Thalidomide-based multidisciplinary treatment for patients with advanced hepatocellular carcinoma: a retrospective analysis

AIM: To evaluate the efficacy of thalidomide in combination with other therapies to treat patients with advanced hepatocellular carcinoma (HCC).METHODS: We performed a retrospective analysis of all patients with HCC who were treated with thalidomide for at least two months. The medical records of patients with HCC who were treated at our institution between April 2003 and March 2008 were reviewed. Image studies performed before and after treatment, tumor response, overall survival, and the decrease in α-fetoprotein (AFP) levels were evaluated.RESULTS: A total of 53 patients with HCC received either 100 or 200 mg/d of thalidomide. The patient population consisted of 9 women and 44 men with a median age of 61 years. Thirty patients (56.6%) were classified as Child-Pugh A, and 12 patients (22.6%) were classified as Child-Pugh B. Twenty-six patients had portal vein thrombosis (49.1%), and 25 patients had extrahepatic metastasis (47.1%). The median duration of thalidomide treatment was 6.0 mo. Six of the 53 patients achieved a confirmed response (11.3%), one achieved a complete response (1.9%) and 5 achieved a partial response (9.4%). The disease control rate (CR + PR + SD) was 28.3% (95% CI: 17.8-42.4), and the median overall survival rate was 10.5 mo. The 1- and 2-year survival rates were 45% and 20%, respectively. Only one complete response patient showed an improved overall survival rate of 66.8 mo. Sixteen patients (30.2%) showed more than a 50% decrease in their serum AFP levels from baseline, indicating a better response rate (31.3%), disease control rate (43.8%), and overall survival time (20.7 mo). The therapy was well tolerated, and no significant toxicities were observed.CONCLUSION: Thalidomide was found to be safe for advanced HCC patients, demonstrating anti-tumor activity including response, survival, and AFP decreases of greater than 50% from baseline.     

Effects of the combined treatment with thalidomide, megestrol and interleukine-2 in cirrhotic patients with advanced hepatocellular carcinoma: A pilot study

BACKGROUND: Thalidomide, an anti-angiogenic agent, does not have a good therapeutic effect for advanced hepatocellular carcinoma when used alone. Megestrol and interleukin-2 have been proposed as a palliative treatment for hepatocellular carcinoma. AIMS.: We assessed the effectiveness/safety of a combined therapy with thalidomide+megestrol+interleukin-2 in cirrhotic patients with advanced hepatocellular carcinoma. PATIENTS AND METHODS: Nine cirrhotic patients with advanced hepatocellular carcinoma received oral megestrol (160 mg/day) and thalidomide (from 50 mg/day to the maximal tolerated dose). Four patients also received subcutaneous interleukin-2 (1 million U/day for 21 days/month). RESULTS: The maximal tolerated dose of thalidomide was 150 mg/day. All patients complained of sedation and other neurological or digestive adverse effects. In all but one patient the adverse effects disappeared after thalidomide withdrawal or dose reduction. Interleukin-2 administration caused a flu-like syndrome and a reaction at the injection site. During treatment, alpha-fetoprotein increased in six patients, remained stable in two and decreased in one. Eight patients showed tumour progression and one had a stable disease. Eight patients died. The median survival was 9.9 (range 2.6-18.6) months. CONCLUSION: In cirrhotic patients, the combined treatment with thalidomide+megestrol (+/-interleukin-2) does not control hepatocellular carcinoma growth, possibly due to the low tolerance to thalidomide and interleukin-2 preventing the use of appropriate dosages.     

Predictors of survival in patients with established cirrhosis and hepatocellular carcinoma treated with sorafenib

