Phase 2 open‐label study of single‐agent sorafenib in treating advanced hepatocellular carcinoma in a hepatitis B–endemic Asian population

BACKGROUND:

The current study was a phase 2 open–label study to evaluate the efficacy and tolerability of single‐agent sorafenib in the treatment of advanced HCC patients in a hepatitis B–endemic Asian population.

METHODS:

Patients with advanced hepatocellular carcinoma (HCC) received sorafenib at a dose of 400 mg twice daily in 4‐week cycles. Tumor response was assessed every 3 cycles using Response Evaluation Criteria in Solid Tumors criteria.

RESULTS:

Fifty‐one patients were enrolled in the study and were treated with sorafenib for at least 12 weeks. The median age was 56 years (range, 28‐79 years). Approximately 90% had hepatitis B virus–related HCC. Thirty‐six (71%) patients had underlying Child‐Pugh A cirrhosis, 13 (26%) Child‐Pugh B, and 2 (3%) Child‐Pugh C. Four (8%) patients achieved partial responses, and 9 (18%) patients had stable disease for at least 12 weeks. The median overall survival was 5 months (range, 4‐17 months). Patients without extrahepatic spread, particularly without lung metastasis (P<.01), are more likely to benefit from sorafenib treatment. The most common toxicities were diarrhea (67%), malaise (55%), and hand‐foot‐skin reaction (54%). The majority of patients had transient liver function derangement. Patients with and without underlying portal vein thrombosis had similar therapeutic benefits and likewise shared a similar treatment‐related toxicity profile with sorafenib treatment.

CONCLUSIONS:

Single‐agent sorafenib demonstrates good efficacy and acceptable tolerability in treating an advanced HCC patient population in a hepatitis B–endemic area. The presence of lung metastasis predicts poor response to sorafenib in advanced HCC patients. Cancer 2009. © 2009 American Cancer Society.     

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.     

TACE联合索拉非尼治疗中晚期肝细胞性肝癌的临床研究

目的探讨经导管动脉化疗栓塞（transcatheterarterialchemoembolization,TACE）联合索拉非尼治疗中晚期肝细胞性肝癌（hepatocellularcarcinoma,HCC）的疗效及安全性。方法选择我院70例中晚期HCC患者,其中35例给予TACE联合索拉非尼治疗（观察组）,35例单纯行TACE治疗（对照组）。每4-8周根据实体瘤疗效评估标准（RECIST）行肿瘤应答评价,评估临床疗效及索拉非尼毒副反应,比较两组患者治疗后的中位生存期及中位疾病进展时间。结果观察组和对照组中位0s分别为14_8个月和8．2个月,差异有统计学意义（P〈0．05）,中位TIP分别为10．3个月和5．8个月,差异有统计学意义（P〈0．05）。观察组服用索拉非尼后有27例（77．1％）患者出现毒副反应,经对症治疗后好转。结论TACE联合索拉非尼治疗中晚期HCC疗效好,不良反应可耐受,有望成为中晚期HCC的一种治疗模式。     

Combination treatment of localized concurrent chemoradiation therapy and transarterial chemoembolization in locally advanced hepatocellular carcinoma with intrahepatic metastasis

Purpose

Although sorafenib has been approved for treating advanced hepatocellular carcinoma (HCC), its high cost, frequent adverse events, and unsatisfactory efficacy remain unresolved. We evaluated the efficacy and safety of the combination treatment of localized concurrent chemoradiation therapy (CCRT) for locally advanced HCC with portal vein thrombosis (PVT) and transarterial chemoembolization (TACE) for intrahepatic metastasis.

Methods

Between January 2006 and June 2011, 30 patients with HCC with portal vein invasion and intrahepatic metastasis were enrolled. After TACE for intrahepatic metastasis, localized CCRT (45 Gy over 5 weeks with conventional fractionation and hepatic artery infusional chemotherapy using 5-fluorouracil as a radiosensitizer, administered during the first and fifth weeks of radiotherapy) was used to treat main HCC with PVT. The modified response evaluation criteria in solid tumors (mRECIST) were used to evaluate tumor response.

