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.     

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.     

Efficacy and safety of thalidomide in patients with hepatocellular carcinoma

INTRODUCTION Hepatocellular carcinoma (HCC) is the fifth most prevalent cancer in the world. About one million people die of it each year[1,2]. Particularly in Taiwan, it poses a tremendous threat to citizens’ health and lives. HCC has been the leading c…     

Radiotherapy for 65 patients with advanced unresectable hepatocellular carcinoma

AIM： To evaluate the efficacy of radiotherapy （RT） in patients with advanced unresectable hepatocellular carcinoma （HCC）. METHODS： A total of 65 patients were treated with RT in the Korea University Medical Center. The median age of the patients was 60 years, and 86.2% were men. 18.5% and 81.5% of the patients were diagnosed as TNM stage Ⅲ and Ⅳ-A, respectively. Treatment response was assessed 4 mo after initiation of RT. Tumor regression rate 1 mo after initiation of RT （TRR1m） was also assessed. Duration of survival was calculated from the initiation of RT. RESULTS： The objective treatment response was 56.9%. The 12 mo survival rate was 34.7%. Predictive factors for survival were Child-Pugh grade, α-fetoprotein level and treatment response. An objective response was achieved more frequently in patients with TRR1m ≥ 20% than in those with TRR1m 〈 20% （P 〈 0.001）. CONCLUSION： RT is effective in treating advanced HCC with a tumor response rate of 56.9%.     

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。     

Image-guided therapies in the treatment of hepatocellular carcinoma: A multidisciplinary perspective

A multidisciplinary approach to the treatment of patients with unresectable hepatocellular carcinoma(HCC) has led to improvements in screening, detection,and treatments. Interventional techniques includethermal ablation, transarterial chemoembolization, and radioembolization whilst stereotactic body radiation therapy also uses imaging to target the radiation. Both survival rates and cure rates have improved markedly since the introduction of these techniques. This review article describes the image guided techniques used for the treatment of HCC.     

Effective treatment strategies other than sorafenib for the patients with advanced hepatocellular carcinoma invading portal vein

Patients with hepatocellular carcinoma(HCC) accompanying portal vein tumor thrombosis(PVTT) have relatively few therapeutic options and an extremely poor prognosis. These patients are classified into barcelonaclinic liver cancer stage C and sorafenib is suggested as the standard therapy of care. However, overall survival(OS) gain from sorafenib is unsatisfactory and better treatment modalities are urgently required. Therefore, we critically appraised recent data for the various treatment strategies for patients with HCC accompanying PVTT. In suitable patients, even surgical resection can be considered a potentially curative strategy. Transarterial chemoembolization(TACE) can be performed effectively and safely in a carefully chosen population of patients with reserved liver function and sufficient collateral blood flow nearby the blocked portal vein. A recent metaanalysis demonstrated that TACE achieved a substantial improvement of OS in HCC patients accompanying PVTT compared with best supportive care. In addition, transarterial radioembolization(TARE) using yttrium-90 microspheres achieves quality-of-life advantages and is as effective as TACE. A large proportion of HCC patients accompanying PVTT are considered to be proper for TARE. Moreover, TACE or TARE achieved comparable outcomes to sorafenib in recent studies and it was also reported that the combination of radiotherapy with TACE achieved a survival gain compared to sorafenib in HCC patients accompanying PVTT. Surgical resectionbased multimodal treatments, transarterial approaches including TACE and TARE, and TACE-based appropriate combination strategies may improve OS of HCC patients accompanying PVTT.     

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.     