AIM:To investigate in greater detail the efficacy and safety of sorafenib for the treatment of hepatocellular carcinoma(HCC)in patients with established cirrhosis.METHODS:From October 2009 to July 2012 patients with an established diagnosis of cirrhosis and HCC treated with sorafenib were consecutively enrolled.According to the Barcelona Clinic Liver Cancer(BCLC)classification,patients were in the advanced stage(BCLC-C)or in the intermediate stage(BCLC-B)but unfit or unresponsive to other therapeutic strategies.Treatment was evaluated performing a 4-phase computed tomography or magnetic resonance imaging scan every 2-3 mo,and analyzed according to the modified Response Evaluation Criteria in Solid Tumors.Sorafenib was administered at 800 mg/d,until radiological progression or occurrence of unacceptable adverse events(AEs).Univariate and multivariate analyses identified predictors of 16-wk clinical benefit and overall survival.RESULTS:Forty-four patients were enrolled,15 had intermediate HCC and 14 a Child-Pugh score of B7.AEs caused treatment interruption in 19 patients(43%),and median treatment duration was shorter in this subset(5 wk vs 19 wk,P<0.001)and in the BCLC-C subgroup(13 wk vs 40 wk,P=0.015).No significant differences in the reason for treatment interruption or in treatment duration were found comparing patients in Child-Pugh class A vs B or in patients older or younger than 70 years.After 16 wk of treatment,18 patients(41%)had stable disease or partial response.Patients with viral infection or BCLC-C were at higher risk of disease progression.ECOG,extrahepatic spread,macrovascular invasion,alpha-fetoprotein or alkaline phosphatase levels at admission were independent predictors of overall survival.CONCLUSION:In patients with cirrhosis and HCC treated with sorafenib,AEs are a common cause of early treatment withdrawal.Vascular invasion and extrahepatic spread condition early response to treatment and survival.Baseline biochemical parameters may be helpful to identify patients at higher risk of shorter overall survival.     

Effects of thalidomide on angiogenesis and tumor growth and metastasis of human hepatocellular carcinoma in nude mice

AIM: To investigate the effects of thalidomide on angiogenesis, tumor growth and metastasis of hepatocellular carcinoma in nude mice. METHODS: Twenty-four nude mice were randomly divided into therapy group and control group, 12 mice in each group. Thalidomide dissolved in 0.5% sodium carboxyl methyl cellulose (CMC) suspension was administered intraperitoneally once a day at the dose of 200 mg/kg in therapy group, and an equivalent volume of 0.5% CMC in control group. Mice were sacrificed on the 30th d, tumor size and weight and metastases in liver and lungs were measured. CD34 and VEGF mRNA in tumor tissue were detected by immunohistochemistry and semi-quantitative RT-PCR respectively and microvessel density (MVD) was counted. Serum concentrations of TNF-α and ALT and AFP were also tested. RESULTS: MVD and VEGF mRNA in therapy group were less than those in control group (31.08±16.23 vessels/HP vs 80.00±26.27 vessels/HP, 0.0538±0.0165 vs 0.7373±0.1297, respectively, P<0.05). No statistical difference was observed in tumor size and weight and metastases in liver and lungs. TNF-α was significantly lower in therapy group than in control group (28.64±4.64 ng/L vs 42.69±6.99 ng/L, P<0.05). No statistical difference in ALT and AFP was observed between groups. CONCLUSION: Thalidomide can significantly inhibit angiogenesis and metastasis of hepatocellular carcinoma. It also has inhibitory effects on circulating TNF-α.     

Efficacy of splenectomy for hypersplenic patients with advanced hepatocellular carcinoma

Aim: Chemotherapy for advanced hepatocellular carcinoma (HCC) patients with hypersplenism is generally unsatisfactory, as a lower-dose therapy is usually administered. Splenectomy may represent a better approach to overcoming the complication due to hypersplenism in patients with advanced HCC. This retrospective study was conducted to evaluate whether HCC patients who undergo splenectomy show improved prognosis. Methods: We examined 34 HCC patients. Twenty-two had thrombocytopenia and/or leucopenia and underwent laparoscopic splenectomy. The completion rate of full-dose drug regimens, the response rate, the toxicity of chemotherapy and the cumulative survival rate were compared between the splenectomy and non-splenectomy groups. Results: The response rate and the cumulative survival rate in the splenectomy group were significantly better than that in the non-splenectomy group. Conclusions: Splenectomy is an efficient method for advanced HCC patients with hypersplenism treated by chemotherapy.     

