Sorafenib With and Without Transarterial Chemoembolization for Advanced Hepatocellular Carcinoma With Main Portal Vein Tumor Thrombosis: A Retrospective Analysis

Background.

The survival benefit of combining sorafenib and transarterial chemoembolization (TACE) therapy compared with sorafenib monotherapy for patients with advanced hepatocellular carcinoma (HCC) and main portal vein tumor thrombosis (MPVTT) is unclear.

Methods.

Between January 2009 and June 2013, 183 consecutive patients with advanced HCC (Barcelona Clinic Liver Cancer stage C) and MPVTT were retrospectively reviewed. Of these, 89 patients with advanced HCC and MPVTT were enrolled in this study: 45 were treated with combination therapy (sorafenib-TACE group), and the other 44 treated with sorafenib monotherapy (sorafenib group).

Results.

The mean number of TACE sessions per patient was 2.6 (range: 1–5). The median duration of sorafenib in the sorafenib-TACE group and sorafenib group was 5.6 months and 5.4 months, respectively. The disease control rate was similar between the two groups. Median time to progression was 3.0 months (95% confidence interval [CI]: 2.2, 3.7) in the sorafenib-TACE group, and 3.0 months (95% CI: 2.1, 3.8) in the sorafenib group (p = .924). Median overall survival was 7.0 months (95% CI: 6.1, 7.8) and 6.0 months (95% CI: 4.7, 7.3) in the sorafenib-TACE group and the sorafenib group, respectively (p = .544). The adverse events related to sorafenib were comparable between the two groups. Twenty-one adverse events of grade 3–4 related to TACE occurred in 12 patients (26.7%), and 2 of them died (4.4%).

Conclusion.

This study demonstrated no advantage of combination therapy over sorafenib monotherapy. Considering the patients’ morbidity after TACE, sorafenib monotherapy is appropriate for managing patients with advanced HCC and MPVTT.

Implications for Practice:

For patients with advanced hepatocellular carcinoma (HCC) and main portal vein tumor thrombosis (MPVTT), no benefit was seen in this study in terms of disease control rate, time to progression, and overall survival for patients receiving sorafenib and transarterial chemoembolization compared with those receiving sorafenib monotherapy. Considering the patients’ morbidity after combination therapy, monotherapy is appropriate for managing patients with advanced HCC and MPVTT.     

Sorafenib Therapy for Hepatocellular Carcinoma in an HIV–HCV Coinfected Patient: A Case Report

Background/Aims.

HIV and hepatitis C virus (HCV) share common modes of transmission, resulting in about 33% incidence of coinfection among people infected with HIV. The survival benefit from highly effective antiretroviral therapy (HAART) for HIV infection is resulting in an increased incidence of hepatocellular carcinoma (HCC) in this population. There are no reports to date regarding the coadministration of HAART and sorafenib for hepatocellular carcinoma.

Methods.

We report the case of a 42-year-old male patient coinfected with HIV and HCV who developed advanced HCC not amenable to curative therapy. The patient was treated with sorafenib, an oral multikinase inhibitor shown to lead to a longer median survival time and time to progression in patients with advanced HCC. Antiretroviral therapy was continued during sorafenib therapy.

Results.

The patient achieved a partial tumor response after 3 months and continued to respond at subsequent assessments. His serum α-fetoprotein normalized from 2,172 IU/ml to 2 IU/ml. He had durable stable disease after 23 months of therapy. Antiretroviral therapy was efficacious (CD4⁺ lymphocyte count, 377/μl; HIV viremia, <50 copies/ml). The simultaneous administration of these therapies was well tolerated. No grade 3 or 4 toxicities were observed. Exacerbation of pre-existing hypertension, grade 2 diarrhea, and grade 1 skin reaction were observed.

Conclusions.

This is the first report in which sorafenib has been successfully used to treat HCC in a patient with HIV–HCV coinfection.     