Results

The median age of the patients (26 men, 4 women) was 51 years. Objective response rates were 30.0 % (9/30) and 32.1 % (9/28) in the intention-to-treat and per protocol analyses, respectively. The median progression-free survival (PFS) and overall survival (OS) were 4.5 and 9.8 months, respectively. Baseline α-fetoprotein (AFP) correlated significantly with PFS (P = 0.008), whereas baseline AFP, completion of the protocol, and overall radiological response influenced OS significantly (all P < 0.05). All adverse events were predictable and manageable with conservative care.

Conclusions

Combination treatment of localized CCRT and TACE was effective and tolerable in patients with locally advanced HCC with PVT and intrahepatic metastasis. This protocol may be an alternative option when sorafenib cannot be prescribed.     

Sorafenib therapy in advanced hepatocellular carcinoma: the SHARP trial

Until now, no effective systemic treatment options have been available for patients with unresectable advanced hepatocellular carcinoma (HCC). In the Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP), patients with unresectable advanced HCC with Child–Pugh liver function class A and who had not received prior systemic therapy, received either oral sorafenib (400 mg twice daily) or placebo until radiological and symptomatic progression. The two groups of patients were well balanced with respect to baseline characteristics. The study was stopped at the second planned interim analysis because of an advantage in the median overall survival (10.7 vs 7.9 months; hazard ratio: 0.69; 95% CI: 0.55–0.87; p < 0.001) and the median time to radiological progression (5.5 vs 2.8 months; p < 0.001) in the sorafenib arm. However, sorafenib was not able to increase the time to symptomatic progression. In terms of toxicity, there were more cases of diarrhea, weight loss, hand–foot skin reaction and hypophosphatemia among the patients receiving sorafenib, the majority of which were of grade 1 or 2 severity. The SHARP trial has demonstrated that sorafenib is effective in prolonging median survival and time-to-progression in patients with advanced HCC and that it is generally well tolerated with a manageable adverse events profile.     

索拉非尼治疗进展期肝细胞癌的疗效及预后因素分析

  目的  评价索拉非尼治疗进展期肝细胞癌（HCC）的疗效及分析其预后影响因素。  方法  前瞻性分析2007年8月至2009年7月间110例接受索拉非治疗的进展期HCC患者,评价其疗效、不良反应,以总生存期和无肿瘤进展生存期为预后指标进行单因素和Cox比例风险模型多因素分析。  结果  110例患者随访中位时间9（2~18）个月,服用索拉非尼中位时间6.5（2~18）个月。14例（12.7%）获得完全缓解（CR）,16例（14.5%）部分缓解（PR）,40例（36.4%）病情稳定（SD）,总有效率为70例（63.6%）。中位生存期和无肿瘤进展生存期分别为10.5个月（95%CI:8.7~12.3）和5.0个月（95%CI:3.7~6.3）。多因素分析显示:联合局部治疗（肝动脉化疗栓塞或氩氦刀）、美国东部肿瘤协作组活动状态评分（Eastern Cooperative Oncology Group performance status score,ECOG PS）和Child-Pugh分级是影响无肿瘤进展生存时间的独立预后因素,而联合局部治疗、ECOG PS评分和AFP（alfa-fetopro? tein）水平是影响总生存期的独立预后因素。亚组分析显示:在肝癌进展组患者中继续服用索拉非尼其总生存期明显长于终止索拉非尼治疗者（11个月vs. 7.5个月,P < 0.001）。  结论  索拉非尼治疗进展期HCC,ECOG PS评分是影响生存期的一个重要因素,联合局部治疗有益于改善生存期。      

Oxaliplatin-based Chemotherapy: A New Option in Advanced Hepatocellular Carcinoma. A Systematic Review and Pooled Analysis