Comparative effectiveness of traditional chemoembolization with or without sorafenib for hepatocellular carcinoma

AIM: To compare the overall survival (OS) and progression-free survival (PFS) with associated adverse events (AE) in patients with unresectable hepatocellular carcinoma (HCC) treated with transarterial chemoembolization (TACE) + sorafenib vs TACE alone. METHODS: In this retrospective cohort study we collected data on all consecutive patients with a diagnosis of unresectable HCC between 2007 and 2011 who had been treated with TACE + sorafenib or TACE alone. We hypothesized that the combination therapy is superior to TACE alone in improving the survival in these patients. Data extracted included patient’s demographics, etiology of liver disease, histology of HCC, stage of liver disease with respect to model of end stage liverdisease score and Child-Turcotte-Pugh (CTP) classification and Barcelona Clinic Liver Cancer (BCLC) staging for HCC. Computed tomography scan findings, alpha fetoprotein levels, number of treatments and related AE were also recorded and analyzed. RESULTS: Of the 43 patients who met inclusion criteria, 13 were treated with TACE + sorafenib and 30 with TACE alone. There was no significant difference in median survival: 20.6 mo (95%CI: 13.4-38.4) for the TACE + sorafenib and 18.3 mo (95%CI: 11.8-32.9) for the TACE alone (P = 0.72). There were also no statistically significant differences between groups in OS (HR = 0.82, 95%CI: 0.38-1.77; P = 0.61), PFS (HR = 0.93, 95%CI: 0.45-1.89; P = 0.83), and treatment-related toxicities (P = 0.554). CTP classification and BCLC staging for HCC were statistically significant (P = 0.001, P = 0.04 respectively) in predicting the survival in patients with HCC. The common AE observed were abdominal pain, nausea, vomiting and mild elevation of liver enzymes. CONCLUSION: Combination therapy with TACE + sorafenib is safe and equally effective as TACE alone in patients with unresectable HCC. CTP classification and BCLC staging were the significant predictors of survival. Future trials with large number of patients are needed to further validate this observation.     

索拉非尼联合国产PD-1抑制剂治疗不可手术切除的肝细胞癌的疗效及不良反应

目的研究索拉非尼联合国产程序性细胞死亡受体-1(programmed cell death receptor-1,PD-1)抑制剂在不可手术切除的肝细胞癌(hepatocellular carcinoma, HCC)中的疗效及不良反应。方法回顾性分析2019年6月至2021年1月于北京地坛医院肿瘤内科使用国产PD-1抑制剂联合索拉非尼治疗的不可手术切除的HCC患者的临床资料,资料完整且符合入组条件者共22例,其中卡瑞利珠单抗联合索拉非尼组9例,信迪利单抗联合索拉非尼组13例,随访患者,主要研究终点为统计客观缓解率(objective response rate, ORR)、疾病控制率(disease control rate, DCR)和无进展生存期(progression-free survival, PFS),次要研究终点为总生存期(overall survival, OS)和安全性。结果在可评价疗效的22例患者中,7例患者疗效评价为部分缓解(partial remission, PR),10例患者疗效评价为疾病稳定(stable disease, SD),5例患者疗效评价为疾病进展(progressive disease, PD),ORR为31.8%,DCR为77.3%。中位无进展生存期(median progression-free survival, mPFS)为8.0个月(5.4~10.6个月)。不良反应发生率为77.3%,最常见的不良反应为腹泻(27.3%)、手足综合征(22.7%)、转氨酶升高(22.7%)、疲乏(18.2%)。结论索拉非尼联合国产PD-1抑制剂治疗不可手术切除的HCC临床效果显著,不良反应可控,是一种安全、有效的治疗方案。     

Angiogenesis of hepatocellular carcinoma: An immunohistochemistry study

BACKGROUND Although hepatocellular carcinoma(HCC) is one of the most vascular solid tumors, antiangiogenic therapy has not induced the expected results.AIM To uncover immunohistochemical(IHC) aspects of angiogenesis in HCC.METHODS A retrospective cohort study was performed and 50 cases of HCC were randomly selected. The angiogenesis particularities were evaluated based on the IHC markers Cyclooxygenase-2(COX-2), vascular endothelial growth factor(VEGF) A and the endothelial area(EA) was counted using the antibodies CD31 and CD105.RESULTS The angiogenic phenotype evaluated with VEGF-A was more expressed in small tumors without vascular invasion(pT1), whereas COX-2 was rather expressed in dedifferentiated tumors developed in non-cirrhotic liver. The CD31-related EA value decreased in parallel with increasing COX-2 intensity but was higher in HCC cases developed in patients with cirrhosis. The CD105-related EA was higher in tumors developed in patients without associated hepatitis.CONCLUSION In patients with HCC developed in cirrhosis, the newly formed vessels are rather immature and their genesis is mediated via VEGF. In patients with non-cirrhotic liver, COX-2 intensity and number of mature neoformed vessels increases in parallel with HCC dedifferentiation.     

