%, 43.5%, and 33.3% respectively, P=0.02). With competing risk analysis, the cumulative incidence of dropout at 1- and 3-year after listing was lower after SBRT(15.1% and 23.3%) compared with TACE(28.9% and 45.8%,P=0.034) and HIFU(33.3% and 45.1%, P=0.032). Time-to-progression at 1- and 3-year was also superior after SBRT(10.8%, 18.5% in SBRT, 45%, 54.9% in TACE and 47.6%, 62.8% in HIFU, P<0.001). The peri-procedural toxicity was similar, without any difference in perioperative complications, and patient and recurrence-free survival rates after transplant. Pathological complete response was more frequent after SBRT compared to TACE and HIFU(48.1% vs. 25% vs. 17.9% respectively, P=0.037). In multivariable analysis, tumor size <3cm, listing AFP <200ng/ml, Child's A and SBRT significantly reduced the risk of dropout.SBRT was safe, with significantly higher tumor control rate and reduced the risk of waitlist dropout, and should be utilized as an alternative to conventional bridging therapies.This article is protected by copyright. All rights reserved.
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| [402] |
There is limited information on the use of stereotactic body radiotherapy (SBRT) as a bridge to liver transplantation for hepatocellular carcinoma and no study comparing its efficacy to transarterial chemoembolization (TACE) and radiofrequency ablation (RFA). We aimed to ascertain the safety and efficacy of SBRT on an intention-to-treat basis compared with TACE and RFA as a bridge to liver transplantation in a large cohort of patients with hepatocellular carcinoma.Outcomes between groups were compared from the time of listing and from the time of transplant. Between July 2004 and December 2014, 379 patients were treated with either SBRT (n=36, SBRT group), TACE (n=99, TACE group) or RFA (n=244, RFA group).The drop-out rate was similar between groups (16.7% SBRT group vs. 20.2% TACE group and 16.8% RFA group, p=0.7); 30 patients were transplanted in the SBRT group, 79 in the TACE group and 203 in the RFA group. Postoperative complications were similar between groups. Patients in the RFA group had more tumor necrosis in the explant. The 1-, 3- and 5-year actuarial patient survival from the time of listing was 83%, 61% and 61% in the SBRT group vs. 86%, 61% and 56% in the TACE group, and 86%, 72% and 61% in the RFA group, p=0.4. The 1-, 3- and 5-year survival from the time of transplant was 83%, 75% and 75% in the SBRT group vs. 96%, 75% and 69% in the TACE group, and 95%, 81% and 73% in the RFA group, p=0.7.In conclusion, SBRT can be safely utilized as a bridge to LT in patients with HCC, as an alternative to conventional bridging therapies.Patients with liver cancer included in the waiting list for liver transplantation are at risk of tumor progression and death. Stereotactic body radiotherapy may be a good alternative to conventional therapies to reduce this risk.Copyright © 2017 European Association for the Study of the Liver. All rights reserved.
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| [403] |
Centrally located hepatocellular carcinoma (HCC) is a special type of HCC whose outcome is unsatisfactory when treated with surgery alone. No standard adjuvant or neoadjuvant treatment for this disease has been established that improves clinical outcomes.To evaluate the effectiveness and safety of adding neoadjuvant intensity-modulated radiotherapy (IMRT) before surgery in patients with centrally located HCC.This phase 2, single-center, single-group prospective nonrandomized controlled trial was conducted between December 16, 2014, and January 29, 2019, at the Cancer Institute and Hospital of the Chinese Academy of Medical Sciences in Beijing, China. The last follow-up was on July 30, 2021. Patients with centrally located HCC who underwent neoadjuvant IMRT and surgery were included in the analysis.Neoadjuvant IMRT followed by hepatectomy.The primary end point was 5-year overall survival (OS). The secondary end points were tumor response to IMRT, 5-year disease-free survival (DFS), and treatment-related adverse events.Thirty-eight patients (mean [SD] age, 55.6 [9.3] years; 35 male [92.1%] individuals) completed the prescribed neoadjuvant IMRT without interruption. Radiographic tumor response to IMRT before surgery included partial response (16 [42.1%]) and stable disease (22 [57.9%]). Thirteen patients (34.2%) achieved major pathological response, of which 5 (13.2%) achieved pathologic complete response. With a median follow-up of 45.8 months, the median OS was not reached, and the OS rates were 94.6% at 1 year, 75.4% at 3 years, and 69.1% at 5 years. The median DFS was 45.8 months, and DFS rates were 70.3% at 1 year, 54.1% at 3 years, and 41.0% at 5 years. Radiotherapy-related grade 3 adverse events were observed in 3 patients (7.9%). Nineteen operative complications developed in 13 patients (34.2%), including grade I to II complications in 12 patients (31.6%) and grade IIIa complication in 1 patient (2.6%). No grade IIIb or higher operative complications were observed.Results of this trial suggest that neoadjuvant IMRT plus surgery is effective and well-tolerated in patients with centrally located HCC. These data may inform a future randomized clinical trial of this new treatment strategy.ClinicalTrials.gov Identifier: NCT02580929.
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| [404] |
Surgical resection is the primary treatment for hepatocellular carcinoma (HCC); however, it is associated with a high rate of recurrence and death. We conducted this phase II study to investigate the efficacy and safety of postoperative intensity-modulated radiotherapy (IMRT) for HCC after narrow-margin hepatectomy.We designed a single-arm, prospective phase II trial to evaluate overall survival (OS), disease-free survival (DFS), recurrence patterns, and toxicity in patients receiving adjuvant radiotherapy. The eligibility criteria included the following: pathological diagnosis of HCC after hepatectomy, with narrow pathological margins (<1 cm); age >18 years; and Eastern Cooperative Oncology Group performance status score of 0 or 1. Patients received IMRT within 4-6 weeks after surgical resection. This trial was registered at ClinicalTrials.gov (number: NCT01456156). Between 2008 and 2016, a total of 76 eligible patients who underwent narrow-margin resection were enrolled. The median follow-up duration was 70 months; the 3-year OS and DFS rates were 88.2% and 68.1%, respectively; and the 5-year OS and DFS rates were 72.2% and 51.6%, respectively. Intrahepatic recurrence was the primary recurrence pattern. No marginal recurrence was found. Intrahepatic, extrahepatic, and combined recurrences at the first relapse were found in 33, five, and one patient, respectively. The most common radiation-related grade-3 toxicities were leukopenia (7.9%), elevated alanine aminotransferase (3.9%) and aspartate aminotransferase (2.6%) levels, and thrombocytopenia (1.3%). Classical or non-classical radiation-induced liver disease was not noted.Adjuvant radiotherapy is an effective, well-tolerated, and promising adjuvant regimen in HCC patients who have undergone narrow-margin hepatectomy. Our trial provides evidence and a rationale for planning a future phase III trial.This article is protected by copyright. All rights reserved.
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| [405] |
Marginal resection frequently occurred in hepatectomy for hepatocellular carcinoma (HCC), leading to increased local recurrence, especially among patients with microvascular invasion (MVI). Stereotactic body radiotherapy (SBRT) showed effectiveness in controlling tumour and tumour thrombosis. This study aimed to investigate the efficacy of SBRT, targeting on suboptimal resection margin, as adjuvant setting in MVI-positive HCC.This was a single-centre randomised controlled trial conducted in Eastern Hepatobiliary Surgery Hospital, Shanghai, China. Participants with MVI-positive HCC receiving marginal resection were randomly assigned to the postoperative adjuvant SBRT or surgery alone (SA) group. SBRT was delivered by the CyberKnife® system with marker tracking devices, targeting on resection margin one month after surgery. The disease-free survival (DFS) and overall survival (OS) were compared between the groups, and the adverse events (AEs) were monitored. This trial was registered on ClinicalTrials.gov, NCT04891874.A total of 76 participants were enrolled, with 38 in each group. The one-, three-, and five-year DFS rates were 92.1%, 65.8%, and 56.1% in SBRT group versus 76.3%, 36.8%, and 26.3% in SA group, respectively (p = 0.005). The one-, three-, and five-year OS rates were 100%, 89.5%, and 75.0% in SBRT group versus 100.0%, 68.4%, and 53.7% in SA group, respectively (p = 0.053). The total dose of SBRT for single participant was 35 Gy, and the biological effective dose (BED) was 59.5 Gy. The overall incidence of radiotherapy-related AE was 31.6% (12/38), and no grade 3 or higher grade AE was developed.SBRT on the resection margin provides a safe therapeutic modality of adjuvant setting in MVI-positive HCC with suboptimal resection margin. It prevents local recurrence and improves DFS.NCT04891874.Copyright © 2022 Elsevier Ltd. All rights reserved.
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| [406] |
To investigate the role of post‐operative intensity‐modulated radiotherapy (IMRT) in patients receiving narrow‐margin hepatectomy for hepatocellular carcinoma (HCC) located close to the major vessels.
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| [407] |
Microvascular invasion (MVI) is considered to be one of the important prognostic factors that affect postoperative recurrence in patients with hepatocellular carcinoma (HCC) with variable results across their treatment options. This study was carried out to investigate efficacy of postoperative adjuvant RT in HCC patients with MVI.This was single center, prospective study carried out in HCC patients with MVI, aged 35-72 years. All patients were non-randomly allocated to receive standard postoperative treatment of HBV/HCV and nutritional therapy or RT in addition to standard postoperative treatment (1:1). The primary endpoints assessed were relapse-free survival and overall survival. The prognostic factors associated with survival outcomes were also analyzed. The safety events were graded according to NCI-CTCAE v4.03 criteria.Of the 115 patients eligible for study, 59 patients were included in analysis. Univariate analysis revealed that MVI classification (P = 0.009), post-operative treatment strategies (P = 0.009) were prognostic factors for worst RFS; tumor size (P = 0.011), MVI classification (P = 0.005) and post-operative treatment (P = 0.015) were associated for OS. The 1-, 2-, 3-year RFS rates were 86.2, 70.5 and 63.4% for patients in RT group, and 46.4, 36.1, and 36.1% in control group. For OS, corresponding rates were 96.6, 80.7, and 80.7% for patients in RT group and 79.7, 58.3, and 50.0% in control group. Subgroup classification of HCC patients according to low risk MVI showed significantly longer RFS (P = 0.035) and OS (P = 0.004) in RT group than control group, while for high risk MVI, RT depicted longer OS than control group with no significance (P = 0.106). Toxicities were usually observed in acute stage with no grade 4 toxicities.Postoperative adjuvant RT following hepatectomy offers better RFS for HCC patients with MVI than with standard postoperative therapy. Also, it will be useful to control microscopic lesions in both M1 (low risk) and M2 (high risk) subgroups of HCC patients with MVI.Trial Registration number: ChiCTR1800017371. Date of Registration: 2018-07-26. Registration Status: Retrospectively registered.
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| [408] |
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| [409] |
Most patients with locally advanced hepatocellular carcinoma (HCC) recur within the liver following systemic therapy.To determine whether stereotactic body radiation therapy (SBRT) improves outcomes in patients with locally advanced HCC compared with sorafenib alone.This multicenter phase 3 randomized clinical trial randomized patients with HCC 1:1 to sorafenib or SBRT followed by sorafenib, stratified by performance status, liver function, degree of metastases, and macrovascular invasion. Eligible patients had HCC unsuitable for or refractory to standard local-regional therapies and were candidates for first-line systemic therapy. Data were collected from April 2013 to March 2021, and data were analyzed from July 2022 to August 2023.Personalized SBRT, 27.5 to 50 Gy in 5 fractions.The primary end point was overall survival (OS). Secondary end points were progression-free survival (PFS), adverse events, and quality of life.Of 193 patients randomized, 177 were eligible. Accrual was stopped early due to a change in standard-of-care systemic therapy. Of 177 included patients, 150 (84.7%) were male, and the median (IQR) age was 66 (60-72) years. Macrovascular invasion was seen in 131 (74.0%). As of July 1, 2022, the median OS was 12.3 months (90% CI, 10.6-14.3) with sorafenib vs 15.8 months (90% CI, 11.4-19.2) following SBRT and sorafenib (hazard ratio [HR], 0.77; 90% CI, 0.59-1.01; 1-sided P = .06). Adjusting for stratification factors, OS was improved with SBRT (HR, 0.72; 95% CI, 0.52-0.99; 2-sided P = .04). Median PFS was improved from 5.5 months (95% CI, 3.4-6.3) with sorafenib to 9.2 months (95% CI, 7.5-11.9) with SBRT and sorafenib (HR, 0.55; 95% CI, 0.40-0.75; 2-sided P < .001). Treatment-related grade 3 or higher adverse events were seen in 37 of 88 (42%) and 39 of 83 (47%) of patients treated with sorafenib vs SBRT and sorafenib, respectively (P = .52). There were 2 treatment-related deaths in the sorafenib group (death not otherwise specified and liver failure) and 1 in the SBRT and sorafenib group (lung infection). At 6 months, improved quality of life was seen in 2 of 20 (10%) and 6 of 17 (35%) of patients treated with sorafenib and SBRT and sorafenib, respectively.In this phase 3 randomized clinical trial, among patients with locally advanced HCC, SBRT was associated with a clinically important but not statistically significant improved overall survival compared with sorafenib alone.ClinicalTrials.gov Identifier: NCT01730937.
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| [410] |
We aimed to investigate the efficacy of a novel regimen, external beam radiation (RT) combined with trans arterial chemoembolization (TACE) and lenvatinib (LEN), in the treatment of hepatocellular carcinoma (HCC) with portal vein tumor thrombus.