Advanced hepatocellular carcinoma (HCC), for which locoregional treatment is not an option, is a candidate for palliative systemic therapy, but an accepted chemotherapy regimen does not exist. We have conducted a systematic literature review and meta-analyses to quantify the benefits of oxaliplatin (OXA)-based chemotherapy in advanced HCC in patients not exposed to sorafenib. Studies that enrolled advanced HCC patients treated with first-line OXA-based chemotherapy were identified using PubMed, Web of Science, SCOPUS, The Cochrane Register of Controlled Trials and EMBASE. A systematic review was conducted to calculate the pooled response rate and 95% confidence interval. The pooled median progression-free survival (PFS) and overall survival, weighted on the number of patients of each selected trials, were also calculated. We tested for significant heterogeneity by Cochran's chi-squared test and I-square index. Thirteen studies were included in this review, with a total of 800 patients analysed. The pooled response rate was 16.8%. The median PFS and overall survival were 4.2 and 9.3 months, respectively, with a 1 year overall survival of 37%. The weighted median PFS/overall survival and response rate were 4.5/11 months and 20% in Western patients. Conversely, in Asiatic studies, the median PFS/overall survival and response rate were 2.43/6.47 months and 13.2%, respectively. OXA-based chemotherapy is effective in advanced HCC and represents a viable option in these patients. A head to head comparison with sorafenib or a second-line agent should be verified in prospective trials.     

FPN1、DMT1在肝细胞癌中的表达及其与药物疗效的关系

目的 研究膜铁转运蛋白1（ferroportin 1,FPN1）和二价金属离子转运体1（divalent metal transporter 1,DMT1）在人肝细胞癌（hepatocellular carcinoma,HCC）癌组织中的表达及与临床病理特征、药物疗效的关系。方法 回顾性收集行肝癌切除术后复发转移并接受化疗或索拉非尼治疗的HCC患者的临床及病理资料。采用免疫组化法检测HCC癌组织中FPN1及DMT1的表达,分析其与HCC患者临床病理特征、药物疗效的关系。结果 27例HCC患者无完全缓解者,其中接受奥沙利铂联合替吉奥方案化疗16例,获部分缓解2例,疾病稳定2例,疾病控制率（DCR）为25.0%;接受索拉非尼治疗11例,部分缓解1例,疾病稳定 2例,疾病控制率为27.3%。全组患者中位PFS为5.4个月,中位OS为10.0个月。FPN1和DMT1在HCC癌组织中的阳性表达率分别为62.96% 和81.48%,FPN1及DMT1的表达与肿瘤分化程度相关（P＜0.05）,与其他临床病理特征无关（P＞0.05）。FPN1阳性患者的DCR为41.2%,中位PFS为6.7个月,中位OS为15.7个月,优于阴性患者的10.0%、1.8个月和8个月（P＜0.05）;DMT1 阳性患者的DCR为18.2%,中位PFS为3.2个月,中位OS为 9.3个月,低于阴性患者的60.0%、18.6个月和35.9个月（P＜0.05）。结论 FPN1和DMT1在HCC中的表达可能受癌细胞分化程度影响,与晚期HCC患者药物治疗后的远期生存有关。     

The outcome of chemotherapy by sorafenib in advanced hepatocellular carcinoma

We analyzed the treatment outcome and effect of sorafenib in advanced hepatocellular carcinoma. Nine patients were received the therapy of sorafenib between June 2009 and October 2009. The overall incidence of treatment-related adverse events was 87.5%. Grade 3 drug-related adverse events included a hand-foot skin reaction (two patients) and fatigue (one patient). Grade 2 hypertension (three patients), grade 1 diarrhea (two patients) and anorexia (four patients) occurred at this study. The response rate was 0% (CR/PR 0, SD 2, PD 6) and median overall survival length was 101 days. Now there are two patients undergoing the therapy of sorafenib. Effect of sorafenib in advanced hepatocellular carcinoma was not good in this study, and drug-related adverse events had a high rate. However, the continuous treatment was possible with dose modified chemotherapy.     

Efficacy and Safety of Sorafenib in Advanced Hepatocellular Carcinoma Under Daily Practice Conditions

Abstract

Sorafenib has recently been shown to be effective for the treatment of advanced hepatocellular carcinoma in randomized controlled trials. Here, we report the experience with sorafenib in 25 patients with advanced HCC under daily practice conditions. Tolerance to sorafenib was acceptable and side effects were manageable, although the ECOG performance status was reduced in all patients. The most prevalent grade 2/3 side effects were fatigue (40%) and diarrhea (24%), and withdrawal from therapy occurred in 29% of patients. Disease stabilization was documented in 60% of patients. The median treatment time was 2.7 months and overall survival was 11.0 months. No significant serum alpha-fetoprotein decline was noted at the time of the first radiological control in a subgroup of patients with baseline levels >50 ng/ml who achieved stable disease. In conclusion, in daily practice sorafenib is safe and disease stabilization can be achieved in the majority of patients. However, intolerance to sorafenib can affect treatment adherence substantially.     