Predictors of hepatocellular carcinoma in HCV cirrhotic patients treated with direct acting antivirals

Background

Despite the dramatic improvement in viral eradication rates that has been reached with direct antiviral agents (DAAs), the real benefit of viral eradication after DAAs on hepatocellular carcinoma (HCC) development is still controversial.

沙利度胺联合吉西他滨及奥沙利铂方案治疗中晚期肝癌的临床对照研究

目的观察沙利度胺联合吉西他滨及奥沙利铂组成的Gemox方案治疗中晚期肝癌前后VEGF的变化及不良反应。方法56例中晚期肝癌患者,随机分为两组,治疗组29例采用沙利度胺联合吉西他滨及奥沙利铂组成的Gemox方案治疗,对照组27例采用吉西他滨联合奥沙利铂的Gemox方案治疗。治疗2个周期后观察临床疗效,并检测治疗前后VEGF水平的变化。结果两组有效率分别为51.72%和44.44%,差异无统计学意义(P>0.05)。治疗组治疗后VEGF较治疗前明显下降,对照组治疗前后VEGF变化的水平不明显(P>0.05)。两组不良反应的发生无明显差异,治疗组KPS评分明显高于对照组。结论沙利度胺联合Gemox方案有望提高中晚期肝癌的治疗有效率,降低血清VEGF,且能改善患者的一般状况,提高患者对全身化疗的耐受性。     

Feasibility and safety of sorafenib treatment in hepatocellular carcinoma patients with spontaneous rupture

AIM:To report the outcome of patients with ruptured hepatocellular carcinoma(HCC)treated at a single center during a 5-year period.METHODS:We retrospectively analyzed 32 patients who presented with ruptured HCC at Shandong Provincial Hospital Affiliated to Shandong University between2008 and 2013.RESULTS:The mean age of the patients was 53 years(range 39-71 years).Of these patients,22 received surgical management,10 underwent transarterial embolization(TAE)or transarterial chemoembolization(TACE),and 12 received sorafenib after surgery,TAE or TACE.Cumulative survival rates at 4,8 and 12 mo were72.9%,50.0%and 33.3%,respectively,in the surgery only group and were 90.0%,80.6%and 64.1%,respectively,in the surgery plus sorafenib group.Cumulative survival rates at 4,8 and 12 mo were 68.4%,43.6%and 19.4%,respectively,in the surgery only or TAE/TACE only groups,and were 91.7%,75.0%and 60.2%,respectively,in the sorafenib combination groups(P=0.04).No unexpected side effects due to sorafenib were observed.The most common side effect was hand-foot skin reaction.To date,5 patients have died.Median follow-up from the start of sorafenib therapy for the remaining 7 patients is 12.7 mo(range5.8-32.2 mo).CONCLUSION:Sorafenib can be used in patients with ruptured HCC as it has interesting activity and is well tolerated;dose adjustment is generally not required.However,a larger prospective study is necessary to determine the efficacy of sorafenib in this group of patients.     

Efficacy and safety of lenvatinib for patients with advanced hepatocellular carcinoma:A retrospective,real-world study conducted in China