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| [411] |
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| [412] |
This study aimed to investigate the clinical benefits of locoregional radiation therapy (RT) before, after, and concurrent with sorafenib therapy for Barcelona Clinic Liver Cancer (BCLC) stage C hepatocellular carcinoma (HCC) patients.
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| [413] |
Advanced hepatocellular carcinoma (HCC) has a very low resectable rate. This meta-analysis aimed to compare efficacy of three combination strategies in treatment of advanced unresectable HCC with a view of guiding future selection of the best combination therapy for sorafenib and local therapy. A search was conducted to identify relevant literature published between April 2013 and May 2022, and then compared efficacy of sorafenib combined with external radiotherapy (SOF + RT), sorafenib with transarterial chemoembolization (SOF + TACE), sorafenib with hepatic artery infusion chemotherapy (SOF + HAIC), sorafenib (SOF), external radiotherapy (RT), transarterial chemoembolization (TACE), and hepatic artery infusion chemotherapy (HAIC) were studied and analyzed. Finally, the results were statistically analyzed using R 3.5.3 software and Stata/SE 15.0 software. A total of 46 studies, involving 7595 patients, were included in the meta-analysis. Analysis of overall survival (OS) and progression-free survival (PFS) of seven related treatment interventions revealed that the combination therapy had significantly higher efficacy than monotherapies. Among the combination therapies, SOF + RT was associated with the best OS and PFS rates, and the least adverse events compared to the other treatment modalities. The efficacy of combination therapy was better than monotherapy. In combination therapy, the overall survival time and progression-free survival time of SOF + RT were longer, and the adverse reactions were less. Therefore, SOF + RT may be the best choice for sorafenib combined with local therapy.
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| [414] |
To determine the maximally tolerated dose of sorafenib delivered before, during, and after stereotactic body radiation therapy (SBRT) in hepatocellular carinoma (HCC).Eligible patients had locally advanced Child-Pugh class A HCC, showed Eastern Cooperative Oncology Group performance status 0-1, and were ineligible for standard local-regional therapies. Sorafenib was dose escalated in 2 strata: (1) low effective irradiated liver volume (veff) < 30% and (2) high veff 30%to 60%. Sorafenib (400 mg daily = dose level 1) was administered for 12 weeks, with 6 fractions SBRT delivered weeks 2 and 3, and escalation to full dose (400 mg twice daily) after 12 weeks as tolerated. Standard 3 + 3 cohorts with dose escalation of sorafenib were planned.Sixteen patients (4 low veff, median dose 51 Gy; 12 high veff, median dose 33 Gy) were treated at 2 sorafenib dose levels. Of those patients 75% were had Barcelona Clinic Liver Cancer stage C, and 63% had main branch portal vein invasion. In the low veff stratum, no dose-limiting toxicities (DLTs) were observed in 4 patients treated with SBRT and sorafenib 400 mg. Inb the high veff stratum: 2 of 3 evaluable patients treated with sorafenib 400 mg experienced DLT (grade 3 large bowel bleed and grade 4 bowel obstruction 51 and 27 days, respectively, after SBRT). One of 6 evaluable patients at dose level -1 (200 mg once daily) experienced a grade 3 tumor rupture at week 5. Median overall survival and in-field local progression have not been reached. Worsening of Child-Pugh liver function class was seen in 6 of 12 patients in the high veff stratum.Significant toxicity was observed in the high veff stratum, and concurrent SBRT with sorafenib is not recommended outside a clinical trial.Copyright © 2016. Published by Elsevier Inc.
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| [415] |
To investigate the maximum tolerated dose (MTD) of apatinib delivered during and after intensity-modulated radiotherapy (IMRT) for unresectable hepatocellular carcinoma (HCC).Patients with unresectable HCC who were not eligible for radiofrequency ablation (RFA), transcatheter arterial chemoembolization (TACE), or residual/ recurrent after the prior local treatment were enrolled. Patients were scheduled to be treated with IMRT at 50-60 Gy/25-30 fractions. Oral apatinib tablets were administered concurrently with IMRT and continued thereafter. We used a 3 + 3 dose-escalation design, with three dose levels of apatinib (250, 500, and 750 mg). Grade 3 or more severe adverse events (AEs) were defined as dose-limiting toxicities (DLTs). The treatment response was calculated using the Modified Response Evaluation Criteria in Solid Tumours.Nine patients with Barcelona Clinic Liver Cancer Stage C were included. One patient withdrew from the apatinib 250 mg group and another patient was added. No DLTs occurred in the apatinib 250 mg group. Five patients were included in the apatinib 500 mg group, and 2 cases of DLT (grade 3 leukopenia) were found among them. Dose escalation was terminated and the MTD was determined to be 250 mg. Common grade 1-2 AEs included fatigue, hypertension, dizziness, bone marrow suppression, and hyperbilirubinemia. The median follow-up time for all patients was 16.0 months. Three patients achieved complete response and another three achieved partial response. The objective response rate was 6/9 (66.7%), and the disease control rate was 9/9 (100%). Three patients relapsed out of the radiation field. The median progression-free survival was 17.0 months, and the median overall survival was 16.7 months.When combined with IMRT, apatinib 250 mg daily was recommended for a phase 2 study of unresectable HCC. The antitumor activity of the combination treatment was encouraging. The safety and efficacy of apatinib combined with IMRT for unresectable HCC should be further investigated in future studies.Registration No. ChiCTR1800018309. Registered 11 September 2018. Retrospectively registered, https://www.chictr.org.cn/showproj.aspx?proj=30461.© 2022. The Author(s).
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| [416] |
Although the treatment effect and availability of therapeutic options for advanced hepatocellular carcinoma (HCC) are limited, the downstaging strategy may improve patient prognosis. This study aimed to investigate the potential of combination therapy as a downstaging strategy for treating advanced HCC with portal vein tumor thrombus (PVTT).
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| [417] |
Due to its widespread occurrence and high mortality rate, hepatocellular carcinoma (HCC) is an abhorrent kind of cancer. Immunotherapy is a hot spot in the field of cancer treatment, represented by immune checkpoint inhibitors (ICIs), which aim to improve the immune system’s ability to recognize, target and eliminate cancer cells. The composition of the HCC immune microenvironment is the result of the interaction of immunosuppressive cells, immune effector cells, cytokine environment, and tumor cell intrinsic signaling pathway, and immunotherapy with strong anti-tumor immunity has received more and more research attention due to the limited responsiveness of HCC to ICI monotherapy. There is evidence of an organic combination of radiotherapy, chemotherapy, anti-angiogenic agents and ICI catering to the unmet medical needs of HCC. Moreover, immunotherapies such as adoptive cellular therapy (ACT), cancer vaccines and cytokines also show encouraging efficacy. It can significantly improve the ability of the immune system to eradicate tumor cells. This article reviews the role of immunotherapy in HCC, hoping to improve the effect of immunotherapy and develop personalized treatment regimens.
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| [418] |
The role of stereotactic body radiotherapy (SBRT), which can deliver high radiation doses to focal tumors, has greatly increased in not only early-stage hepatocellular carcinoma (HCC), but also in portal vein or inferior vena cava thrombi, thus expanding this therapy to pre-transplantation and the treatment of oligometastases from HCC in combination with immune checkpoint inhibitors (ICI). In early-stage HCC, many promising prospective results of SBRT have been reported, although SBRT is not usually indicated as a first treatment potion in localized HCC according to several guidelines. In the treatment of portal vein or inferior vena cava tumor thrombi, several reports using various dose-fraction schedules have shown relatively good response rates with low toxicities and improved survival due to the rapid advancements in systemic therapy. Although SBRT is regarded as a substitute therapy when conventional bridging therapies to transplantation, such as transarterial chemoembolization (TACE) and radiofrequency ablation (RFA), are not applicable or fail in controlling tumors, SBRT may offer advantages in patients with borderline liver function who may not tolerate TACE or RFA, according to several reports. For oligometastases, the combination of SBRT with ICI could potentially induce an abscopal effect in patients with HCC, which is expected to provide the rationale for SBRT in the treatment of oligometastatic disease in the near future.
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| [419] |
Previous studies have explored cancer immunotherapy with radiotherapy or anti-angiogenic therapy, but no trials have reported a triple therapy approach. This study aimed to investigate safety and clinical outcome of PD-1/PD-L1 inhibitors combined with palliative radiotherapy and targeted angiogenesis therapy in hepatocellular carcinoma (HCC) of Barcelona Clinic Liver Cancer (BCLC) stage C.
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| [420] |
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| [421] |
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| [422] |
Systemic treatments are listed as first-line therapies for hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT), resulting in modest efficacy. We aimed to evaluate the efficacy and safety of sintilimab plus bevacizumab combined with radiotherapy (Sin-Bev-RT) in HCC with PVTT and to identify prognostic biomarkers.This open-label, multicenter, single-arm, phase 2 clinical trial was conducted at three tertiary hospitals in China. A total of 46 HCC patients with PVTT were enrolled. All the patients received the first cycle of intravenous sintilimab (200 mg, day 1) plus bevacizumab (15 mg/kg, day 1) within 3 days after enrollment. Radiotherapy (30-50 Gy/10 fractions) was administered after 2 cycles of Sin-Bev. Sin-Bev was disrupted during radiotherapy and resumed 2 weeks after radiotherapy and continued every 3 weeks thereafter until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was objective response rate (ORR). Patients obtained an ORR of 58.7% and a disease control rate of 100%. After a median follow-up time of 26.0 months (95% CI: 24.0-26.0), the median overall survival (OS) was 24.0 months (95% confidence interval [CI]: 19.0-not applicable) and the median progression-free survival (PFS) was 13.8 months (95% CI: 12.0-21.0), respectively. No unexpected adverse events or treatment-related deaths occurred. Mutations of PCTMD1 were predictive of shorter OS and PFS.Sintilimab plus bevacizumab combined with radiotherapy provides favorable treatment response and survival outcomes along with an acceptable safety profile in the first-line setting for HCC patients with PVTT. (ClinicalTrials.gov Identifier: NCT05010434).Copyright © 2024 American Association for the Study of Liver Diseases.
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| [423] |
To describe outcomes of prospective trials of stereotactic body radiotherapy (SBRT) for hepatocellular carcinoma (HCC).
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| [424] |
| [425] |
External beam radiotherapy (EBRT) has been reported to be effective in palliating painful bone metastases, but the optimal fractions and doses for treating bone metastases from hepatocelluar carcinoma (HCC) are not established. This study aimed to compare toxicity and efficacy for conventional fraction versus hypofraction schedules. From January 2009 through December 2014, 183 patients with HCC bone metastases were randomly assigned to conventional fraction EBRT (Group A) or hypofraction radiotherapy (Group B). Study outcomes were pain relief, response rate and duration, overall survival, and toxicity incidence. Median follow-up time was 9.3 months. Response times were 6.7 ± 3.3 fractions in Group A and 4.1 ± 1.2 fractions in Group B (p <0.001). Pain relief rates were 96.7% and 91.2% in Group A and B, respectively (p=0.116). Time to treatment failure for Group A was significantly longer than Group B (p=0.025). Median overall survival was similar between two groups (p=0.628). Toxicity incidence in both groups was minimal, with no significant differences observed. In conclusion, hypofractionated radiotherapy is safe for patients with HCC bone metastases and may achieve earlier pain relief compared to conventional radiotherapy. This protocol should be considered for patients with shorter predicted survival times.
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| [426] |
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| [427] |
Radiotherapy (RT) is an effective treatment for hepatocellular carcinoma (HCC) patients with lymph node metastasis (LNM), which is a rare clinical situation with a poor prognosis. We evaluated the responses and toxicities in HCC patients with abdominal LNM treated with either image-guided intensity-modulated radiotherapy (IG-IMRT) or non-IG-IMRT.Retrospective review of the records of HCC patients with regional LNM treated with IG-IMRT (n=43) or non-IG-IMRT (n=42). The tumor responses, local control rates (LCRs), overall survival (OS) rates, and toxicities were evaluated.The mean biological effective dose with α/β =10 Gy (BED10) delivered to IG-IMRT group was 67.23±8.48 vs. 63.43±5.01 Gy delivered to non-IG-IMRT group (P=0.008). OS in IG-IMRT group vs. non-IG-IMRT group was 15.3 vs. 9.7 months (P=0.098). The one-year survival of IG-IMRT group was superior (69% vs. 38.1% for non-IG-IMRT, P=0.006). Whereas two-year survival was not significantly different. Negative independent prognostic factors included ≥2 positive lymph nodes and previous treatment without surgery, while BED10 ≥65 Gy was a protective factor. Toxicities were mild for both groups, while IG-IMRT group showed less late hepatotoxicity.The therapeutic dose delivered by IG-IMRT is slightly higher than non-IG-IMRT which was more effective and showed superior short-term survival and local control in HCC patients with LNM.