The Prognosis of Hepatocellular Carcinoma Treated with Sorafenib in Combination with TACE

Objective: Sorafenib have been shown to be effective in the treatment of advanced HCC and has been standard therapy since its release in Japan in 2009 (Llovet et al., 2008; Cheng et al., 2009). However, due to a low response rate, more aggressive combination treatment has been utilized as a multimodal strategy. The present study aimed to determine the efficacy of sorafenib alone and in combination with transarterial chemoembolization (TACE) for the treatment of advanced HCC. Methods: All patients with unresectable advanced HCC who were prescribed sorafenib at Kanto Rosai Hospital were included in the study. Five-year overall survival (OS) rates were estimated for patients treated with sorafenib alone or in combination with TACE. Multivariate and univariate regression analyses were performed to identify factors affecting OS. Analysis using propensity score matching and inverse-probability weights were also performed. Results: A total of 46 patients were treated with sorafenib up to June 2018. The total sorafenib dose administered was higher in the TACE combination group (70900 mg vs. 24000 mg vs. with sorafenib alone), although the relative dose intensity was lower (11.7% vs. 17.6%, respectively). The 5-year survival prognosis estimated using the Kaplan-Meier method was longer in patients treated with sorafenib in combination with TACE versus sorafenib alone (36.3% vs. 7.7%). Combination with TACE was the only factor associated with improved OS in both univariate and multivariate analysis. Among cases matched by propensity scores the hazard rate for combination with TACE was 0.067 (95% CI 0.091-1.128). Conclusion: With an array of therapeutic options currently available, it is important to determine the efficacy of different multimodal strategies, such as sorafenib combined TACE, for patients with unresectable HCC.     

The Blood Neutrophil-to-lymphocyte Ratio Predicts Survival in Patients with Advanced Hepatocellular Carcinoma Receiving Sorafenib

Background and Aim: Increasing evidence correlates the presence of systemic inflammation with poorsurvival in patients with hepatocellular carcinoma (HCC). The aim of this study was to investigate theprognostic significance of the blood neutrophil-to-lymphocyte ratio (NLR) in patients with advanced HCC whoreceived sorafenib monotherapy. Methods: A total of sixty-five patients with advanced HCC, not eligible forlocoregional therapy, treated with sorafenib were enrolled. Potential prognostic factors such as age, gender,tumoral characteristics, performance status and NLR were analyzed. Results: Median OS and TTP for the entirecohort were 10.0 months (95%CI, 7.6-12.3 months) and 4.5 months (95% CI, 4.0-4.9 months). The mean NLRat baseline was 2.89. The median OS of patients with a high NLR (>4) was 6.5 months (95%CI, 5.2-7.7 months)compared with 12.5 months (95%CI, 9.9-15.0) for patients with a normal NLR (≤4) (P=0.01). Age ≤65, NLR>4, extrahepatic metastases and vascular invasion were all predictors of poorer overall survival. Multivariateanalysis showed that NLR > 4, vascular invasion and extrahepatic metastases were independent predictors ofpoorer overall survival. The median TTP of patients with a high NLR was 2.5 months (95%CI, 1.4-3.6 months)compared with 4.5 months (95%CI, 3.9-5.1 months) for patients with a normal NLR (P=0.012). Conclusions: Highbaseline NLR was associated with worse OS and TTP for patients with advanced HCC treated with sorafenib.     

Sorafenib for Egyptian patients with advanced hepatocellular carcinoma; single center experience

BackgroundAccording to the results of a number of phase 3 randomized studies, sorafenib is the only approved systemic therapy for advanced HCC; however the issue of high economic cost remains challenging; thus we have conducted this retrospective analysis of our HCC patients treated with sorafenib.MethodsHCC patients treated at Ain Shams University Hospitals, in the period between 2010 and 2012 were reviewed. Eligible patients were those who had received sorafenib for advanced HCC not eligible for or progressed after surgery or locoregional therapy. We investigated the impact of baseline clinicopathological factors (age, gender, child status, performance score, BCLC tumor stage, cause of chronic liver disease, median baseline alpha fetoprotein level and previous treatment received for HCC) on overall survival (OS) in an adjusted Cox regression model.Results41 patients were included in the analysis fulfilling the inclusion criteria. At a median follow up period of 13 months, the median PFS for the whole group was 4 months; the median OS for the whole group is 6.25 months. Multivariate analysis identified three baseline characteristics that were prognostic indicators for overall survival: ECOG performance status (median OS for ECOG 1 = 7.01 months and for ECOG 2 = 3.03 months), Child–Pugh status (median OS for child A = 12.04 months and for child B = 5.23 months), and median baseline levels of alpha-fetoprotein.ConclusionsIn limited resource countries like Egypt, we suggest that the use of sorafenib for the treatment of advanced HCC cases should be restricted to a highly selected subgroup of patients with good performance and child A.     