BACKGROUND Lenvatinib has become an indispensable part of treatment regimens for patients with advanced hepatocellular carcinoma(a HCC).Several recent real-world studies appear to have confirmed this;however,there are etiological differences.This necessitates further real-world studies of lenvatinib across diverse populations,such as in China.AIM To investigate the efficacy and safety of lenvatinib in a Chinese HCC patient population under real-world conditions.METHODS This is a retrospective and multiregional study involving patients with a HCC receiving lenvatinib monotherapy.Efficacy was assessed using the Response Evaluation Criteria in Solid Tumors version 1.1.Baseline characteristics and adverse events(AEs) were recorded throughout the entire study.RESULTS In total,54 HCC patients treated with lenvatinib monotherapy were included for final analysis.The objective response rate was 22%(n = 12) with a progressionfree survival(PFS) of 168 d;however,AEs occurred in 92.8% of patients.Multivariate analysis showed that the Barcelona Clinic Liver Cancer stage [hazard ratio(HR) 0.465;95%CI:0.23-0.93;P = 0.031],portal vein tumor thrombus(HR 0.38;95%CI:0.15-0.94;P = 0.037) and Child-Pugh classifications(HR 0.468;95%CI:0.22-0.97;P = 0.042) were significant factors affecting PFS.The sensitivity(56.7%) and specificity(83.3%) of decreasing serum biomarkers including alphafetoprotein were calculated in order to predict tumor size reduction.Gene sequencing also provided insights into potential gene mutation signatures related to the effect of lenvatinib.CONCLUSION Our findings confirm previous evidence from the phase III REFLECT study.The majority of patients in this Chinese sample were suffering from concomitant hepatitis B virus-related HCC.However,further analysis suggested that baseline characteristics,changes in serum biomarkers and gene sequencing may hold the key for predicting lenvatinib responses.Further large-scale prospective studies that incorporate more basic medical science measures should be conducted.     

肝细胞癌的非手术治疗

肝细胞癌（HCC）是原发性肝癌的最主要类型。肝切除术可根治 HCC,使患者长期生存,但肝切除术受到一定的限制,主要在于：（1）肿瘤细胞恶性程度高、病情进展快,极易发生播散和转移;（2）HCC 患者多存在严重的肝硬化基础,因为肝功能失代偿而无法手术;（3）大部分肿瘤为多中心发生,很难切除完全。因此,切除率低和复发率高乃是制约手术治疗 HCC 患者的主要障碍。联合应用手术治疗与各种非手术治疗,多种方案的优化组合将成为综合治疗 HCC 患者的优先选择,提高疗效[1,2]。目前,常用的非手术治疗方法主要有肝动脉化疗栓塞（TACE）、局部消融、放射治疗、系统化疗和分子靶向治疗等。     

几种不同治疗手段对原发性肝癌的疗效比较研究

目的对原发性肝癌儿种不同治疗手段疗效进行比较分析,为临床合理化治疗方案的确定提供参考与帮助.方法我院1999年6月至2003年6月收治原发性肝癌病例中80例分为A组:单纯手术组;B组:手术切除 植入式肝动脉化疗泵化疗组;C组:单纯肿瘤内注射无水酒精组;D组:股动脉穿刺介入治疗组.对不同治疗手段疗效进行比较分析.结果治疗后A、B、C、D四组1年生存率分别为60.13%、71.26%、43.15%、42.78%,2年生存率分别为46.52%、51.38%,26.64%,25.83%.A、B组术后1年复发率分别为60.33%,49.28%,术后2年复发率分别为76.59%,61.24%.结论对原发性肝癌的治疗以手术切除病灶加化疗的综合治疗效果最佳,单纯手术切除较荷瘤的其他治疗手段效果好,但对无法手术切除的病例肿瘤局部用药的治疗手段仍具有一定的控制效果.     

索拉非尼联合肝动脉化疗栓塞术治疗中晚期肝细胞癌疗效观察

目的观察经导管肝动脉化疗栓塞术(TACE)与靶向治疗药相结合治疗中晚期肝细胞癌的疗效和安全性。方法 2008年1月至2012年12月我院收治的中晚期肝细胞癌患者60例,均采用TACE治疗,其中37例术后口服索拉非尼(400 mg,2次/d),根据不良反应调整用量,定期复查腹部CT。根据m RECIST标准进行疗效评价,观察患者的肿瘤进展时间和总生存期,并记录索拉非尼不良反应和TACE前后的肝功能变化。结果 37例应用TACE联合索拉非尼治疗患者的中位生存期为(13±0.98)m,显著长于23例单纯TACE治疗组[(7.3±1.20)m,P=0.001],肿瘤进展时间为(7.5±1.21)m,显著长于单纯TACE治疗组[(5±0.62)m,P=0.001];在随访结束时,联合治疗组疾病控制率为48.6%,显著高于单纯TACE组的17.4%(P0.01);多因素分析显示有无联合应用索拉非尼、有无门脉癌栓、是否抗病毒治疗是显著影响生存时间的风险因素;索拉非尼治疗主要的相关不良反应为手足皮肤反应。结论 TACE联合索拉非尼治疗可延长中晚期肝细胞癌患者的疾病进展时间及总生存期,安全性好。     