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| [428] |
To investigate the efficacy of radiation dose escalation in patients with hepatocellular carcinoma (HCC) after incomplete transarterial chemoembolization (TACE).This study evaluated retrospective data of 323 HCC patients who received radiotherapy after incomplete TACE from 2001-2016. Radiation dose in biologically effective dose (BED) (α/β = 10) was categorized as <72 Gy (261 patients) and ≥72 Gy (62 patients). Simultaneous integrated boost-intensity modulated radiation therapy (SIB-IMRT) was used significantly more frequently in the high-dose group (64.5% vs. 12.9%; P < 0.001). Local failure-free rate (LFFR), progression-free rate (PFR), and toxicities were compared between the two groups. Additionally, propensity score matching was performed.Median follow-up time for patients who were alive at the time of analysis was 47 months (range 18-189 months). Median overall survival after radiotherapy was 14 months. In multivariate analysis, BED ≥72 Gy was an independent predictor of favorable LFFR (hazard ratio [HR] 0.32; 95% confidence interval [CI] 0.14-0.72; P = 0.006) and PFR (HR 0.67; 95% CI 0.45-0.98; P = 0.04). In the propensity score-matched cohort (62 pairs), 1‑year LFFR (94% vs. 81%; P = 0.002), and 1‑year PFR (49% vs. 42%; P = 0.01) were significantly higher in the high-dose group. Treatment-related toxicities were comparable between the high-dose and low-dose groups (classic radiation-induced liver disease: 5.3% [3/57] vs. 13.8% [29/210], P = 0.08; grade 2-4 gastrointestinal bleeding: 3.2% [2/62] vs. 7.3% [19/261], P = 0.39).Radiation dose with BED ≥72 Gy improved LFFR and PFR without increasing toxicity. In radiotherapy for incomplete TACE of HCC, dose escalation using SIB-IMRT should be actively considered to improve oncologic outcome.
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| [429] |
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| [430] |
While abdominal compression (AC) can be used to reduce respiratory liver motion in patients receiving helical tomotherapy for hepatocellular carcinoma, the nature and extent of this effect is not well described. The purpose of this study was to evaluate the changes in magnitude of three-dimensional liver motion with abdominal compression using four-dimensional (4D) computed tomography (CT) images of several plate positions.From January 2012 to October 2015, 72 patients with intrahepatic carcinoma and divided into four groups underwent 4D-CT scans to assess respiratory liver motion. Of the 72 patients, 19 underwent abdominal compression of the cephalic area between the subxiphoid and umbilicus (group A), 16 underwent abdominal compression of the caudal region between the subxiphoid area and the umbilicus (group B), 11 patients underwent abdominal compression of the caudal umbilicus (group C), and 26 patients remained free breathing (group D). 4D-CT images were sorted into ten-image series, according to the respiratory phase from the end inspiration to the end expiration, and then transferred to treatment planning software. All liver contours were drawn by a single physician and confirmed by a second physician. Liver relative coordinates were automatically generated to calculate the liver respiratory motion in different axial directions to compile the 10 ten contours into a single composite image. Differences in respiratory liver motion were assessed with a one-way analysis of variance test of significance.The average respiratory liver motion in the Y axial direction was 4.53 ± 1.16, 7.56 ± 1.30, 9.95 ± 2.32, and 9.53 ± 2.62 mm in groups A, B, C, and D, respectively, with a significant change among the four groups (p < 0.001). Abdominal compression was most effective in group A (compression plate on the subxiphoid area), with liver displacement being 2.53 ± 0.93, 4.53 ± 1.16, and 2.14 ± 0.92 mm on the X-, Y-, and Z-axes, respectively. There was no significant difference in respiratory liver motion between group C (displacement: 3.23 ± 1.47, 9.95 ± 2.32, and 2.92 ± 1.10 mm on the X-, Y-, and Z-axes, respectively) and group D (displacement: 3.35 ± 1.55, 9.53 ± 2.62, and 3.35 ± 1.73 mm on the X-, Y-, and Z-axes, respectively). Abdominal compression was least effective in group C (compression on caudal umbilicus), with liver motion in this group similar to that of free-breathing patients (group D).4D-CT scans revealed significant liver motion control via abdominal compression of the subxiphoid area; however, this control of liver motion was not observed with compression of the caudal umbilicus. The authors, therefore, recommend compression of the subxiphoid area in patients undergoing external radiotherapy for intrahepatic carcinoma.
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| [431] |
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| [432] |
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| [433] |
This study aimed to assess the imaging appearances of focal liver reactions following stereotactic body radiotherapy (SBRT) for small hepatocellular carcinoma (HCC) and to examine relationships between imaging appearance and baseline liver function. We retrospectively studied 50 lesions in 47 patients treated with SBRT (30-40 Gy in 5 fractions) for HCC, who were followed up for more than 6 months. After SBRT, all patients underwent regular follow-ups with blood tests and dynamic CT scans. At a median follow-up of 18.1 months (range 6.2-43.7 months), all lesions but one were controlled. 3 density patterns describing focal normal liver reactions around HCC tumours were identified in pre-contrast, arterial and portal-venous phase scans: iso/iso/iso in 4 patients (Type A), low/iso/iso in 8 patients (Type B) and low/iso (or high)/high in 38 patients (Type C). Imaging changes in the normal liver surrounding the treated HCC began at a median of 3 months after SBRT, peaked at a median of 6 months and disappeared 9 months later. Liver function, as assessed by the Child-Pugh classification, was the only factor that differed significantly between reactions to treatment showing "non-enhanced" (Type A and B) and "enhanced" (Type C) appearances in CT. Hence, liver tissue with preserved function is more likely to be well enhanced in the delayed phase of a dynamic contrast-enhanced CT scan. The CT appearances of normal liver seen in reaction to the treatment of an HCC by SBRT were therefore related to background liver function and should not be misread as recurrence of HCC.
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| [434] |
郝光远, 庞军, 陈燕, 等. 原发性肝癌立体定向消融放疗后 CT 影像学随访观察[J]. 临床军医杂志, 2014, 42(4):393-395. DOI:10.3969/j.issn.1671-3826.2014.04.21.
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| [435] |
The refinement of radiation therapy and radioembolization techniques has led to a resurgent interest in radiation-induced liver disease (RILD). The awareness of technical and clinical parameters that influence the chance of RILD is important to guide patient selection and toxicity minimization strategies. "Classic" RILD is characterized by anicteric ascites and hepatomegaly and is unlikely to occur after a mean liver dose of approximately 30 Gy in conventional fractionation. By maintaining a low mean liver dose and sparing a "critical volume" of liver from radiation, stereotactic delivery techniques allow for the safe administration of higher tumor doses. Caution must be exercised for patients with hepatocellular carcinoma or pre-existing liver disease (eg, Child-Pugh score of B or C) because they are more susceptible to RILD that can manifest in a nonclassic pattern. Although no pharmacologic interventions have yet been proven to mitigate RILD, preclinical research shows the potential for therapies targeting transforming growth factor-β and for the transplantation of stem cells, hepatocytes, and liver progenitor cells as strategies that may restore liver function. Also, in the clinical setting of veno-occlusive liver disease after high-dose chemotherapy, agents with fibrinolytic and antithrombotic properties can reverse liver failure, suggesting a possible role in the setting of RILD.Copyright © 2011 Elsevier Inc. All rights reserved.
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| [436] |
<b><i>Background:</i></b> Stereotactic body radiation therapy (SBRT) is an advanced technique of external beam radiation therapy that delivers large ablative doses of radiation. In the past decade, many cancer centers have adopted SBRT as one mode of radically treating small-sized hepatocellular carcinoma (HCC), based on encouraging clinical outcomes. SBRT thus seems reasonable as first-line treatment of inoperable HCC confined to the liver. However, most of the clinical studies to date have been retrospective in nature, with key issues still under investigation. <b><i>Summary:</i></b> The above-mentioned publications were subjected to scrutiny, fueling discussions at the 7th Asia-Pacific Primary Liver Cancer Expert (APPLE 2016) Meeting on various clinical variables, such as indications for SBRT, therapeutic outcomes, treatment-related toxicities, doses prescribed, and specific techniques. The consensus reached should be of interest to all professionals active in the treatment of HCC, especially radiation oncologists. <b><i>Key Messages:</i></b> SBRT is a safe and effective therapeutic option for patients with small-sized HCC, offering substantial local control, improved overall survival, and low toxicity.
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| [437] |
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| [438] |
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| [439] |
中华医学会核医学分会转移性骨肿瘤治疗工作委员会. 氯化锶[89Sr]治疗转移性骨肿瘤专家共识 (2017 年版)[J]. 中华核医学与分子影像杂志, 2018, 38(6):412-415. DOI: 10.3760/cma.j.issn.2095-2848.2018.06.008.
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Immunotherapy combinations have revolutionised the therapeutic landscape of advanced hepatocellular carcinoma (HCC), but not all yield a significant overall survival benefit, underscoring the need for novel effective agents. Anlotinib plus penpulimab has demonstrated encouraging activity and safety in a phase 2 study. In this phase 3 trial, we aimed to assess whether the combination of anlotinib plus penpulimab improved survival versus sorafenib in patients with unresectable HCC.APOLLO was a multicentre, open-label, parallel-controlled, randomised, phase 3 trial conducted at 79 centres in China. Patients aged 18-75 years with unresectable HCC, no previous systemic therapy, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 were randomly assigned (2:1) to anlotinib (10 mg orally once daily on days 1-14) plus penpulimab (200 mg intravenously on day 1), or sorafenib (400 mg orally twice daily) every 3 weeks. Randomisation was done centrally using block randomisation with a fixed block size of 3 and stratified by the presence of macrovascular invasion or extrahepatic metastasis, α-fetoprotein concentration, and ECOG performance status. Sex (male or female) and ethnicity (Chinese or other) were self-reported. The co-primary endpoints were progression-free survival assessed by masked independent review committee and overall survival in the intention-to-treat population. Safety was assessed in all participants who received at least one dose of the study drug and had at least one recorded safety assessment. Final progression-free survival and second interim overall survival analyses are presented. This trial is registered at ClinicalTrials.gov, NCT04344158, and follow-up is ongoing.From Aug 11, 2020, to June 20, 2023, 940 patients were screened for inclusion in the trial, 291 were excluded, and 649 were randomly assigned to an intervention (433 were assigned to the anlotinib plus penpulimab group and 216 were assigned to the sorafenib group. 551 (85%) of the 649 patients were male and 98 (15%) were female. All patients were Chinese with a median age of 57 years (IQR 50-65). For the final analysis of progression-free survival (June 5, 2023), 636 patients (424 patients in the anlotinib plus penpulimab group vs 212 patients in the sorafenib group) comprised the intention-to-treat population. For the second interim analysis of overall survival (Jan 29, 2024), 649 patients (433 vs 216) comprised the intention-to-treat population. Median follow-up was 6·2 months (IQR 5·5-7·5) for the anlotinib plus penpulimab group and 4·2 months (2·9-7·1) for the sorafenib group for final progression-free survival analysis, and 15·3 months (14·3-17·3) for the anlotinib plus penpulimab group and 14·5 months (11·5-17·0) for the sorafenib group for the second interim overall survival analysis. Median progression-free survival was significantly extended with anlotinib plus penpulimab versus sorafenib (6·9 months [95% CI 5·8-8·0] vs 2·8 months [2·7-4·1]; hazard ratio [HR] 0·52 [95% CI 0·41-0·66]; p<0·0001). Median overall survival was significantly prolonged with anlotinib plus penpulimab compared with sorafenib (16·5 months [95% CI 14·7-19·0] vs 13·2 months [9·7-16·9]; HR 0·69 [95% CI 0·55-0·87]; p=0·0014). The most common grade 3 or worse treatment-related adverse events were hypertension (75 [17%] patients in the anlotinib plus penpulimab group vs 22 [10%] in the sorafenib group) and decrease in platelet count (39 [9%] vs 13 [6%]). Treatment-related serious adverse events occurred in 90 (21%) and 19 (9%) patients in the respective groups; treatment-related deaths occurred in one (<1%) patient in the anlotinib plus penpulimab group (upper gastrointestinal haemorrhage) and two (1%) patients in the sorafenib group (hepatic failure and death of unknown cause).Anlotinib plus penpulimab significantly improved progression-free survival and overall survival versus sorafenib in unresectable HCC and might be a new first-line option. These findings require verification in other regions of the world.Chia Tai Tianqing Pharmaceutical Group.Copyright © 2025 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.
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| [448] |
Donafenib, a novel multikinase inhibitor and a deuterated sorafenib derivative, has shown efficacy in phase Ia and Ib hepatocellular carcinoma (HCC) studies. This study compared the efficacy and safety of donafenib versus sorafenib as first-line therapy for advanced HCC.