微波消融术联合索拉非尼治疗晚期肝细胞癌的临床研究

目的 比较微波消融术(MWA)联合索拉非尼与索拉非尼单药治疗晚期肝细胞癌(HCC)的临床疗效及不良反应.方法 回顾性分析57例晚期原发性HCC患者的病历和随访资料,其中25例患者接受MWA联合索拉非尼治疗(联合组),32例患者接受索拉非尼单药治疗(单药组),观察终点为两组患者的治疗疗效、无进展生存时间(PFS)、总生存时间(0S)及不良反应.结果 联合组和单药组客观缓解率分别为16.0％和3.1％,差异无统计学意义(χ2=1.521,P=0.217).联合组的疾病控制率为80.0％,明显高于单药组的50.0％,差异有统计学意义(χ2=5.429,P=0.020).联合组的中位PFS显著长于单药组(6.0个月:3.2个月,x2 =7.675,P=0.006),而联合组与单药组的中位OS差异无统计学意义(11.5个月:8.5个月,x2=2.480,P=0.115).联合组和单药组3～4级不良反应发生率分别为44.0％和34.4％,差异无统计学意义(x2=0.549,P=0.459).结论 联合组与单药组比较虽OS无明显延长,但联合组PFS长于单药组,且没有增加严重不良反应发生风险.     

Increasing incidence of brain metastasis in patients with advanced hepatocellular carcinoma in the era of antiangiogenic targeted therapy

Aim.

Brain metastasis was regarded, until recently, as a rare and late-stage event in patients with hepatocellular carcinoma (HCC). With the prolongation of survival in patients with advanced HCC by molecular targeted agents, this may have changed. We aimed to examine whether or not the incidence of brain metastasis in these patients has increased.

Methods.

Between June 2005 and May 2009, 158 advanced HCC patients in total with either metastatic or locally advanced disease untreatable by locoregional therapies were enrolled in clinical trials of first-line antiangiogenic therapies. The clinicopathologic features and survival times of those who developed brain metastasis were analyzed.

Results.

Eleven (7%) of 158 advanced HCC patients, with a median follow-up of 26.6 months, were diagnosed with brain metastasis as a result of compatible symptoms, confirmed by brain imaging. All 11 patients had extrahepatic metastasis upon enrollment, and 10 of them had lung metastasis. The median time to brain metastasis was 9.6 months (range, 0.6–19.6 months). The median overall survival (OS) time after diagnosis of brain metastasis was 4.6 months (range, 0.7–12.6 months). Four patients received brain tumor excision, and their survival duration after brain metastasis tended to be longer than that of those who did not (median OS time, 6.1 months versus 3.1 months).

Conclusions.

In the era of antiangiogenic targeted therapy, the importance of brain metastasis for advanced HCC patients may have increased.     

索拉非尼治疗43例中晚期肝细胞癌的临床观察

目的 探讨索拉非尼治疗中晚期肝细胞癌（HCC）的疗效和安全性。方法 回顾性分析吉林大学第一医院肿瘤中心2008年6月至2011年12月持续应用索拉非尼（400mg/次,2次/日）治疗3个月以上的43例中晚期HCC患者,其中22例患者口服索拉非尼单药治疗,另21例患者口服索拉非尼联合局部治疗。评价客观疗效、不良反应及总生存期。结果 全组43例患者获CR 2例,PR 15例,13例持续6个月以上SD,疾病控制率（DCR）为69.8％。其中索拉非尼单药组获PR 2例,SD（持续6个月以上）10例,DCR为54.5％（12/22）;索拉非尼联合组获CR 2例,PR 13例,SD（持续6个月以上）3例,DCR为85.7％（18/21）。两组DCR比较,差异有统计学意义（P=0.03）。 43例患者的中位生存期（OS）为22个月（4～39个月）。亚组分析显示,巴塞罗那分期（BCLC）A期患者的中位OS为未达到,B期为12个月,C期为9个月,三者比较差异有统计学意义（P=0.038）;肝功能Child-Pugh A级患者的中位OS优于Child-Pugh B级患者（24.0个月vs.4.9个月,P=0.002）;索拉非尼联合治疗组的中位OS优于索拉非尼单药组（25.0个月vs.8.7个月,P=0.043）。43例患者的主要不良反应为手足综合征、高血压、腹泻等。除3例出现3级不良反应外,其他均为2级及以下,经对症治疗好转。结论 索拉非尼治疗中晚期HCC安全有效,不良反应多数患者可以耐受。     