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。     

Concomitant lung metastasis in patients with advanced hepatocellular carcinoma

AIM: To investigate the clinical features and prognostic factors of advanced hepatocellular carcinoma (HCC) patients presenting with lung metastasis at initial diagnosis.METHODS: Between 2001 and 2010, we recruited 76 consecutive HCC patients initially presenting with lung metastasis, without co-existing metastasis from other sites. These patients were divided into three groups: untreated group (n = 22), single treatment group (n = 19), and combined treatment group (n = 35).RESULTS: Metastasis of bilateral lung lobes was common and noted in 35 patients (46.1%), and most of patients (59/76, 77.6%) presented with multiple lung metastatic nodules. Nineteen patients (25.0%) received single-method treatment, including hepatectomy in 4, transcatheter arterial chemoembolization in 6, radiotherapy in 5, and oral sorafenib in 4. Thirty-five patients (46.1%) received combined treatment modalities. The overall median survival of the all patients was 8.7 ± 0.6 mo; 4.1 ± 0.3, 6.3 ± 2.5 and 18.6 ± 3.9 mo, respectively in the untreated group, single treatment group and combined treatment group, respectively, with a significant difference (log-rank test, P < 0.001). Multivariate analysis revealed that Child-Pugh score, the absence or presence of portal vein tumor thrombus, and treatment modality were three independent prognostic factors affecting survival of patients with advanced HCC and concomitant lung metastasis.CONCLUSION: Combined treatment modalities tend to result in a better survival as compared with the conservative treatment or single treatment modality for HCC patients initially presenting with lung metastasis.     

Cyberknife treatment for advanced or terminal stage hepatocellular carcinoma

AIM: To investigate the safety and efficacy of the Cyberknife treatment for patients with advanced or terminal stage hepatocellular carcinoma(HCC).METHODS: Patients with HCC with extrahepatic metastasis or vascular or bile duct invasion were enrolled between May 2011 and June 2015. The Cyberknife was used to treat each lesion. Treatment response scores were based on Response Evaluation Criteria in Solid Tumors v1.1. The trends of tumor markers,including alpha fetoprotein(AFP) and proteins induced by vitamin K absence Ⅱ(PIVKA Ⅱ) were assessed. Prognostic factors for tumor response and tumor markers were evaluated with Fisher's exact test and a logistic regression model. Survival was evaluated with the Kaplan-Meier method and multivariate analysis was performed using the Cox proportional hazards model.RESULTS: Sixty-five patients with 95 lesions were enrolled. Based on the Barcelona Clinic Liver Cancer classification,all patients were either in the advanced or terminal stage of the disease. The target lesions were as follows: 52 were bone metastasis; 9,lung metastasis; 7,brain metastasis; 9,portal vein invasion;4,hepatic vein invasion; 4,bile duct invasion; and 10 other lesion types. The response rate and disease control rate were 34% and 53%,respectively. None of the clinical factors correlated significantly with tumor response. Fiducial marker implantation was associated with better control of both AFP(HR = 0.152; 95%CI: 0.026-0.887; P = 0.036) and PIVKA Ⅱ(HR = 0.035; 95%CI: 0.003-0.342; P = 0.004). The median survival time was 9 mo(95%CI: 5-15 mo). Terminal stage disease(HR = 9.809; 95%CI: 2.589-37.17,P 0.001) and an AFP of more than 400 ng/m L(HR = 2.548; 95%CI: 1.070-6.068,P = 0.035) were associated with worse survival. A radiation dose higher than 30 Gy(HR = 0.274; 95%CI: 0.093-0.7541,P = 0.012) was associated with better survival. In the 52 cases of bone metastasis,36 patients(69%) achieved pain relief. One patient had cerebral bleeding and another patient had an esophageal ulcer after treatment.CONCLUSION: The Cyberknife can be safely administered to patients with advanced or terminal stage HCC. High AFP levels were associated with worse survival,but a higher radiation dose improved the survival.     