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| [449] |
In a phase 2 trial, lenvatinib, an inhibitor of VEGF receptors 1-3, FGF receptors 1-4, PDGF receptor α, RET, and KIT, showed activity in hepatocellular carcinoma. We aimed to compare overall survival in patients treated with lenvatinib versus sorafenib as a first-line treatment for unresectable hepatocellular carcinoma.This was an open-label, phase 3, multicentre, non-inferiority trial that recruited patients with unresectable hepatocellular carcinoma, who had not received treatment for advanced disease, at 154 sites in 20 countries throughout the Asia-Pacific, European, and North American regions. Patients were randomly assigned (1:1) via an interactive voice-web response system-with region; macroscopic portal vein invasion, extrahepatic spread, or both; Eastern Cooperative Oncology Group performance status; and bodyweight as stratification factors-to receive oral lenvatinib (12 mg/day for bodyweight ≥60 kg or 8 mg/day for bodyweight <60 kg) or sorafenib 400 mg twice-daily in 28-day cycles. The primary endpoint was overall survival, measured from the date of randomisation until the date of death from any cause. The efficacy analysis followed the intention-to-treat principle, and only patients who received treatment were included in the safety analysis. The non-inferiority margin was set at 1·08. The trial is registered with ClinicalTrials.gov, number NCT01761266.Between March 1, 2013 and July 30, 2015, 1492 patients were recruited. 954 eligible patients were randomly assigned to lenvatinib (n=478) or sorafenib (n=476). Median survival time for lenvatinib of 13·6 months (95% CI 12·1-14·9) was non-inferior to sorafenib (12·3 months, 10·4-13·9; hazard ratio 0·92, 95% CI 0·79-1·06), meeting criteria for non-inferiority. The most common any-grade adverse events were hypertension (201 [42%]), diarrhoea (184 [39%]), decreased appetite (162 [34%]), and decreased weight (147 [31%]) for lenvatinib, and palmar-plantar erythrodysaesthesia (249 [52%]), diarrhoea (220 [46%]), hypertension (144 [30%]), and decreased appetite (127 [27%]) for sorafenib.Lenvatinib was non-inferior to sorafenib in overall survival in untreated advanced hepatocellular carcinoma. The safety and tolerability profiles of lenvatinib were consistent with those previously observed.Eisai Inc.Copyright © 2018 Elsevier Ltd. All rights reserved.
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| [450] |
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, and additional first-line treatments are needed. The programmed cell death protein 1 inhibitor tislelizumab demonstrated efficacy and a tolerable safety profile as second-line HCC treatment.To investigate efficacy and safety of tislelizumab vs sorafenib tosylate for first-line treatment of unresectable HCC.The open-label, global, multiregional phase 3 RATIONALE-301 randomized clinical trial enrolled systemic therapy-naive adults with histologically confirmed HCC, Barcelona Clinic Liver Cancer stage B or C disease, disease progression following (or patient was not amenable to) locoregional therapy, Eastern Cooperative Oncology Group performance status of 1 or less, and Child-Pugh class A, between December 27, 2017, and October 2, 2019. Data cutoff was July 11, 2022.Patients were randomized 1:1 to receive tislelizumab, 200 mg intravenously every 3 weeks, or sorafenib tosylate, 400 mg orally twice daily.The primary end point was overall survival (OS); secondary end points included objective response rate, progression-free survival, duration of response, and safety.A total of 674 patients were included in the analysis (570 men [84.6%]; median age, 61 years [range, 23-86 years]). As of July 11, 2022, minimum study follow-up was 33 months. The primary end point of OS noninferiority of tislelizumab vs sorafenib was met in the intention-to-treat population (n = 674); median overall survival was 15.9 (95% CI, 13.2-19.7) months vs 14.1 (95% CI, 12.6-17.4) months, respectively (hazard ratio [HR], 0.85 [95.003% CI, 0.71-1.02]), and superiority of tislelizumab vs sorafenib was not met. The objective response rate was 14.3% (n = 49) for tislelizumab vs 5.4% (n = 18) for sorafenib, and median duration of response was 36.1 (95% CI, 16.8 to not evaluable) months vs 11.0 (95% CI, 6.2-14.7) months, respectively. Median progression-free survival was 2.1 (95% CI, 2.1-3.5) months vs 3.4 (95% CI, 2.2-4.1) months with tislelizumab vs sorafenib (HR, 1.11 [95% CI, 0.92-1.33]). The incidence of treatment-emergent adverse events (AEs) was 96.2% (325 of 338 patients) for tislelizumab and 100% (n = 324) for sorafenib. Grade 3 or greater treatment-related AEs were reported in 75 patients (22.2%) receiving tislelizumab and 173 (53.4%) receiving sorafenib. There was a lower incidence of treatment-related AEs leading to drug discontinuation (21 [6.2%] vs 33 [10.2%]) and drug modification (68 [20.1%] vs 187 [57.7%]) with tislelizumab vs sorafenib.In RATIONALE-301, tislelizumab demonstrated OS benefit that was noninferior vs sorafenib, with a higher objective response rate and more durable responses, while median progression-free survival was longer with sorafenib. Tislelizumab demonstrated a favorable safety profile vs sorafenib.ClinicalTrials.gov Identifier: NCT03412773.
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| [451] |
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| [452] |
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| [453] |
Sorafenib has shown survival benefits in patients with advanced hepatocellular carcinoma (HCC) and Child-Pugh (CP) class A liver function. There are few prospective data on sorafenib in patients with HCC and CP class B.A consecutive prospective series of 300 patients with CP class A or B HCC were enrolled in a dual-phase trial to determine survival and safety data according to liver function (class A or B) in patients receiving oral sorafenib 800 mg daily. [Results of this study were presented in part at the ASCO 2012 Gastrointestinal Cancers Symposium, 19-21 January 2012. J Clin Oncol 2012; 30 (Suppl 4): abstract 306.] RESULTS: Overall progression-free survival (PFS), time to progression (TTP) and overall survival (OS) were 3.9, 4.1 and 9.1 months, respectively. For patients with CP class A versus B status, PFS was 4.3 versus 2.1 months, TTP was 4.2 versus 3.8 months and OS was 10.0 versus 3. 8 months. Extrahepatic spread was associated with worse outcomes but taken together with CP class, liver function played a greater role in reducing survival. Adverse events for the two CP groups were similar.Although patients with HCC and CP class B liver function have poorer outcomes than those with CP class A function, data suggest that patients with CP class B liver function can tolerate treatment and may still benefit from sorafenib.© 2012 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.
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| [454] |
To determine whether FOLFOX4 (infusional fluorouracil, leucovorin, and oxaliplatin) administered as palliative chemotherapy to patients with advanced hepatocellular carcinoma (HCC) provides a survival benefit and efficacy versus doxorubicin.This multicenter, open-label, randomized, phase III study in mainland China, Taiwan, Korea, and Thailand involved 371 patients age 18 to 75 years who had locally advanced or metastatic HCC and were ineligible for curative resection or local treatment. They were randomly assigned at a ratio of one to one to receive either FOLFOX4 (n = 184) or doxorubicin (n = 187). The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS), response rate (RR) by RECIST (version 1.0), and safety.At the prespecified final analysis, median OS was 6.40 months with FOLFOX4 (95% CI, 5.30 to 7.03) and 4.97 months with doxorubicin (95% CI, 4.23 to 6.03; P =.07; hazard ratio [HR], 0.80; 95% CI, 0.63 to 1.02). Median PFS was 2.93 months with FOLFOX4 (95% CI, 2.43 to 3.53), and 1.77 months with doxorubicin (95% CI, 1.63 to 2.30; P <.001; HR, 0.62; 95% CI, 0.49 to 0.79). RR was 8.15% with FOLFOX4 and 2.67% with doxorubicin (P =.02). On continued follow-up, the trend toward increased OS with FOLFOX4 was maintained (P =.04; HR, 0.79; 95% CI, 0.63 to 0.99). Toxicity was consistent with previous experiences with FOLFOX4; proportions of grade 3 to 4 adverse events were similar between treatments.Although the study did not meet its primary end point, the trend toward improved OS with FOLFOX4, along with increased PFS and RR, suggests that this regimen may confer some benefit to Asian patients, but an OS benefit cannot be concluded from these data.
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| [455] |
The EACH study assessed the efficacy of oxaliplatin, 5-fluorouracil, and leucovorin (the FOLFOX4 regimen) compared with doxorubicin alone in terms of overall survival (OS), progression-free survival (PFS), and safety in patients with advanced hepatocellular carcinoma (HCC). We present the results of this study in Chinese patients.In a multicenter, open-label, randomized, phase III study (NCT00471965), 371 patients (279 patients from the People's Republic of China) were randomized 1:1 to receive either FOLFOX4 or doxorubicin until disease progression, intolerable toxicity, death, or surgical resection.Baseline characteristics of the Chinese patients enrolled in the study were similar for the 2 treatment groups and in comparison with the whole EACH cohort. Median OS at the prespecified time point of treatment was 5.7 months with FOLFOX4 and 4.3 months with doxorubicin (hazard ratio [HR]: 0.74; 95% confidence interval [CI]: 0.55-0.98; p =.03). At the end of the follow-up period, median OS was 5.9 months with FOLFOX4 and 4.3 months with doxorubicin (HR: 0.75; 95% CI: 0.58-0.98; p =.03). Median PFS was 2.4 months and 1.7 months in the FOLFOX4 and doxorubicin groups, respectively (HR: 0.55; 95% CI: 0.45-0.78; p =.0002). The response rate (RR) and disease control rate (DCR) were significantly higher in the FOLFOX4 group than in the doxorubicin group (RR: 8.6% vs. 1.4%, p =.006; DCR: 47.1% vs. 26.6%, p =.0004). Hematological toxicity was more frequently reported in the FOLFOX4 group.For Chinese HCC patients enrolled in the EACH study, FOLFOX4 significantly improved the RR and DCR and prolonged survival compared with doxorubicin. Systemic chemotherapy with oxaliplatin-based regimens may play an important role in the treatment of Chinese patients with advanced HCC.©AlphaMed Press.
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| [456] |
This is a summary of results from a phase 3 clinical study called HIMALAYA. HIMALAYA looked at treatment with one dose of a medication called tremelimumab combined with multiple doses of a medication called durvalumab (the STRIDE regimen) or multiple doses of durvalumab alone. These treatments were compared with a medication called sorafenib in participants with unresectable hepatocellular carcinoma (HCC). HCC is a type of liver cancer that is difficult to treat because it is often diagnosed when it is unresectable, meaning it can no longer be removed with surgery. Sorafenib has been the main treatment for unresectable HCC since 2007. However, people who take sorafenib may experience side effects that can reduce their quality of life, so alternative medicines are being trialed. Tremelimumab and durvalumab are types of drugs called immunotherapies, and they both work in different ways to help the body's immune system fight cancer.Participants who took STRIDE lived longer than participants who took sorafenib, whilst participants who took durvalumab alone lived a similar length of time as participants who took sorafenib. Participants who took STRIDE or durvalumab had a lower relative risk of experiencing worsening in their quality of life than participants who took sorafenib. The side effects that participants who received STRIDE or durvalumab experienced were expected for these types of treatments and could mostly be managed.Overall, STRIDE is more effective than sorafenib for people with unresectable HCC. NCT03298451 (HIMALAYA) (ClinicalTrials.gov).
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| [457] |
In the phase III HIMALAYA study (NCT03298451), STRIDE (Single Tremelimumab Regular Interval Durvalumab) significantly improved overall survival (OS) vs. sorafenib in unresectable HCC and demonstrated long-term survival benefits. We report an updated exploratory analysis of OS after 5 years of follow-up, including survival by multiple tumour response measures.Participants were randomised to STRIDE (tremelimumab plus durvalumab), durvalumab or sorafenib. OS, depth of response and serious adverse events were assessed. Extended long-term survivors (≥48 months beyond randomisation) were described. The updated data cut-off was 01 March 2024.Median (95% CI) follow-up durations were 62.49 (59.47-64.79) months (STRIDE) and 59.86 (58.32-61.54) months (sorafenib). The OS hazard ratio (95% CI) for STRIDE vs. sorafenib was 0.76 (0.65-0.89). OS rates at 60 months for STRIDE vs. sorafenib were 19.6% vs. 9.4% overall, 28.7% vs. 12.7% in participants achieving disease control per RECIST v1.1, and 50.7% vs. 26.3% in participants achieving >25% tumour shrinkage. No late-onset treatment-related serious adverse events were reported for STRIDE. There were more extended long-term survivors with STRIDE (83/393, 21.1%) than sorafenib (45/389, 11.6%), and extended long-term survival occurred across all clinically relevant subgroups.At 5 years, STRIDE sustained an OS benefit vs. sorafenib and maintained a manageable safety profile. OS benefit with STRIDE was improved in participants with disease control. Data suggest that any degree of tumour shrinkage with STRIDE can be associated with improved OS, indicating that conventional response measures may not fully capture the benefits of STRIDE. Nevertheless, participants experiencing deep responses appear to have the greatest benefit. STRIDE continues to set new benchmarks in unresectable HCC with 1 in 5 patients alive at 5 years.NCT03298451.The phase III HIMALAYA study showed that STRIDE (Single Tremelimumab Regular Interval Durvalumab) improved overall survival (OS) vs. sorafenib in participants with unresectable HCC, including after 4 years of follow-up. Understanding the efficacy and safety of STRIDE over the longer term is important for healthcare providers; here, we demonstrate that STRIDE sustained an OS benefit vs. sorafenib and maintained a manageable safety profile after 5 years of follow-up. OS benefit with STRIDE was improved in participants with disease control and any degree of tumour shrinkage, indicating that conventional response measures may not fully capture the benefits of STRIDE. These findings are important as they set new benchmarks in unresectable HCC and may help guide clinical decisions in the future.Copyright © 2025 The Authors. Published by Elsevier B.V. All rights reserved.
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| [458] |
Previous studies evaluating antiangiogenic agents plus immune checkpoint inhibitors for unresectable hepatocellular carcinoma (HCC) have shown encouraging results. This study was conducted to investigate the efficacy and safety of donafenib combined with sintilimab (Don-Sin) for advanced HCC.