TACE联合131I美妥昔单克隆抗体治疗介入术后复发的肝细胞癌患者疗效及安全性分析

目的探讨经肝动脉化疗栓塞术（TACE）联合¹³¹I美妥昔单克隆抗体治疗经介入术后复发的肝细胞癌患者的临床疗效及安全性。方法选取我院2013年5月至2014年8月收治的经TACE治疗后复发的肝细胞癌患者58例,其中29例接受TACE联合美妥昔单抗治疗,29例只接受TACE治疗。通过导管将¹³¹I美妥昔单克隆抗体5 ml （0.75 mCi/kg）注射入靶血管,再进行常规TACE治疗。随访12 m,比较两者疗效、生存率和不良反应。结果美妥昔单抗组与对照组总有效率分别为55.17%和31.03%,差异有统计学意义（P<0.05）;治疗后1 w复查,与治疗前比,美妥昔单抗组白蛋白水平显著下降（P<0.05）,胆红素水平显著升高（P<0.05）,差异有统计学意义（P<0.05）;与治疗前比,对照组白蛋白水平显著下降（P<0.05）,胆红素水平显著升高（P<0.05）,差异有统计学意义（P<0.05）; 美妥昔单抗组不良反应发生率为10.34%,对照组不良反应发生率为3.45%（P>0.05）;美妥昔单抗组1 a生存率为55.17%,对照组为48.27%（Log-rank检验统计量为5.782,P=0.016）;治疗组和对照组平均疾病进展时间为（4.83±4.10） m和（2.54±2.07） m,差异有统计学意义（P<0.05）。结论TACE联合¹³¹I美妥昔单克隆抗体治疗经介入术后复发的肝细胞癌患者的临床疗效优于单纯TACE治疗,且安全可行。     

肝硬化患者肝细胞癌的预防和治疗

肝硬化患者肝细胞癌的预防主要在于如何降低相关危险因素,尤其是对HBV、HCV相关性肝硬化的预防。HBV、HCV疫苗的应用是预防的关键,抗病毒药物预防有助于减少HBV、HCV的复制,降低HCC的发生率。HCC的根治治疗主要包括手术切除和肝移植,对于不能行根治的患者选用适当的非手术切除的多种介入疗法;其他治疗如辅以免疫治疗、分子靶向治疗也有助于改善肝细胞癌患者的预后。     

Phase II and pharmacokinetic study of thalidomide in Japanese patients with relapsed/refractory multiple myeloma

To obtain approval from the Ministry of Health, Labor and Welfare of Japan, a phase II study was conducted to assess the pharmacokinetics and pharmacodynamics of thalidomide along with its efficacy and safety in Japanese patients with multiple myeloma. Between 2005 and 2006, 42 patients were enrolled, and 37 patients met eligibility criteria. Of the 37 patients, 3 were excluded from efficacy analysis because of short duration of thalidomide administration (<4 weeks). The overall response rate was 35.3% (12/34), including partial response of 14.7% (5/34) and minimal response of 20.6% (7/34). The adverse events observed in high frequency (>40%) were leukopenia, neutropenia, drowsiness, dry mouth, and constipation. Grade 3 neutropenia was observed in nine cases. Peripheral neuropathy and eruption were observed in about one-quarter of the patients. Deep vein thrombosis was not observed. At a single oral dose of thalidomide (100 mg), the C _max was 1.68 ± 0.41 μg/ml, T _max was 4.54 ± 1.71 h, T _1/2 was 4.86 ± 0.44 h, and AUC was 15.87 ± 3.05 μg h/ml. Low-dose thalidomide was an effective and tolerable treatment for Japanese patients with relapsed/refractory myeloma. Leukopenia and neutropenia were the most serious adverse events. The pharmacokinetics was similar to those observed in Caucasian patients.