肝动脉化疗栓塞术中注入重组人血管内皮抑制素治疗中晚期肝癌的疗效及安全性分析

目的：观察重组人血管内皮抑制素经肝动脉灌注联合TACE治疗中晚期肝癌的近期及远期疗效。方法将64例中晚期肝癌患者分为对照组（n=30例),仅予以TACE治疗,和观察组（n=34例）,在行TACE治疗时,同时经肝动脉注入重组人血管内皮抑制素,比较两组近、远期疗效,观察治疗前后肿瘤直径、KPS评分及AFP变化,分析两组毒副反应。结果观察组治疗总有效率（64.7%）明显高于对照组（43.3%,P<0.05）;两组患者治疗后肿瘤直径[（4.0±1.2） cm和（4.9±1.3） cm]较治疗前[（6.7±2.0） cm和（6.6±2.2） cm]明显缩小（P<0.05）,KPS评分明显升高[（92.5±9.8）对（76.1±4.5）和（84.8±8.6）对（75.2±3.4）,P<0.05],AFP明显降低[（547.2±160.7）μg/L对（1275.3±316.8）μg/L和（558.5±176.4）μg/L 对（1218.8±337.9）μg/L,P<0.05],且观察组肿瘤直径[（4.0±1.2） cm、KPS评分（92.5±9.8）较对照组缩小（4.9±1.3） cm或升高（84.8±8.6）更为显著,P<0.05];两组毒副反应比较差异无显著性（P>0.05）;随访1年,观察组患者病死率（5.9%）和肝外转移率（14.7%）明显低于对照组患者（16.7%和26.7%, P<0.05）。结论在行TACE治疗时加用重组人血管内皮抑制素治疗中晚期肝癌患者可明显提高近期及远期疗效,缩小肿瘤直径和改善KPS评分,且不会加重毒副反应。     

Preoperative evaluation and prediction of clinical scores for hepatocellular carcinoma microvascular invasion: a single-center retrospective analysis

IntroductionMicrovascular invasion (MVI) of is generally considered to be an important prognostic factor for hepatocellular carcinoma (HCC) after operation, An accurate prediction of MVI before operation is helpful for clinical decision-making before operation.Material and methodsA retrospective analysis of 227 cases of hepatocellular carcinoma patients after hepatectomy has been confirmed the pathological result whether there was MVI, and has been determined the independent risk factors of MVI. Based on these independent risk factors, we constructed a clinical scoring risk model for predicting MVI.ResultsAmong the 227 patients with HCC, 74 (34.6%) were MVI positive. Using receiver operating characteristic (ROC) curve and logistic regression model, we found that alpha-fetoprotein(AFP)≥158 ng/mL(odds ratio[OR] = 4.152,95% confidence interval [95%CI]:1.602∼10.760,p = 0.003), Des-γ-carboxy prothrombin (DCP)≥178mAU/mL(OR = 9.730,95%CI:3.392∼27.910,p < 0.001), circulating tumor cells (CTCs)≥3/3.2 ml(OR = 7.747,95%CI:3.019∼19.881,P < 0.001), maximum tumor diameter≥59 mm(OR = 3.467,95%CI:1.368∼8.669,p = 0.008) and tumor margin unsmoothness(OR = 0.235,95%CI:0.096∼0.573,p = 0.001) were independent risk factors for MVI, they predicted that the area under the curve of MVI was 0.752, 0.777, 0.857, 0.743 and 0.333, respectively. Based on these five independent risk factors, we constructed a clinical scoring risk model for predicting MVI. The model predicts that the area under the curve of MVI is 0.922, and its prevalence rate from 0 to 5 are 3.1%(1/32), 5.3%(4/76), 12.2%(5/41), 66.7%(20/30), 87.9%(29/33), 100%(15/15), respectively (P < 0.001).ConclusionBased on AFP, DCP, CTC, maximum tumor diameter and tumor margin unsmoothness, we constructed a model to predict the risk of MVI clinical score, so as to make a more accurate individualized treatment plan before operation, which has important clinical significance and application prospect to improve the curative effect of HCC.     

Systemic chemotherapy for hepatocellular carcinoma in non-cirrhotic liver： A retrospective study