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| [459] |
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| [460] |
There are no systemic treatments for patients with hepatocellular carcinoma (HCC) whose disease progresses during sorafenib treatment. We aimed to assess the efficacy and safety of regorafenib in patients with HCC who have progressed during sorafenib treatment.In this randomised, double-blind, parallel-group, phase 3 trial done at 152 sites in 21 countries, adults with HCC who tolerated sorafenib (≥400 mg/day for ≥20 of last 28 days of treatment), progressed on sorafenib, and had Child-Pugh A liver function were enrolled. Participants were randomly assigned (2:1) by a computer-generated randomisation list and interactive voice response system and stratified by geographical region, Eastern Cooperative Oncology Group performance status, macrovascular invasion, extrahepatic disease, and α-fetoprotein level to best supportive care plus oral regorafenib 160 mg or placebo once daily during weeks 1-3 of each 4-week cycle. Investigators, patients, and the funder were masked to treatment assignment. The primary endpoint was overall survival (defined as time from randomisation to death due to any cause) and analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01774344.Between May 14, 2013, and Dec 31, 2015, 843 patients were screened, of whom 573 were enrolled and randomised (379 to regorafenib and 194 to placebo; population for efficacy analyses), and 567 initiated treatment (374 received regorafenib and 193 received placebo; population for safety analyses). Regorafenib improved overall survival with a hazard ratio of 0·63 (95% CI 0·50-0·79; one-sided p<0·0001); median survival was 10·6 months (95% CI 9·1-12·1) for regorafenib versus 7·8 months (6·3-8·8) for placebo. Adverse events were reported in all regorafenib recipients (374 [100%] of 374) and 179 (93%) of 193 placebo recipients. The most common clinically relevant grade 3 or 4 treatment-emergent events were hypertension (57 patients [15%] in the regorafenib group vs nine patients [5%] in the placebo group), hand-foot skin reaction (47 patients [13%] vs one [1%]), fatigue (34 patients [9%] vs nine patients [5%]), and diarrhoea (12 patients [3%] vs no patients). Of the 88 deaths (grade 5 adverse events) reported during the study (50 patients [13%] assigned to regorafenib and 38 [20%] assigned to placebo), seven (2%) were considered by the investigator to be related to study drug in the regorafenib group and two (1%) in the placebo group, including two patients (1%) with hepatic failure in the placebo group.Regorafenib is the only systemic treatment shown to provide survival benefit in HCC patients progressing on sorafenib treatment. Future trials should explore combinations of regorafenib with other systemic agents and third-line treatments for patients who fail or who do not tolerate the sequence of sorafenib and regorafenib.Bayer.Copyright © 2017 Elsevier Ltd. All rights reserved.
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| [461] |
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| [462] |
Patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations have poor prognosis. We aimed to establish the efficacy of ramucirumab in patients with advanced hepatocellular carcinoma and α-fetoprotein concentrations of 400 ng/mL or higher.REACH-2 was a randomised, double-blind, placebo-controlled, phase 3 trial done at 92 hospitals, clinics, and medical centres in 20 countries. Eligible patients were aged 18 years or older and had histologically or cytologically confirmed hepatocellular carcinoma, or diagnosed cirrhosis and hepatocellular carcinoma, Barcelona Clinic Liver Cancer stage B or C disease, Child-Pugh class A liver disease, Eastern Cooperative Oncology Group (ECOG) performance statuses of 0 or 1, α-fetoprotein concentrations of 400 ng/mL or greater, and had previously received first-line sorafenib. Participants were randomly assigned (2:1) via an interactive web response system with a computer-generated random sequence to 8 mg/kg intravenous ramucirumab every 2 weeks or placebo. All patients received best supportive care. The primary endpoint was overall survival. Secondary endpoints were progression-free survival, proportion of patients achieving an objective response, time to radiographic progression, safety, time to deterioration in scores on the Functional Assessment of Cancer Therapy Hepatobiliary Symptom Index 8 (FHSI-8), and time to deterioration in ECOG performance status. We also pooled individual patient data from REACH-2 with data from REACH (NCT01140347) for patients with α-fetoprotein concentrations of 400 ng/mL or greater. Efficacy analyses were by intention to treat, whereas safety analyses were done in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT02435433.Between July 26, 2015, and Aug 30, 2017, 292 patients were randomly assigned, 197 to the ramucirumab group and 95 to the placebo group. At a median follow-up of 7·6 months (IQR 4·0-12·5), median overall survival (8·5 months [95% CI 7·0-10·6] vs 7·3 months [5·4-9·1]; hazard ratio [HR] 0·710 [95% CI 0·531-0·949]; p=0·0199) and progression-free survival (2·8 months [2·8-4·1] vs 1·6 months [1·5-2·7]; 0·452 [0·339-0·603]; p<0·0001) were significantly improved in the ramucirumab group compared with the placebo group. The proportion of patients with an objective response did not differ significantly between groups (nine [5%] of 197 vs one [1%] of 95; p=0·1697). Median time to deterioration in FHSI-8 total scores (3·7 months [95% CI 2·8-4·4] vs 2·8 months [1·6-2·9]; HR 0·799 [95% CI 0·545-1·171]; p=0·238) and ECOG performance statuses (HR 1·082 [95% CI 0·639-1·832]; p=0·77) did not differ between groups. Grade 3 or worse treatment-emergent adverse events that occurred in at least 5% of patients in either group were hypertension (25 [13%] in the ramucirumab group vs five [5%] in the placebo group), hyponatraemia (11 [6%] vs 0) and increased aspartate aminotransferase (six [3%] vs five [5%]). Serious adverse events of any grade and cause occurred in 68 (35%) patients in the ramucirumab group and 28 (29%) patients in the placebo group. Three patients in the ramucirumab group died from treatment-emergent adverse events that were judged to be related to study treatment (one had acute kidney injury, one had hepatorenal syndrome, and one had renal failure).REACH-2 met its primary endpoint, showing improved overall survival for ramucirumab compared with placebo in patients with hepatocellular carcinoma and α-fetoprotein concentrations of at least 400 ng/mL who had previously received sorafenib. Ramucirumab was well tolerated, with a manageable safety profile. To our knowledge, REACH-2 is the first positive phase 3 trial done in a biomarker-selected patient population with hepatocellular carcinoma.Eli Lilly.Copyright © 2019 Elsevier Ltd. All rights reserved.
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| [463] |
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| [464] |
We evaluated the efficacy and safety of pembrolizumab in patients from Asia with previously treated advanced hepatocellular carcinoma (HCC).
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| [465] |
Blocking the interaction between PD-1 and its ligands is a promising treatment strategy for advanced hepatocellular carcinoma. This study aimed to assess the antitumour activity and safety of the anti-PD-1 inhibitor camrelizumab in pretreated patients with advanced hepatocellular carcinoma.This is a multicentre, open-label, parallel-group, randomised, phase 2 trial done at 13 study sites in China. Eligible patients were aged 18 years and older with a histological or cytological diagnosis of advanced hepatocellular carcinoma, had progressed on or were intolerant to previous systemic treatment, and had an Eastern Cooperative Oncology Group performance score of 0-1. Patients were randomly assigned (1:1) to receive camrelizumab 3 mg/kg intravenously every 2 or 3 weeks, via a centralised interactive web-response system using block randomisation (block size of four). The primary endpoints were objective response (per blinded independent central review) and 6-month overall survival, in all randomly assigned patients who had at least one dose of study treatment. Safety was analysed in all treated patients. This study is registered with ClinicalTrials.gov, number NCT02989922, and follow-up is ongoing, but enrolment is closed.Between Nov 15, 2016, and Nov 16, 2017, 303 patients were screened for eligibility, of whom 220 eligible patients were randomly assigned and among whom 217 received camrelizumab (109 patients were given treatment every 2 weeks and 108 every 3 weeks). Median follow-up was 12·5 months (IQR 5·7-15·5). Objective response was reported in 32 (14·7%; 95% CI 10·3-20·2) of 217 patients. The overall survival probability at 6 months was 74·4% (95% CI 68·0-79·7)]. Grade 3 or 4 treatment-related adverse events occurred in 47 (22%) of 217 patients; the most common were increased aspartate aminotransferase (ten [5%]) and decreased neutrophil count (seven [3%]). Two deaths were judged by the investigators to be potentially treatment-related (one due to liver dysfunction and one due to multiple organ failure).Camrelizumab showed antitumour activity in pretreated Chinese patients with advanced hepatocellular carcinoma, with manageable toxicities, and might represent a new treatment option for these patients.Jiangsu Hengrui Medicine.Copyright © 2020 Elsevier Ltd. All rights reserved.
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| [466] |
We assessed the efficacy and safety of camrelizumab [an anti-programmed death (PD-1) mAb] plus apatinib (a VEGFR-2 tyrosine kinase inhibitor) in patients with advanced hepatocellular carcinoma (HCC).
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| [467] |
This study assessed the safety and efficacy of SHR-1210 (anti-PD-1 antibody) and apatinib (VEGFR2 inhibitor) as combination therapy in patients with advanced hepatocellular carcinoma (HCC), gastric, or esophagogastric junction cancer (GC/EGJC).This was an open-label, dose-escalation (phase Ia) and expansion study (phase Ib). In phase Ia, patients (= 15) received SHR-1210 200 mg every 2 weeks and apatinib 125-500 mg once daily until unacceptable toxicity or disease progression. In phase Ib, patients (= 28) received apatinib at the phase Ia-identified recommended phase II dose (RP2D) plus SHR-1210. The primary objectives were safety and tolerability and RP2D determination.At data cutoff, 43 patients were enrolled. In phase Ia, four dose-limiting toxicity events were observed (26.7%): one grade 3 lipase elevation (6.7%) in the apatinib 250 mg cohort and three grade 3 pneumonitis events (20%) in the apatinib 500 mg cohort. The maximum tolerated RP2D for apatinib was 250 mg. Of the 33 patients treated with the R2PD combination, 20 (60.6%) experienced a grade ≥3 treatment-related adverse event; adverse events in ≥10% of patients were hypertension (15.2%) and increased aspartate aminotransferase (15.2%). The objective response rate in 39 evaluable patients was 30.8% (95% CI: 17.0%-47.6%). Eight of 16 evaluable HCC patients achieved a partial response (50.0%, 95% CI: 24.7%-75.4%).SHR-1210 and apatinib combination therapy demonstrated manageable toxicity in patients with HCC and GC/EGJC at recommended single-agent doses of both drugs. The RP2D for apatinib as combination therapy was 250 mg, which showed encouraging clinical activity in patients with advanced HCC.©2018 American Association for Cancer Research.
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| [468] |
Introduction: Tislelizumab (anti-programmed cell death protein 1 antibody) showed preliminary antitumor activity and tolerability in patients with advanced solid tumors, including hepatocellular carcinoma (HCC). This study aimed to assess the efficacy and safety of tislelizumab in patients with previously treated advanced HCC. Methods: The multiregional phase 2 study RATIONALE-208 examined single-agent tislelizumab (200 mg intravenously every 3 weeks) in patients with advanced HCC with Child-Pugh A, Barcelona Clinic Liver Cancer stage B or C, and who had received one or more prior lines of systemic therapy. The primary endpoint was objective response rate (ORR), radiologically confirmed per Response Evaluation Criteria in Solid Tumors version 1.1 by the Independent Review Committee. Safety was assessed in patients who received ≥1 dose of tislelizumab. Results: Between April 9, 2018, and February 27, 2019, 249 eligible patients were enrolled and treated. After a median study follow-up of 12.7 months, ORR was 13% (n = 32/249; 95% confidence interval [CI], 9–18), including five complete and 27 partial responses. The number of prior lines of therapy did not impact ORR (one prior line, 13% [95% CI, 8–20]; two or more prior lines, 13% [95% CI, 7–20]). Median duration of response was not reached. The disease control rate was 53%, and median overall survival was 13.2 months. Of the 249 total patients, grade ≥3 treatment-related adverse events were reported in 38 (15%) patients; the most common was liver transaminase elevations in 10 (4%) patients. Treatment-related adverse events led to treatment discontinuation in 13 (5%) patients or dose delay in 46 (19%) patients. No deaths were attributed to the treatment per investigator assessment. Conclusion: Tislelizumab demonstrated durable objective responses, regardless of the number of prior lines of therapy, and acceptable tolerability in patients with previously treated advanced HCC.
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Tumours respond differently to immunotherapies compared with chemotherapeutic drugs, raising questions about the assessment of changes in tumour burden-a mainstay of evaluation of cancer therapeutics that provides key information about objective response and disease progression. A consensus guideline-iRECIST-was developed by the RECIST working group for the use of modified Response Evaluation Criteria in Solid Tumours (RECIST version 1.1) in cancer immunotherapy trials, to ensure consistent design and data collection, facilitate the ongoing collection of trial data, and ultimate validation of the guideline. This guideline describes a standard approach to solid tumour measurements and definitions for objective change in tumour size for use in trials in which an immunotherapy is used. Additionally, it defines the minimum datapoints required from future trials and those currently in development to facilitate the compilation of a data warehouse to use to later validate iRECIST. An unprecedented number of trials have been done, initiated, or are planned to test new immune modulators for cancer therapy using a variety of modified response criteria. This guideline will allow consistent conduct, interpretation, and analysis of trials of immunotherapies.Copyright © 2017 Elsevier Ltd. All rights reserved.