肝癌首发部位对患者术后复发的影响

目的探讨肝癌首发部位及联合血清甲胎蛋白(AFP)表达对于预测肝癌患者术后复发及预后的意义。方法回顾性分析2005年3月-2009年10月行肝癌手术并长期随访的256例患者,运用Kaplan-Meier生存曲线分析总体生存率及术后复发率,Logrank检验P值,Cox比例风险模型进行单因素及多因素分析术后复发高危因素。结果肝癌首发部位不同,其术后总体生存率差异有统计学意义(P=0.022),且肝癌首发于全肝或肝左叶组患者较肝右叶组患者具有更高的术后复发风险(P=0.002)。分层分析发现,在AFP阴性(AFP<25 ng/ml)亚组中两者术后复发率差异有统计学意义(P<0.001)。Cox单因素及多因素分析显示远处转移(P=0.016)、血清AFP(P=0.002)及门脉癌栓(P<0.001)可以作为预测肝癌术后复发的独立危险因素,而肝癌首发部位不能作为一个独立的危险因素(P=0.088)。结论肝癌首发部位可以作为一个预测患者术后复发的危险因素。     

Clinical Outcome and Predictive Factors of Variceal Bleeding in Patients with Hepatocellular Carcinoma in Thailand

Objective: Hepatocellular carcinoma (HCC) is common cancer in ASEAN. Variceal bleeding (VB) is consideredto be fatal complication of cirrhosis with HCC. However, limited studies were reported in ASEAN. Aim of this studywas to evaluate overall survival rate and predictors of VB in HCC patients. Methods: We conducted a retrospectivecohort study of HCC patients aged ≥15 years between January 2012-January 2016 and follow up through June 2016 atThammasat University Hospital, Thailand. Clinical information and radiologic findings were collected from reviewingcomputer database of medical records. Results: 333 patients had completely retrievable information. Of which, 27patients (8.1%) had documented with VB. Clinical presentations with weight loss and jaundice were higher in VB thannon-VB groups (40.74% vs. 34.64%, p=0.525 and 7.41% vs. 2.29%, p=0.116) but the differences were not significant.The most common causes of cirrhosis in HCC patients with VB were chronic HBV infection (55.56%). In multivariateanalysis; presence of ascites, Child-Pugh score>6, presence of varices were independent risk factors of having VB inHCC patients (OR=7.59, 95%CI=1.13-50.88, p=0.037; OR=5.07, 95%CI=1.08-23.76, p=0.039; OR=23.51, 95%CI=4.71-117.35, p<0.001, respectively). In HCC patients with VB, 1-year and 2.5-year survival rates were 56.6% and 28.3%.Conclusions: HCC patients with ascites, Child-Pugh score>6 and presence of varices might be important predictivefactors of VB. Having VB were greatly impact to the survival rate of HCC patients. Clinical suspicion and regularsurveillance of VB in HCC patients at risk could improve treatment outcomes.     