索拉非尼治疗国人晚期肝癌的临床观察

目的：观察索拉非尼治疗国人晚期肝细胞肝癌（ＨＣＣ）的有效性和安全性。方法：２０例晚期ＨＣＣ患者,口服索拉非尼单药治疗（４００ｍｇ,ｂｉｄ）,持续至疾病进展或出现不可耐受的不良反应,每６周按照ＲＥＣＩＳＴ标准（１.０版）进行疗效评价,按ＮＣＩ-ＣＴＣ（３.０版）评价毒性并动态监测甲胎蛋白（ＡＦＰ）的变化和随访生存情况。结果：在１９例可评价的患者中,获得ＳＤ１２例,ＰＤ７例,疾病控制率（ＤＣＲ）为６３.２％,中位肿瘤进展时间（ｍＴＴＰ）为３.８个月（９５％ＣＩ：２.５４～５.０６个月）,中位总生存期（ｍＯＳ）为６.０个月（９５％ＣＩ：３.９４～８.０６个月）,治疗前１２例ＡＦＰ高于正常,治疗后明显下降３例,稳定４例,升高５例。主要不良反应为手足皮肤反应、食欲下降和腹泻。结论：索拉非尼单药治疗晚期ＨＣＣ具有一定疗效,不良反应可以耐受,值得推广应用。     

索拉非尼治疗不能手术的原发性肝细胞癌的疗效及预后因素

目的 研究索拉非尼治疗不能手术的原发性肝细胞癌(HCC)的疗效以及预后影响因素.方法 2005年12月至2009年3月间,50例肝功能分级为Child-Pugh A级的不能手术的原发性HCC患者连续口服索拉非尼治疗,索拉非尼用法为400 mg/次,每日2次.每6～8周复查CT或MRI,根据实体瘤疗效评价标准(RECIST)进行疗效评价,根据美国国立癌症研究所常见毒性分级标准评价不良反应,观察患者的总生存时间(OS)和疾病进展时间(TTP).结果 50例患者均可评价疗效,其中疾病稳定(SD)28例,疾病稳定率为56.0%;疾病进展(PD)22例,占44.0%;无完全缓解(CR)和部分缓解(PR)患者.中位随访时间为15个月,随访期间共有17例患者死亡,全组患者的中位TTP为4个月,中位OS为14个月.索拉非尼治疗不能手术的原发性HCC患者的不良反应为皮肤损害、腹泻、高血压、脱发、骨髓抑制和肝功能损害等,大多为Ⅰ～Ⅱ级,经对症处理或调整用药剂量后多可恢复.单因素分析结果显示,有无远处转移是影响HCC患者TTP的主要因素.结论 索拉非尼可有效治疗不能手术的原发性HCC,有无远处转移是影响HCC患者TTP的主要因素.     

A phase Ib study of selumetinib (AZD6244, ARRY-142886) in combination with sorafenib in advanced hepatocellular carcinoma (HCC)