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Advanced hepatitis B virus (HBV)‐related hepatocellular carcinoma HCC with poor prognosis is often associated with chronic inflammation, immune tolerance, and marked heterogeneity. The interleukin‐6 (IL‐6)/JAK/STAT3 signal pathways play multiple regulatory roles in modulating inflammation and immunity in cancers. Polarization of myeloid‐derived suppressor cells (MDSCs) is involved in HBV‐related immunosuppression and CD8+ T‐cell activation through ERK/IL‐6/STAT3. Icaritin is a small molecule that has displayed anticancer activities through IL‐6/JAK/STAT3 pathways in tumor cells and immune cells including CD8+ T cells, MDSCs, neutrophils, and macrophages. This study aimed to confirm icaritin immunomodulation in advanced HBV‐related HCC patients with poor prognosis. Immunomodulation of MDSCs was evaluated in BALB/c mice in vivo. Immunomodulation of serum cytokines and a panel of immune checkpoint proteins were assessed in HBV‐related, histologically confirmed HCC patients. Poor prognostic characteristics included HBV infection, bulky tumors, Child‐Pugh B classification, and metastasis. Clinical end‐points included safety, tumor response, and overall survival (OS). Icaritin treatment‐induced dynamics of serum cytokines IL‐6, IL‐8, IL‐10, and tumor necrosis factor‐α, and soluble immune checkpoint proteins TIM3, LAG3, CD28, CD80, and CTLA‐4 were assessed. No grade III/IV treatment‐related adverse events were observed. Time‐to‐progression was significantly associated with the prognostic factors. Improved survival was observed in the advanced HCC patients with dynamic changes of cytokines, immune checkpoint proteins, and immune cells. Median OS (329‐565 days) was significantly correlated with baseline hepatitis B surface antigen positivity, cytokines, tumor neoantigens, and Stenotrophomonas maltophilia infection. Composite biomarker scores of high‐level α‐fetoprotein and T helper type I (Th1)/Th2 cytokines associated with favorable survival warrant further clinical development of icaritin as an alternative immune‐modulatory regimen to treat advanced HCC patients with poor prognosis.
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Hepatocellular carcinoma (HCC) resistant to both chemotherapy and immunotherapy is among the deadliest malignancies. Doxorubicin widely used in transarterial chemotherapy in HCC can induce immunogenic cell death (ICD), but the resulting immunogenicity is still weak. We aim to seek a strategy for improving the efficacy of ICD in HCC based on an immunoregulatory drug called icaritin. Icaritin induced mitophagy and apoptosis to provoke ICD both in mouse Hepa1-6 and human Huh7 HCC cells. A combination of icaritin and doxorubicin with a molar ratio of 1:2 played a synergistic role in ICD induction. The poly lactic--glycolic acid (PLGA)-polyethylene glycol (PEG)-aminoethyl anisamide (AEAA) nanoparticle (NP) targeted codelivery of icaritin and doxorubicin remodeled the immunosuppressive tumor microenvironment and triggered a robust immune memory response, which efficiently improved anti-HCC effect at an early stage in mouse HCC model. In addition, the combo PLGA-PEG-AEAA NP together with lenvatinib significantly prolonged survival time of mice at the advanced stage of HCC. Collectively, our findings reveal an anti-HCC mechanism of icaritin on mitophagy and provide an effective immune-based therapeutic strategy for HCC.
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成远, 华海清. 榄香烯治疗原发性肝癌的研究进展[J]. 临床肿瘤学杂志, 2017, 22(10):950-953. DOI: 10.3969/j.issn.1009-0460.2017.10.018.
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范隼, 李庆源, 周志涛, 等. TACE 联合金龙胶囊治疗原发性肝癌的效果研究[J]. 中国实用医药, 2019, 14(21):42-44. DOI: 10.14163/j.cnki.11-5547/r.2019.21.022.
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路大鹏, 王玉强, 赵卫林, 等. 康莱特联合肝动脉化疗栓塞术治疗肝癌的临床研究[J]. 世界临床医学, 2017, 11(5):70.
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国际肝胆胰协会中国分会, 中国抗癌协会肝癌专业委员会, 中国研究型医院学会肝胆胰外科专业委员会, 等. 乙肝病毒相关肝细胞癌抗病毒治疗中国专家共识(2023 版)[J]. 中华消化外科杂志, 2023, 22(1):29-41.DOI:10.3760/cma.j.cn115610-20221024-00612.
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中华医学会肝病学分会, 中华医学会感染病学分会. 慢性乙型肝炎防治指南(2022年版)[J]. 中华肝脏病杂志, 2022, 30(12):1309-1331.DOI:10.3760/cma.j.cn501113-20221204-00607.
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中华医学会肝病学分会, 中华医学会感染病学分会. 丙型肝炎防治指南(2022 年版)[J]. 中华传染病杂志, 2023, 41(1):29-46.DOI:10.3760/cma.j.cn311365-20230217-00045.
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中国临床肿瘤学会指南工作委员会. 中国临床肿瘤学会(CSCO)肿瘤放化疗相关中性粒细胞减少症规范化管理指南(2021) [J]. 临床肿瘤学杂志, 2021, 26(7):638-648. DOI: 10.3969/j.issn.1009-0460.2021.07.011.
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中华医学会血液学分会血栓与止血学组. 促血小板生成药物临床应用管理中国专家共识 (2023 年版)[J]. 中华血液学杂志, 2023, 44(7):535-542. DOI:10.3760/cma.j.issn.0253-2727.2023.07.002.
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国家感染性疾病临床医学研究中心, 北京医学会肝病学分会, 中国老年学和老年医学学会转化医学分会, 等. 肝病相关血小板减少症临床管理中国专家共识[J]. 临床肝胆病杂志, 2023, 39(10):2307-2320. DOI:10.3969/j.issn.1001-5256.2023.10.007.
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Spontaneous rupture of hepatocellular carcinoma (rHCC) is a life-threatening complication occurring in 3-15% of patients with HCC. This review discusses the most recent updates in the epidemiology, pathophysiology, risk factors, diagnosis and presentation, management, and prognostic factors of rHCC.A comprehensive systematic review was performed using MEDLINE/PubMed and Web of Science databases, with the end of search date being December 1, 2023, regarding rHCC diagnosis, imaging, and management.Achieving adequate hemostasis and stabilization of the patient remains the primary objective in managing patients presenting with rHCC. In earlier studies, the mortality rate in the acute phase of rHCC has been reported to be 25-75%. However, more recent studies reviewed here have demonstrated that transcatheter arterial embolization/chemoembolization (TAE/TACE) followed by elective hepatectomy in select patients may offer significantly improved survival benefits and decrease perioperative complications compared to TAE/TACE alone or emergent/one-stage hepatectomy.Although prognosis for rHCC remains the lowest among causes of death related to HCC, more recent studies have demonstrated that improved short- and long-term patient outcomes may be achieved through active surveillance efforts for HCC combined with advanced multimodal diagnostic tools and multidisciplinary management strategies.Copyright © 2024 Society for Surgery of the Alimentary Tract. Published by Elsevier Inc. All rights reserved.
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Spontaneous rupture is a life-threatening complication of hepatocellular carcinoma (HCC). Recent trends in surgical treatments avoid emergency hepatectomy (EH) and favor emergency transarterial embolization (TAE) followed by delayed hepatectomy (DH). Still, there is debate on which is the better treatment option and whether delaying hepatectomy increases peritoneal metastasis.To provide evidence-based references for the optimal management of patients with spontaneously ruptured HCC by comparing the outcomes of EH and DH.Literature on postoperative outcomes of EH and DH in patients with spontaneously ruptured HCC published between the date of the database establishment and May 2022, was identified in the PubMed, EMBASE, and Cochrane Library databases. Revman 5.3 software was used for statistical analyses.Nine publications were identified, including a total of 681 patients. Of those, 304 underwent EH, and 377 underwent TAE followed by DH. The meta-analysis results indicated that the in-hospital mortality rate in the EH patient group was significantly higher than that in the DH patient group (relative risk (RR) = 2.17, 95% confidence interval (CI) 1.03-4.57, p =0.04). There was no significant differences in the rates of postoperative complications (RR = 1.21, 95% CI 0.77-1.90, p = 0.40), postoperative hospital stay (WMD = - 0.64, 95% CI - 5.61-4.34, p = 0.80), recurrence (RR = 1.09, 95% CI 0.94-1.25, p = 0.27), peritoneal metastasis (RR = 1.06, 95% CI 0.66-1.71, p = 0.80), 1-year survival (RR = 0.91, 95% CI 0.80-1.02, p = 0.11), or 3-year survival (RR = 0.81, 95% CI 0.61-1.09, p = 0.17) in survivors between the two patient groups.The postoperative outcomes of the spontaneously ruptured HCC survivors who received EH were similar to those who received emergency TAE followed by DH. However, the in-hospital mortality rate was higher in EH patients. Based on the findings, DH with TAE first strategy might be considered over EH as the first line treatment modality. However, these findings await further validation by future high-quality studies.© 2022. The Author(s).
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茆丽娜, 董艳彬, 张忠满, 等. 急诊可切除破裂出血肝癌病人治疗策略的选择及预后因素分析[J]. 介入放射学杂志, 2022, 31(6):572-576. DOI:10.3969/j.issn.1008-794X.2022.06.010.
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龚程, 田银生, 刘爽. 不同时间窗手术治疗原发性肝癌自发破裂出血病人 2 年生存率比较[J]. 实用肝脏病杂志, 2023, 26(2):274-277.DOI:10.3969/j.issn.1672-5069.2023.02.031.
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Spontaneous rupture is a fatal complication of advanced hepatocellular carcinoma (HCC) with an extremely poor prognosis. Although immune checkpoint inhibitors, targeted therapies, and nutritional therapy have shown potential in the treatment of advanced HCC, their combined efficacy in complex cases with high tumor burden complicated by rupture and bleeding remains unclear.A 54-year-old male patient was diagnosed with Barcelona Clinic Liver Cancer (BCLC) stage C HCC with high tumor burden, accompanied by a history of chronic hepatitis B and moderate malnutrition. After initial treatment with apatinib (500 mg/day) and nutritional therapy, the patient experienced HCC rupture. Following emergency transarterial embolization for hemostasis, the treatment regimen was adjusted to camrelizumab (200 mg/2 weeks) combined with reduced-dose apatinib (250 mg/day), along with continued nutritional support. After 17 months of treatment, the patient underwent hepatectomy, with pathological examination showing complete remission in the left liver. Postoperative adjuvant therapy included transarterial chemoembolization, nutritional therapy, targeted therapy, and individualized immunotherapy. As of the 4-year follow-up, the patients has good quality of life and has not experienced recurrence.This case showcases a multimodal treatment strategy for patients with advanced HCC with high tumor burden and rupture complications, integrating individualized immuno-targeted therapy, interventional treatment, and nutritional management and providing a possible approach for achieving a long-term survival. This comprehensive treatment method may offer new insights into improving the prognosis of patients with advanced HCC.© 2025. The Author(s).
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| [501] |
There exist no treatment guidelines for spontaneously ruptured hepatocellular carcinoma (srHCC) and its prognosis remains controversial.Patients were retrospectively enrolled and grouped based on hemodynamics and tumor resectability. The 30-day mortality, 5-year overall survival (OS), progression-free survival (PFS), peritoneal metastasis (PM) and intrahepatic metastasis (IM) rates were compared.In general, 239 patients were classified into four groups: patients with stable hemodynamics underwent semi-elective hepatectomy (n = 119), and those with unstable hemodynamics received emergent hepatectomy (n = 17), sequential hemostatic-transcatheter arterial chemoembolization (TACE)/-laparotomy with late hepatectomy (n = 49), or TACE only (n = 54). Hepatectomy was safer and provided better OS and PFS than TACE both before and after propensity score matching. Emergent hepatectomy was associated with higher 30-day mortality (6.2%, P < 0.05) and poorer prognosis whereas semi-elective hepatectomy and sequential treatment had comparable mortality (both 0%) and survival (36.3% vs 45.2%, P > 0.05). Compared with hemostatic TACE in the sequential treatment group, early surgical intervention (semi-elective hepatectomy, emergent hepatectomy, and sequential laparotomy with late hepatectomy) decreased PM (13.6% vs 34.2%, P = 0.003) whereas had higher IM (68.0% vs 50.0%, P = 0.039), but neither procedure had affected OS. In srHCC patients with high risk of recurrence (multiple tumors, micro- and macro-vascular invasion), postoperative adjuvant TACE improved OS.Hepatectomy could provide better prognosis than TACE for srHCC patients while semi-elective hepatectomy and sequential hemostatic-TACE with staged hepatectomy are viable options for srHCCs with stable and unstable hemodynamics, respectively.© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
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| [502] |
A diverse clinical course after the spontaneous rupture of hepatocellular carcinoma (HCC) renders nonstandardized treatment protocols.
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| [503] |
Spontaneous rupture of hepatocellular carcinoma (HCC) remains a life-threatening complication, with a reported mortality rate of between 16 and 30% and an incidence rate of approximately 3% in Europe. Survival data and risk factors after ruptured HCC are lacking, especially for peritoneal metastasis (PM).The aims of this study were to evaluate the pattern of recurrence and mortality after hepatectomy for ruptured HCC, and to focus on PM.We retrospectively reviewed the files of patients admitted to 14 French surgical centers for spontaneous rupture of HCC between May 2000 and May 2012.Overall, 135 patients were included in this study. The median disease-free survival and overall survival (OS) rates were 16.1 (11.0-21.1) and 28.7 (26.0-31.5) months, respectively, and the median follow-up period was 29 months. At last follow-up, recurrences were observed in 65.1% of patients (n = 88). The overall rate of PM following ruptured HCC was 12% (n = 16). Surgical management of PM was performed for six patients, with a median OS of 36.6 months. An α-fetoprotein level > 30 ng/mL (p = 0.0009), tumor size at rupture > 70 mm (p = 0.0009), and vascular involvement (p < 0.0001) were found to be independently associated with an increased likelihood of recurrence. No risk factor for PM was observed.This large-cohort French study confirmed that 12% of patients had PM after ruptured HCC. A curative approach may be an option for highly selected patients with exclusive PD because of the survival benefit it could provide.