AIM： To investigate the efficacy and toxicity of systemic chemotherapy in a retrospective study of patients with hepatocellular carcinoma （HCC） occurring in normal or fibrotic liver without cirrhosis.
METHODS： Twenty-four patients with metastatic or locally advanced HCC in a normal or a fibrotic liver were given systemic chemotherapy （epirubicin, cisplatin and 5-fluorouracil or epirubicin, cisplatin and capecitabine regimens）. Tumor response, time to progression, survival, and toxicity were evaluated.
RESULTS： There were 7 women and 17 men, mean age 54 ± 10 years; 18 patients had a normal liver and 6 had a fibrotic liver （F1/F2 on biopsy）. Mean tumor size was 14 cm, 5 patients had portal vein thrombosis and 7 had metastasis. Patients received a median of 4 chemotherapy sessions. Overall tolerance was good. There were 5 partial responses （objective response rate = 22%）, and tumor control rate was 52%. Second line surgical resection was possible in two patients. Median survival was 11 mo, and 1- and 2-year overall survival rates were 50% ± 10% and 32 ± 11%, respectively.
CONCLUSION： In patients with HCC in a non-cirrhotic liver, chemotherapy was well tolerated and associated with an objective response rate of 22%, including two patients who underwent secondary surgical resection.     

Safety of hepatectomy for elderly patients with hepatocellular carcinoma

The number of elderly patients with hepatocellular carcinoma (HCC) has been increasing. Characteristics of elderly HCC patients are a higher proportion of females, a lower rate of positive hepatitis B surface antigen, and a higher rate of positive hepatitis C antibodies. Careful patient selection is vital for performing hepatectomy safely in elderly HCC patients. Treatment strategy should be decided by not only considering tumor stage and hepatic functional reserve, but also physiological status, including comorbid disease. Various assessment tools have been applied to predict the risk of hepatectomy. The reported mortality and morbidity rates after hepatectomy in elderly HCC patients ranged from 0% to 42.9% and from 9% to 51%, respectively. Overall survival rate after hepatectomy in elderly HCC patients at 5 years ranged from 26% to 75.9%. Both short-term and long-term results after hepatectomy for strictly selected elderly HCC patients are almost the same as those for younger patients. However, considering physiological characteristics and the high prevalence of comorbid disease in elderly patients, it is important to assess patients more meticulously and to select them strictly if scheduled to undergo major hepatectomy.     

Capecitabine in advanced hepatocellular carcinoma: A multicenter experience

BackgroundRecent data suggest a potential activity and a good tolerability of capecitabine in advanced hepatocellular carcinoma (HCC).AimsTo evaluate capecitabine activity and safety in a wide cohort of advanced HCC patients.MethodsRetrospective analysis of 143 capecitabine-treated patients (January 2010 to December 2017) in three centers of the Veneto Oncology Network.ResultsCapecitabine was administered in second and third line, but also in first line instead of sorafenib in Child-Pugh B patients (70%), compromised clinical conditions (14%) or contraindications to antiangiogenetics (16%). Median overall survival (OS) and time to progression (TTP) were 6.9 and 2.8 months, respectively. There were no differences in OS and TTP between the 32 patients treated with non-metronomic scheme (2000 mg/day for 14 days) and the 111 patients treated with metronomic scheme (1000 mg/day) after correction for prognostic factors at baseline with a propensity score analysis. Capecitabine was more active in patients intolerant to sorafenib than in those progressing during treatment (p = 0.024). At least one adverse event (mainly hematological) was experienced by 73% of patients but discontinuation was necessary only in 11 (8%).ConclusionsCapecitabine can be considered an active and safe option in advanced HCC, especially for patients unfit for other treatments.     

肝动脉化疗栓塞联合经皮射频治疗老年中晚期肝癌的疗效

目的 分析肝动脉化疗栓塞（TACE）联合经皮射频消融（RFA）治疗老年中晚期原发性肝癌（HCC）的疗效,为HCC的临床治疗提供参考.方法 按照随机数字表法将80例患者分为TACE联合RFA治疗组（观察组）和RFA治疗组（对照组）,比较两组治疗效果.结果 观察组肿瘤瘤体缩小率高于对照组,两组比较,差异具有统计学意义（P＜0.05）;甲胎蛋白下降超过50％者,观察组（85.7％）与对照组（55.6％）比较差异具有统计学意义（P＜0.05）.两组不良反应发生情况差异无统计学意义（P＞0.05）;术后24个月随访,观察组生存率27例（67.5％）,对照组生存率17例（42.5％）,两组比较差异具有统计学意义（P＜0.05）.结论 HCC患者对TACE联合RFA治疗的耐受性较好,联合治疗的安全性和可行性较好.