Angiogenesis and RAS/RAF/MEK/ERK pathway have been demonstrated to be relevant in hepatocellular carcinoma (HCC). Sorafenib, an oral multikinase inhibitor with activity against RAF kinase and vascular endothelial growth factor receptor-2, is approved for the treatment of advanced HCC. The therapeutic benefit however is modest. While displaying tumour growth inhibition and angiogenesis, sorafenib treatment in pre-clinical models exhibited up-regulation of pERK which may limit its anti-tumour activity. Inhibition of the MEK/ERK pathway by selumetinib enhanced the anti-tumour effect of sorafenib in pre-clinical models of HCC. In this phase I study, we investigated the maximum tolerated dose (MTD), safety and activity of combination sorafenib and selumetinib in patients with advanced HCC. The combination of selumetinib and sorafenib has manageable toxicity and showed encouraging anti-tumour activity. These findings support further evaluation in a phase II study.BackgroundTreatment with sorafenib, although associated with inhibition of tumour growth and angiogenesis in in vivo studies, leads to up-regulation of pERK. The addition of MEK inhibition could potentially abrogate this effect and potentiate anti-tumour activity. This phase I study investigated the maximum tolerated dose (MTD), safety, tolerability, pharmacokinetics (PK) and biomarker correlates of selumetinib combined with sorafenib in patients with advanced hepatocellular carcinoma (HCC).MethodsPatients with Child–Pugh (CP) score ≤7 were treated with 400 mg twice daily of sorafenib with escalating doses of selumetinib in a 3 + 3 study design. The dose-limiting toxicity (DLT) evaluation period was 28 days. PK of selumetinib was determined. Angiogenic effect was evaluated with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI).ResultsTwenty-seven patients of Asian ethnicity were enrolled. The MTD was selumetinib 75 mg daily with sorafenib 400 mg twice daily. DLT included grade 3 transaminitis, diarrhoea and fatigue. Most common treatment-related adverse events at MTD (all grades) were diarrhoea (85%), rash (59%), hypertension (44%), fatigue (30%), anorexia (22%) and hand–foot syndrome (22%). Four patients (15%) had PR and 13 (48%) had SD. PR or SD was observed for ≥6 months in seven patients. The median overall survival was 14.4 months. Selumetinib exposures in combination with sorafenib were comparable to other monotherapy studies. A reduction in permeability-surface area product noted in DCE-MRI with treatment correlated with worse survival outcomes.ConclusionThe MTD of selumetinib was 75 mg daily when combined with sorafenib 400 mg twice a day in CP ≤7 HCC. Acceptable adverse events and encouraging anti-tumour activity warrant further evaluation. DCE-MRI findings deserve prospective evaluation.ClinicalTrials.gov identifierNCT01029418.     

Sorafenib in combination with transarterial chemoembolization and bronchial arterial chemoinfusion in the treatment of hepatocellular carcinoma with pulmonary metastasis

Aim: Hepatocelluar carcinoma (HCC) with pulmonary metastasis is considered incurable. This study addresses the efficacy of the combination of systemic therapy using sorafenib and local treatment using transarterial chemoembolization (TACE) for intrahepatic and bronchial transarterial chemoinfusion (TAI) for pulmonary lesions for this condition. Methods: In all, 52 HCC patients with pulmonary metastasis were treated with sorafenib and TACE/TAI for intrahepatic and intrapulmonary lesions. Response to treatment, progression‐free survival (PFS), overall survival (OS) and treatment‐induced adverse effects were analyzed. Results: With a median follow‐up time of 11.4 months, radiologically confirmed complete response (CR), partial response (PR), stable disease and disease progression for intrahepatic disease were observed in 0, 22, 23 and seven patients, respectively; radiologically confirmed CR, PR, stable disease and disease progression observed for intrapulmonary lesions were in 1, 8, 25 and 18 patients, respectively. Median OS and PFS was 12.0 and 10.0 months, respectively. Median OS of patients who achieved response (i.e., CR + PR + stable disease) in their gross lesion(s) was 14.0 and 13.0 months, respectively, as compared to 4.0 and 3.0 months for patients who progressed (P < 0.003). Significant prognosticators for OS and PFS included performance status, Barcelona Clinic Liver Cancer stage and response to treatment. The combined treatment strategy was well tolerated. Conclusion: The combination of sorafenib, TACE and TAI produced median OS and PFS of 12 and 10 months, respectively, in HCC patients with lung metastasis. The outcomes of patients who achieved a response to their gross lesions were significantly better than those who had disease progression. Further investigation is warranted to test the efficacy of this treatment combination.     

Early Skin Toxicity as a Predictive Factor for Tumor Control in Hepatocellular Carcinoma Patients Treated with Sorafenib

Introduction.

Sorafenib is an oral multikinase inhibitor that targets Raf kinase and receptor tyrosine kinases and has led to a longer median overall survival (OS) time and time to progression (TTP) in patients with advanced hepatocellular carcinoma (HCC). This study was conducted to assess the link between the antitumor efficacy of sorafenib and its early cutaneous side effects in advanced HCC patients.