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| [504] |
\n Ultrasonography (US) is generally recommended for the surveillance of hepatocellular carcinoma (HCC) in patients at risk. However, in patients with cirrhosis who have sufficiently high HCC incidence, surveillance using magnetic resonance imaging (MRI) with liver‐specific contrast showed markedly higher sensitivity in detecting early‐stage HCC than US. This study aimed to compare the cost‐effectiveness of semiannual surveillance using MRI versus US in patients with compensated cirrhosis and to identify the population that would gain optimal cost‐effectiveness through MRI surveillance. We designed a Markov model to compare the expected costs and quality‐adjusted life‐years (QALYs), between MRI and US, with a 20‐year time horizon, from the health care system perspective. The starting age of the cohort was 50 years, and 71% had hepatitis B virus–associated cirrhosis. The cycle length was 6 months. Transition probabilities and costs were obtained mainly from a prospective cohort study (the PRIUS study, NCT01446666). Cost and effectiveness were discounted at 5%. An incremental cost‐effectiveness ratio (ICER) was calculated and tested using sensitivity analyses. The cost‐effectiveness analysis indicated that the use of MRI incurred $5,562 incremental costs, 0.384 incremental life‐years (LYs), and 0.221 incremental QALYs compared to US. The annual HCC incidence was the most influential factor on the ICER. The ICERs were $14,474/LY and $25,202/QALY at an annual HCC incidence of 3%. When the HCC incidence rate was >1.81%, the ICER was below $50,000/QALY. With increased HCC incidence, MRI surveillance was acceptable as a cost‐effective option, even with an increased MRI/US cost ratio.\n Conclusion:\n Semiannual surveillance using MRI with liver‐specific contrast may be more cost‐effective than US in patients with virus‐associated compensated cirrhosis at sufficiently high HCC risk despite the higher test cost of MRI.\n
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| [505] |
Contrast-enhanced ultrasound (CE-US), contrast CT scan and gadolinium dynamic MRI are recommended for the characterisation of liver nodules detected during surveillance of patients with cirrhosis with US.To assess the sensitivity, specificity, diagnostic accuracy and economic impact of all possible sequential combinations of contrast imaging techniques in patients with cirrhosis with 1-2 cm liver nodules undergoing US surveillance.64 patients with 67 de novo liver nodules (55 with a size of 1-2 cm) were consecutively examined by CE-US, CT, MRI, and a fine-needle biopsy (FNB) as diagnostic standard. Undiagnosed nodules were re-biopsied; non-malignant nodules underwent enhanced imaging follow-up. The typical radiological feature of hepatocellular carcinoma (HCC) was arterial phase hypervascularisation followed by portal/venous phase washout.HCC was diagnosed in 44 (66%) nodules (2, <1 cm; 34, 1-2 cm; 8, >2 cm). The sensitivity of CE-US, CT and MRI for 1-2 cm HCC was 26, 44 and 44%, with 100% specificity, the typical vascular pattern of HCC being identified in 22 (65%) by a single technique versus 12 (35%) by at least two techniques carried out at the same time point (p=0.028). Compared with the cheapest dual examination (CE-US+CT), the cheapest single technique of stepwise imaging diagnosis of HCC was equally expensive (euro 26 440 vs euro 28 667), but led to a 23% reduction of FNB procedures (p=0.031).In patients with cirrhosis with a 1-2 cm nodule detected during surveillance, a single imaging technique showing a typical contrast pattern confidently permits the diagnosis of HCC, thereby reducing the need for FNB examinations.
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| [506] |
Ultrasonography (US) is recommended for HCC surveillance in high-risk patients but has limited performance in detecting early-stage HCC. We aimed to compare the diagnostic performance of biannual US and annual non-contrast abbreviated magnetic resonance imaging (NC-AMRI) as HCC surveillance modalities in high-risk patients.This prospective, multicenter cohort study enrolled participants with an estimated annual risk of HCC greater than 5% between October 2015 and April 2017. Participants underwent six rounds of HCC surveillance at 6-month intervals, with both US and NC-AMRI at rounds 1, 3, and 5, and only US at rounds 2, 4, and 6. The sensitivity, diagnostic yield (DY), and false referral rate (FRR) for HCC detection by US and NC-AMRI were compared.In total, 208 participants underwent 980 US and 516 NC-AMRI examinations during 30 months of follow-up. Among them, 34 HCCs were diagnosed in 31 participants, with 20 (64.5%) classified as very early-stage and 11 (35.5%) as early-stage HCC. The sensitivity of annual NC-AMRI (71.0%, 22/31) was marginally higher than that of biannual US (45.2%, 14/31; p = 0.077). NC-AMRI showed a significantly higher DY than US (4.26% vs. 1.43%, p <0.001), with a similar FRR (2.91% vs. 3.06%, p = 0.885). A simulation of alternating US and NC-AMRI at 6-month intervals yielded a sensitivity of 83.9% (26/31), significantly exceeding that of biannual US (p = 0.006).Annual NC-AMRI showed a marginally higher sensitivity than biannual US for HCC detection in high-risk patients. The DY of annual NC-AMRI was significantly higher than that of biannual US, without increasing the FRR. Thus, alternating US and NC-AMRI at 6-month intervals could be an optimal surveillance strategy for high-risk patients.Current guidelines permit the use of magnetic resonance imaging (MRI) as a surveillance tool for hepatocellular carcinoma in patients in whom ultrasonography (US) is inadequate. However, the specific indications, imaging sequences, and intervals for MRI surveillance remain unclear. In our study, we found that annual non-contrast abbreviated MRI exhibited marginally higher sensitivity and significantly better diagnostic yield than biannual US in patients at high risk of hepatocellular carcinoma. Alternating US and non-contrast abbreviated MRI at 6-month intervals led to significantly improved sensitivity compared to biannual US, making it a potentially optimal surveillance strategy for high-risk patients.NCT02551250.Copyright © 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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| [507] |
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| [508] |
We summarized the recent findings of liquid biopsy in cancer field and discussed its potential utility in hepatocellular carcinoma.Literature published in MEDLINE, EMBASE, and Science Direct electronic databases was searched and reviewed.Liquid biopsy specially referred to the detection of nucleic acids (circulating cell-free DNA, cfDNA) and circulating tumor cells (CTCs) in the blood of cancer patients. Compared to conventional single-site sampling or biopsy method, liquid biopsy had the advantages such as non-invasiveness, dynamic monitoring, and the most important of all, overcoming the limit of spatial and temporal heterogeneity. The genomic information of cancer could be profiled by genotyping cfDNA/CTC and subsequently applied to make molecular classification, targeted therapy guidance, and unveil drug resistance mechanisms. The serial sampling feature of liquid biopsy made it possible to monitor treatment response in a real-time manner and predict tumor metastasis/recurrence in advance.Liquid biopsy is a non-invasive, dynamic, and informative sampling method with important clinical translational significance in cancer research and practice. Much work needs to be done before it is used in the management of HCC.
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| [509] |
Background: This study was carried out to determine the prognostic significance of preoperative peripheral epithelial cell adhesion molecule-positive (EpCAM(+)) circulating tumor cell (CTC) and T regulatory (Treg) cell levels in hepatocellular carcinoma (HCC) patients for the prediction of postoperative recurrence following curative resection. Methods: A total of 49 patients about to undergo curative resection for HCC were recruited into the study. PCR and FACS were used to detect the preoperative levels of EpCAM (mRNA+) CTCs and CD4(+)CD25(+)Foxp3(+) Treg cells. The prognostic value of EpCAM(mRNA+) CTCs, CD4(+)CD25(+)Foxp3(+) Treg cells, and other clinicopathological factors were analyzed by applying the Kaplan-Meier method and the multivariate Cox proportional hazards model. Results: The number of EpCAM(mRNA+) CTCs and Treg/CD4(+) cells showed significant correlation as prognostic factors of postoperative HCC recurrence: EpCAM(mRNA+) CTC >= 2.22 (P = 0.001) and Treg/CD4(+) >= 5.07 (P = 0.045), with EpCAM(mRNA+) CTC >= 2.22 (P = 0.003, HR = 6.668) being the most important indicator. Patients with high CTC/Treg levels showed a significantly higher risk of developing postoperative HCC recurrence than those with low CTC/Treg levels (66.7 % vs. 10.3 %, P < 0.001). The high CTC/low Treg group also presented higher 1-year recurrence rates compared with the low CTC/low Treg level group (50.0 % vs. 10.3 %, P = 0.004). Conclusions: Elevated EpCAM(mRNA+) CTC and Treg/CD4(+) levels were associated with early recurrence of HCC, indicative of poor clinical outcome. The combined detection of EpCAM(mRNA+) CTC and Treg/CD4(+) may therefore provide a novel prognostic predictor for HCC patients.
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| [510] |
\n Epithelial cell adhesion molecule–positive (EpCAM+) hepatocellular carcinoma (HCC) cells may constitute a tumor-initiating subpopulation in tumorigenic cell lines and HCC specimens. In the present study, EpCAM+ circulating tumor cells (CTCs) were identified prospectively in HCC patients undergoing curative resection, and the prognostic significance and their stem cell–like characteristics were investigated further. Blood samples from 123 HCC patients were tested prior to resection and 1 month thereafter. CTCs were present in 66.67% of patients, and the cell count measured in 7.5 mL of blood (CTC7.5) ranged between 1 and 34. Fifty-one patients had CTC7.5 of ≥2 preoperatively, and these patients developed tumor recurrence earlier than those with CTC7.5 of <2 CTCs (\n \n P\n \n < 0.001). A preoperative CTC7.5 of ≥2 was an independent prognostic factor for tumor recurrence (\n \n P\n \n < 0.001). Its prognostic significance also applied to patients with alpha-fetoprotein (AFP) levels of ≤400 ng/mL or subgroups with low recurrence risk (all\n \n P\n \n < 0.05). A significant decrease of CTC-positive rates (66.67% to 28.15%,\n \n P\n \n < 0.05) and CTC7.5 values (2.60 ± 0.43 to 1.00 ± 0.36,\n \n P\n \n < 0.05) was observed 1 month after resection. Patients with consistent CTC7.5 <2 had lower recurrence rates than those with values consistently ≥2 (15.5% versus 87.50%,\n \n P\n \n < 0.001). EpCAM+ CTCs displayed cancer stem cell biomarkers (CD133 and ABCG2), epithelial-mesenchymal transition, Wnt pathway activation, high tumorigenic potential, and low apoptotic propensity.\n \n Conclusion\n \n : Stem cell–like phenotypes are observed in EpCAM+ CTCs, and a preoperative CTC7.5 of ≥2 is a novel predictor for tumor recurrence in HCC patients after surgery, especially in patient subgroups with AFP levels of ≤400 ng/mL or low tumor recurrence risk. EpCAM+ CTCs may serve as a real-time parameter for monitoring treatment response and a therapeutic target in HCC recurrence.\n
|
| [511] |
This study aimed to construct a novel platform for the detection of circulating tumor cells (CTC) in patients with hepatocellular carcinoma (HCC) and to investigate the clinical significance of epithelial cell adhesion molecule mRNA-positive (EpCAM(mRNA+)) CTCs using this platform.An optimized platform for CTC detection was constructed by evaluating different negative enrichment, mRNA isolation, and cDNA synthesis procedures and compared with the CellSearch system. A total of 299 patients with HCC were recruited into this prospective study; of these, 157 who received curative resection, 76 who received transcatheter arterial chemoembolization (TACE), and 66 who received radiotherapy were tested using our platform. The diagnostic value of EpCAM(mRNA+) CTCs was investigated in 122 patients with HCC who underwent resection and 120 control subjects.The optimized negative enrichment and quantitative real-time PCR (qRT-PCR)-based CTC detection platform had high sensitivity, specificity, and reproducibility and a low sample volume requirement. This platform showed a potential diagnostic value in patients with HCC and exhibited 76.7% consistency with the CellSearch system (r = 0.54, P < 0.050). Pretreatment CTC level showed prognostic significance in patients with HCC treated with resection, TACE, and radiotherapy (all P < 0.050). Most of the patients showed a decrease in CTC levels after treatment that reflected tumor response. In contrast, patients with an increased CTC level showed disease progression after treatment.We established an optimized platform based on negative enrichment and qRT-PCR for highly sensitive, specific, and reproducible CTC detection. This platform might be clinically useful in auxiliary diagnosis, treatment response assessment, and early decision-making to tailor the most effective antitumor strategies.©2014 American Association for Cancer Research.
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| [512] |
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| [513] |
Purpose: The spatial heterogeneity of phenotypic and molecular characteristics of CTCs within the circulatory system remains unclear. Herein, we mapped the distribution and characterized biological features of CTCs along the transportation route in hepatocellular carcinoma (HCC).
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| [514] |
Postoperative extrahepatic metastases (EHM) contribute to a grim outcome in patients with hepatocellular carcinoma (HCC) who are undergoing curative surgical resection. The current study investigated the clinical value of circulating tumor cells (CTCs) in predicting EHM after curative surgery.