索拉非尼联合TACE术治疗中晚期肝细胞癌的临床疗效分析

目的 探讨索拉非尼联合TACE术治疗中晚期肝细胞癌的临床疗效.方法 根据治疗方法不同将97例中晚期肝细胞癌患者分为实验组(47例)和对照组(50例),对照组患者给予单纯TACE术治疗,实验组患者在此基础上加用索拉非尼治疗,比较两组患者近期疗效和远期疗效.结果 实验组患者疗程结束后总有效率明显高于对照组,差异具有显著性(P＜0.05);实验组患者治疗后血清VEGF水平明显低于对照组,差异具有显著性(P＜0.05);实验组患者手足反应、腹泻、皮疹/脱皮以及高血压发生率及严重程度均明显高于对照组,差异具有显著性(P＜0.05);两组患者乏力、消化道反应、脱发、骨髓抑制和肝功能异常发生率及严重程度比较,差异无统计学意义(P＞0.05);实验组患者2年生存率及中位生存期明显优于对照组,差异具有显著性(P＜0.05).结论 索拉非尼能够有效提高TACE术的近期疗效和远期生存率,但会明显增加患者手足反应、腹泻、皮疹/脱皮以及高血压等不良反应发生率,可作为中晚期肝细胞癌治疗的优选方案,但需注意预防不良反应.     

Hepatitis B Virus DNA Negativity Acts as a Favorable Prognostic Factor in Hepatocellular Carcinoma Patients

Background: This retrospective study was aimed to investigate the efficacy of prophylactic agents inhepatocellular carcinoma (HCC) patients receiving TACE and compare the difference between lamivudine andentecavir. Materials and Methods: A consecutive series of 203 HBV-related HCC patients receiving TACE wereanalyzed including 91 patients given prophylactic agents. Virologic events, defined as an increase in serum HBVDNA level to more than 1 log10 IU/ml higher than the nadir level, hepatitis flares due to HBV reactivation andprogression free survival (PFS) were the main endpoints. Results: Some 48 (69.6%) reached virologic response.Prophylaxis significantly reduced virologic events (8.8% vs 58.0%, p=0.000) and hepatitis flares (1.1% vs 13.4%,p=0.001). Patients presenting undetectable HBV DNA levels displayed a significantly improved PFS as comparedto those who never achieved undetectable HBV DNA. Prophylaxis and e-antigen positivity were the only significantvariables associated with virologic events. In addition, prophylaxis was the only independent protective factor forhepatitis flares. Liver cirrhosis, more cycles of TACE, HBV DNA negativity, a lower Cancer of the Liver ItalianProgram score, non-metastasis and no hepatitis flares were protective factors for PFS. Prophylactic lamivudinedemonstrated similar efficacy as entecavir. Conclusions: Prophylactic agents are efficacious for prevention ofHBV reactivation in HCC patients receiving TACE. Achievement of undetectable HBV DNA levels displayeda significant capability in improving PFS. Moreover, persistent tumor residual lesions, positive HBV DNA andhepatitis B flares might be causes of tumor progression in these patients.     

肿瘤坏死因子联合VP16对小鼠肝细胞癌的疗效观察

以小鼠移植性肝细胞癌为模型，探讨重组人肿瘤坏死因子（ｒｈＴＮＦ）和足叶乙甙（ＶＰ_（１６））的协同抗肿瘤作用。结果显示ｒｈＴＮＦ或ＶＰ_（１６）均能使肿瘤生长受到一定的抑制，肿瘤出现一定程度的坏死，ｒｈＴＮＦ并能抑制腹水的形成，但均不能显著延长荷瘤小鼠的生存时间，而联合应用则显著抑制肿瘤生长，肿瘤出现广泛的出血坏死，无明显腹水形成，荷瘤小鼠生存时间显著延长，且对机体的毒性增加不明显，说明两者具有协同抗肿瘤作用，具有进一步临床应用探讨价值，尤其是对化疗不敏感的肿瘤。     

Increased Serum Granulocyte Colony Stimulating Factor in Turkish Hepatocellular Carcinoma Patients

Purpose: To evaluate the serum levels of G-CSF in patients with hepatocellular carcinoma and to comparewith values in healthy individuals. Patients and Methods: Thirty-three patients with hepatocellular carcinomaand 30 controls were included in the study. Histological confirmation of hepatocellular carcinoma (HCC) wasperformed by core needle biopsy and patients with cirrhosis were classified according to the Child-Pugh score.The serum G-CSF levels of individuals in both groups were calculated as pg/ml and compared for Child-PughClass A, B and C patients with HCC. Results: Median ages of patients with HCC and control group individualswere 58 (range:47-78) and 56 (range 45-70), respectively. Sex distributions were approximately equal. The meanserum level of G-CSF in patients with HCC was 199.4±112.2, as compared to 24.0±8.8 in the controls (p < 0.001).In addition, on subgroup analysis, the serum levels of G CSF were increased with Child-Pugh Class A, B and C,although without statistical significance (p=0.253). Conclusion: Increased levels of G-CSF are observed in patientswith HCC. Further investigations are necessary to clarify the mechanism of G-CSF production and its effects onoutcomes.     