Materials and Methods.

All patients received 800 mg daily of sorafenib until progression or unacceptable toxicities. We retrospectively analyzed the incidence of rash and hand–foot skin reactions (HFSR) during the first month of treatment, comparing tumor control (partial response plus stable disease) and TTP.

Results.

Sixty-five HCC patients treated with sorafenib were included in this analysis: 47 (73.3%) received sorafenib after failure of some local treatment, whereas 18 (27.7%) received it as first-line treatment. Twenty-nine patients developed at least grade 1 skin toxicity (rash, 13; HFSR, 16). In patients who developed skin toxicity, the tumor control rate was 48.3%, versus 19.4% in patients without cutaneous side effects. The median TTP was 8.1 months in the group of patients with skin toxicity versus 4.0 months in those without skin toxicity. This difference was also statistically significant on multivariate analysis. A borderline statistically significant difference was also observed in terms of OS in patients with early skin toxicity.

Conclusions.

Skin toxicity should be closely monitored in HCC patients treated with sorafenib in relation to its potential role as a surrogate marker of efficacy.     

Long-term results of sorafenib in advanced-stage hepatocellular carcinoma: what can we learn from routine clinical practice?

Background and aims: Prospective randomized trials have proven that sorafenib is a valid treatment option for patients with advanced-stage hepatocellular carcinoma (HCC). The aim of the present study is to evaluate the effectiveness and safety of sorafenib in patients encountered in routine clinical practice. Methods: From September 2008 to March 2011, 42 cirrhotic patients (30 male; 12 female; mean age: 70.2 ± 7.6 years; range: 56-85 years) with HCC of Barcelona Clinic Liver Cancer stage B (n = 5) or C (n = 37; mean size: 66.6 ± 42.3 mm; mean number per patient: 3.3 ± 2.8) were treated with sorafenib at either a standard dose of 800 mg/day (n = 29; 69.1%) or at 400 mg/day with subsequent dose escalation (ramp-up strategy; n = 13, 30.9%). Baseline clinical parameters were comparable. Clinical data and side effects, laboratory analyses (in particular, serum α-fetoprotein) and radiological data (tumor response according to amended RECIST criteria) were assessed every 3 months. Survival was calculated by Kaplan-Meier analysis. Results: Mean follow-up was 12.2 ± 9 months (range: 1-32 months). Median overall survival was 26.1 months with overall 6- and 12-month survival rates of 92.1 and 85%, respectively. Median time to radiological progression was 8 months. The progression-free rate was 64.3%. Fatigue, skin disorders and diarrhea were the most frequent grade 3-4 side effects. Treatment discontinuation occurred in 25 patients. The starting dose for the last 13 enrolled patients was 400 mg/day; in the absence of toxicity this dosage was gradually increased to 800 mg/day after 3 weeks ('ramp-up strategy'). No grade 3/4 adverse events were observed in the ramp-up group. Conclusion: Sorafenib is a valid treatment option for advanced-stage HCC. Starting at a lower dosage may allow prolonged compliance to treatment and might be considered according to patient tolerance.     

经导管肝动脉化疗栓塞联合索拉非尼治疗中晚期肝细胞癌的临床观察

目的 观察经导管肝动脉化疗栓塞(TACE)联合索拉非尼治疗中晚期肝细胞癌的有效性和安全性.方法 40例已接受过TACE治疗的中晚期肝细胞癌患者口服索拉非尼单药治疗,400mg,2次/d,直至病情进展或出现不可耐受的毒性反应.按照实体瘤疗效评价标准(RECIST)评价疗效,按照美国国立癌症研究所常见毒性事件标准(NCI-CTCAE)评价不良反应.结果 40例中晚期肝细胞癌患者中,获得完全缓解1例,部分缓解7例,疾病稳定19例,疾病进展13例,疾病控制率为67.5%.全组患者的生存时间为1～18个月,1年生存率为54.0%.主要不良反应为手足皮肤反应,其次是腹泻和血小板计数降低.结论 TACE联合索拉非尼治疗中晚期肝细胞癌是有效和安全的.