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| [515] |
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| [516] |
Liver transplantation (LTx) is one of the most effective treatments for hepatocellular carcinoma (HCC); however, tumour recurrence after LTx often leads to poor outcomes. This study investigated the value of circulating tumour cells (CTCs) as a predictor of recurrence following LTx in patients with HCC.
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| [517] |
The clinical significance of circulating cell-free DNA (cfDNA) integrity as diagnostic and surveillance biomarker in hepatocellular carcinoma (HCC) was investigated and compared to that of alpha fetoprotein (AFP). Liver cancer patients had lower cfDNA integrity than those with benign diseases (= 0.0167) and healthy individuals (= 0.0025). Patients with HCC and non-HCC liver cancers (= 0.7356), and patients with benign diseases and healthy individuals (= 0.9138) had comparable cfDNA integrity respectively. cfDNA integrity increased after hepatectomy in cancer patients (= 0.0003). The AUCs for detecting HCC by cfDNA integrity and AFP were 0.705 (= 0.005) and 0.605 (= 0.156), respectively. We found cfDNA integrity decreased in HCC patients and has the potential as promising biomarker for HCC diagnosis and treatment surveillance.
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| [518] |
Identifying target genetic mutations in hepatocellular carcinoma (HCC) for therapy is made challenging by intratumoral heterogeneity. Circulating cell-free DNAs (cfDNA) may contain a more complete mutational spectrum compared to a single tumor sample. This study aimed to identify the most efficient strategy to identify all the mutations within heterogeneous HCCs.Whole exome sequencing (WES) and targeted deep sequencing (TDS) were carried out in 32 multi-regional tumor samples from five patients. Matched preoperative cfDNAs were sequenced accordingly. Intratumoral heterogeneity was measured using the average percentage of non-ubiquitous mutations (present in parts of tumor regions). Profiling efficiencies of single tumor specimen and cfDNA were compared. The strategy with the highest performance was used to screen for actionable mutations.Variable levels of heterogeneity with branched and parallel evolution patterns were observed. The heterogeneity decreased at higher sequencing depth of TDS compared to measurements by WES (28.1% vs. 34.9%, p<0.01) but remained unchanged when additional samples were analyzed. TDS of single tumor specimen identified an average of 70% of the total mutations from multi-regional tissues. Although genome profiling efficiency of cfDNA increased with sequencing depth, an average of 47.2% total mutations were identified using TDS, suggesting that tissue samples outperformed it. TDS of single tumor specimen in 66 patients and cfDNAs in four unresectable HCCs showed that 38.6% (26/66 and 1/4) of patients carried mutations that were potential therapeutic targets.TDS of single tumor specimen could identify actionable mutations targets for therapy in HCC. cfDNA may serve as secondary alternative in profiling HCC genome.Targeted deep sequencing of single tumor specimen is a more efficient method to identify mutations in hepatocellular carcinoma made from mixed subtypes compared to circulating cell-free DNA in blood. cfDNA may serve as secondary alternative in profiling HCC genome. Identifying mutations may help clinicians choose targeted therapy for better individual treatments.Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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| [519] |
Circulating tumor DNA (ctDNA) is increasingly recognized as liquid biopsy to profile tumor genome. Droplet digital PCR (ddPCR) is a highly sensitive and easily operable platform for mutant detection. Here, we tried to detect ctDNA in hepatocellular carcinoma (HCC) patients using ddPCR.Studies sequencing the genome of HCCs and COSMIC (Catalogue of Somatic Mutations in Cancer) database were reviewed to identify hotspot mutations. Circulating cell-free DNAs (cfDNAs) extracted from 1 ml preoperative plasma sample were analyzed to detect circulating mutants using ddPCR. The DNAs from matched tumor and adjacent liver tissues or peripheral blood mononuclear cells (PBMCs) were sequenced to identify the origin of circulating mutants.Forty-eight HCC patients were enrolled and four gene loci, (c.747G>T), (c.121A>G, c.133T>C), and (c.1-124C>T) were chosen as targets for ddPCR assay. Serial dilution demonstrated the detection limit of ddPCR to be 0.01%. Twenty-seven patients (56.3%, 27/48) were found to have at least one kind of circulating mutants, with the mutant allele frequency ranging from 0.33% to 23.7%. Six patients (22.2%, 6/27) also had matched mutants in tumor tissues while none of the mutants were detected in adjacent liver tissues or PBMCs in all patients, which excluded the nonneoplastic origin of these circulating mutants and qualified them as ctDNA.ctDNA could be readily detected in HCC patients by targeting hotspot mutations using ddPCR and might reflect intratumoral heterogeneity. ctDNA detecting may serve as a promising liquid biopsy in HCC management.
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| [520] |
There has been a recent surge in interest in predicting biological effects associated with genomic alterations in order to implement personalized cancer treatment strategies. However, no reports have yet evaluated the utility of profiling blood-based circulating tumor DNA (ctDNA) in hepatocellular carcinoma (HCC) patients treated with lenvatinib (LEN).We retrospectively performed ctDNA next-generation sequencing (NGS) analysis in 24 patients with advanced HCC at baseline and 4 weeks after initiation of LEN. Association of the changes in variant allele frequencies (VAFs) during treatment and clinical outcome were evaluated.In total, 131 single nucleotide variants, 17 indels, and 23 copy number variations were detected as somatic alterations in 28, 6, and 12 genes, respectively in 23 of 24 patients. The most frequently altered genes were TP53 (54%), CTNNB1 (42%), TERT (42%), ATM (25%), and ARID1A (13%). The reduction in the mean frequency of variants (VAF) following 4 weeks of LEN treatment was associated with longer progression-free survival. The specificity and sensitivity of the reduction of VAF for predicting partial response were 0.67 and 1.0, respectively, which were higher than those of serum α-fetoprotein level (0.10 and 0.93, respectively). No association between the mutation status at baseline and the effectiveness of LEN was observed.Our study demonstrated that somatic alterations could be detected in the majority of advanced HCC patients by ctDNA profiling and that ctDNA-kinetics during LEN treatment was a useful marker of disease progression. These results suggest that ctDNA profiling is a promising method that provides valuable information in clinical practice.
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| [521] |
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| [522] |
DNA modifications such as 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) are epigenetic marks known to affect global gene expression in mammals. Given their prevalence in the human genome, close correlation with gene expression and high chemical stability, these DNA epigenetic marks could serve as ideal biomarkers for cancer diagnosis. Taking advantage of a highly sensitive and selective chemical labeling technology, we report here the genome-wide profiling of 5hmC in circulating cell-free DNA (cfDNA) and in genomic DNA (gDNA) of paired tumor and adjacent tissues collected from a cohort of 260 patients recently diagnosed with colorectal, gastric, pancreatic, liver or thyroid cancer and normal tissues from 90 healthy individuals. 5hmC was mainly distributed in transcriptionally active regions coincident with open chromatin and permissive histone modifications. Robust cancer-associated 5hmC signatures were identified in cfDNA that were characteristic for specific cancer types. 5hmC-based biomarkers of circulating cfDNA were highly predictive of colorectal and gastric cancers and were superior to conventional biomarkers and comparable to 5hmC biomarkers from tissue biopsies. Thus, this new strategy could lead to the development of effective, minimally invasive methods for diagnosis and prognosis of cancer from the analyses of blood samples.
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| [523] |
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| [524] |
Cell-free DNA (cfDNA)–based liquid biopsy is a promising approach for the early detection of cancer. A major hurdle is the limited yield of cfDNA from one blood draw, limiting the use of most samples to one test of either mutation or methylation. Here, we develop a technology, Mutation Capsule Plus (MCP), which enables multiplex profiling of one cfDNA sample, including simultaneous detection of genetic and epigenetic alterations and genome-wide discovery of methylation markers. With this technology, we performed de novo screening of methylation markers on cfDNA samples from 30 hepatocellular carcinoma (HCC) cases and 30 non-HCC controls. The methylation markers enriched in HCC cfDNA were further profiled in parallel with a panel of mutations on a training cohort of 60 HCC and 60 non-HCC cases, resulting in an HCC detection model. We validated the model in an independent retrospective cohort with 58 HCC and 198 non-HCC cases and got 90% sensitivity with 94% specificity. Furthermore, we applied the model to a prospective cohort of 311 asymptomatic hepatitis B virus carriers with normal liver ultrasonography and serum AFP concentration. The model detected four of the five HCC cases in the cohort, showing 80% sensitivity and 94% specificity. These findings demonstrate that the MCP technology has potential for the discovery and validation of multiomics biomarkers for the noninvasive detection of cancer. This study also provides a comprehensive database of genetic and epigenetic alterations in the cfDNA of a large cohort of HCC cases and high-risk non-HCC individuals.
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| [525] |
Alpha-fetoprotein (AFP) is a widely used biomarker for hepatocellular carcinoma (HCC) early detection. However, low sensitivity and false negativity of AFP raise the requirement of more effective early diagnostic approaches for HCC.
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| [526] |
Characterization of metabolic perturbation prior to hepatocellular carcinoma (HCC) may deepen the understanding of causal pathways and identify novel biomarkers for early prevention. We conducted two 1:1 matched nested case‐control studies (108 and 55 pairs) to examine the association of plasma metabolome (profiled using LC‐MS) with the risk of HCC based on two prospective cohorts in China. Differential metabolites were identified by pairedttests and orthogonal partial least‐squares discriminant analysis (OPLS‐DA). Weighted gene coexpression network analysis (WGCNA) was performed to classify metabolites into modules for identifying biological pathways involved in hepatocarcinogenesis. We assessed the risk predictivity of metabolites using multivariable logistic regression models. Among 612 named metabolites, 44 differential metabolites were identified between cases and controls, including 12 androgenic/progestin steroid hormones, 8 bile acids, 10 amino acids, 6 phospholipids, and 8 others. These metabolites were associated with HCC in the multivariable logistic regression analyses, with odds ratios ranging from 0.19 (95% confidence interval [CI]: 0.11‐0.35) to 5.09 (95% CI: 2.73‐9.50). WGCNA including 612 metabolites showed 8 significant modules related to HCC risk, including those representing metabolic pathways of androgen and progestin, primary and secondary bile acids, and amino acids. A combination of 18 metabolites of independent effects showed the potential to predict HCC risk, with an AUC of 0.87 (95% CI: 0.82‐0.92) and 0.86 (95% CI: 0.80‐0.93) in the training and validation sets, respectively. In conclusion, we identified a panel of plasma metabolites that could be implicated in hepatocellular carcinogenesis and have the potential to predict HCC risk.
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| [527] |
Among the multiplicity of factors involved in rising incidence of hepatocellular carcinoma (HCC)-the second deadliest cancer, late diagnosis of early-stage HCC nodules originating from late-stage cirrhotic nodules is the most crucial. In recent years, Tumor-educated platelets (TEPs) have emerged as a strong multimodal tool to be used in liquid-biopsy of cancers because of changes in their mRNA content. This study assessed the reliability of selected mRNA repertoire of platelets as biomarkers to differentiate early HCC from late-stage cirrhotic nodules.
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| [528] |
Several studies have demonstrated that the T-cell receptor (TCR) repertoire is associated with prognosis and immune therapy response in several types of cancer. However, the comprehensive features of TCR repertoire in tumor-infiltrating and circulating T cells, as well as its clinical significance of diagnosis in hepatocellular carcinoma (HCC) patients, are still unknown. In this study, we perform paired tumor/peritumoral tissues and peripheral blood samples from 58 patients with HCC and sequenced them with high-throughput TCR to comprehensively analyze the characteristics of TCR and the clinical significance of peripheral TCR sequence. By exploring the abundance and diversity of TCR repertoires, we observe that there was a significantly higher TCR diversity in peripheral blood than in tumoral and peritumoral tissues, while tumoral and peritumoral tissues showed similar TCR diversity. A substantial difference in the usage frequencies of several Vβ, Jβ genes, and TCRβ VJ pairings was found among three types of tissues. Moreover, we reveal that HCC patients have a unique profile of TCR repertoire in peripheral blood in contrast to healthy individuals. We further establish an HCC diagnostic model based on TCRβ VJ pairing usage in peripheral blood, which yields a best-fit area under the curve (AUC) of 0.9746 ± 0.0481 (sensitivity = 0.9675 ± 0.0603, specificity = 0.9998 ± 0.0007, average of 100 repeats) in the test set. Our study describes the characteristics of tissue infiltration and circulating T-cell bank in patients with HCC and shows the potential of using circulating TCR sequence as a biomarker for the non-invasive diagnosis of patients with HCC.
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| [529] |
Early detection of a tumour remains an unmet medical need, and approaches with high sensitivity and specificity are urgently required. Mass cytometry time-of-flight (CyTOF) is a powerful technique to profile immune cells and could be applied to tumour detection. We attempted to establish diagnostic models for hepatocellular carcinoma (HCC) and pancreatic ductal adenocarcinoma (PDAC).
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| [530] |
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| [531] |
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| [532] |
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| [533] |
Six UK studies investigating stereotactic ablative radiotherapy (SABR) are currently open. Many of these involve the treatment of oligometastatic disease at different locations in the body. Members of all the trial management groups collaborated to generate a consensus document on appropriate organ at risk dose constraints. Values from existing but older reviews were updated using data from current studies. It is hoped that this unified approach will facilitate standardised implementation of SABR across the UK and will allow meaningful toxicity comparisons between SABR studies and internationally.Copyright © 2017 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
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