ABO Blood Group Differentials on Survival in Hepatocellular Carcinoma Patients Treated with Chemoembolization

Background: The association between ABO blood group and the prognosis of hepatocellular carcinoma (HCC) remains unclear. We investigated the impact of ABO blood groups as a prognostic factor in HCC patients treated with transarterial chemoembolization (TACE). Materials and methods: We revisited records of all HCC patients who underwent TACE between January 2007 and December 2019 at a tertiary care hospital. The inclusion criteria were HCC patients, Child-Pugh score A5-B7, and treated with TACE monotherapy. The baseline characteristics of each patient were compared against their blood group and the survival analysis was carried out using Cox’s regression. With Bonferroni adjustment for multiple comparisons, P-values <.0125 were considered statistically significant. Results: Of 211 eligible patients, the frequencies of blood groups O, A, B, and AB were 89, 54, 56, and 12, respectively. Their respective months of median survival were 41, 20, 21, and 42. After adjustments in the six-and-twelve criteria and Child-Pugh scores, and using blood group O as the referent group, the coefficients (SE) of groups A, B, and AB were 0.69 (0.24), 0.47 (0.23), and 0.49 (0.49), respectively. A significant difference in survival was found only between patients with blood group O vs A (hazard ratio, 2.00; confidence interval, 1.25-3.21). Conclusions: ABO blood group is associated with the prognosis of HCC patients treated with TACE monotherapy. In our data, patients with blood group O tended to have the best survival. However, only blood group A patients had a significantly shorter survival rate comparing to blood group O.     

大剂量分割三维适形放疗对原发性肝癌门静脉癌栓的疗效

目的观察大剂量分割三维适形放疗（3-dimensional conformal radiotherapy,3DCRT）对不能手术切除的原发性肝癌（hepatocellular carcinoma,HCC）门静脉癌栓（portal vein tumor thrombus,PVTT）的疗效。方法对56例不能手术切除的HCC伴PVTT患者,根据肿瘤体积大小行大剂量分割3DCRT,放疗剂量为4～8Gy,每周3次,48～58Gy,3.0～3.5周完成。大体肿瘤靶区（GTV）包括癌栓及靠近的原发灶,90%等剂量曲线覆盖计划靶区（PTV）。结果有效率（CR＋PR）为58.9%（33/56）,1、2年生存率分别为47.4%和17.5%。患者耐受性好,无严重放疗并发症。结论大剂量分割3DCRT对HCC合并PVTT有较好的疗效。     

肝细胞癌术前血清C-反应蛋白水平与术后早期复发的关系

目的：研究肝细胞癌术前检测血清C-反应蛋白（CRP）水平与术后早期复发的关系。方法：2000年1月至2004年1月，72例肝细胞癌行肝切除术，术前30min采静脉血，采用散射免疫比浊法检测血清CRP水平血清CRP≥8mtg／L为CRP阳性，血清CRP〈8mg／L为CRP阴性。分析血清CRP水平与肝细胞癌I临床病理的关系、结果：肝细胞癌血清CRP表达阳性率为72．2％（52／72）。肝细胞癌术前血清CRP水平与术后早期复发、血清AFP滴度水平及包膜浸润、门静脉侵犯、肝内转移、肿瘤大小等肿瘤恶性生物学行为明显相关．术前血清CRP阳性及阴性患者术后早期复发率分别为44．2％（23／52）及10％（2／20）。结论：肝细胞癌术前血清CRP水平可能是术后早期复发的良好的预后指标