How to assess the efficacy or failure of targeted therapy:deciding when to stop sorafenib in hepatocellular carcinoma

Sorafenib is thus far the only systemic treatment for hepatocellular carcinoma(HCC) based on the results of two randomized controlled trials performed in Western and in Eastern countries, despite a poor response rate(from 2% to 3.3%) following conventional evaluation criteria. It is now recognized that the criteria(European Association of the Study of the Liver criteria, modified response evaluation criteria in solid tumors) based on contrast enhanced techniques(computed tomography scan, magnetic resonance imaging) aimed to assess the evolution of the viable part of the tumor(hypervascularized on arterial phase) are of major interest to determine the efficacy of sorafenib and of most antiangiogenic drugs in patients with HCC. The role of alphafetoprotein serum levels remains unclear. In 2016, in accordance with the SHARP and the Asia-Pacific trials, sorafenib must be stopped when tolerance is poor despite dose adaptation or in cases of radiological and symptomatic progression. This approach will be different in cases of available second-line therapy trials. Some recent data(in renal cell carcinoma) revealed that despite progression in patients who received sorafenib, this drug can still decrease tumor progression compared to drug cessation. Then, before deciding to continue sorafenib post-progression or shift to another drug, knowing other parameters of post-progression survival(Child-Pugh class, Barcelona Clinic Liver Cancer, alphafetoprotein, post-progression patterns in particular, the development of extrahepatic metastases and of portal vein thrombosis) will be of major importance.     

Practical efficacy of sorafenib monotherapy for advanced hepatocellular carcinoma patients in a Hepatitis B virus-endemic area

Background  This study was conducted to assess the efficacy and safety of sorafenib monotherapy in clinical practice settings for Korean patients with hepatocellular carcinoma (HCC) related primarily to HBV infection. Methods  Medical records of 57 consecutive patients with unresectable or metastatic HCC treated with 400 mg bid sorafenib at the National Cancer Center, Korea between June 2007 and March 2008, were retrospectively reviewed. Results  The median patient age was 55 years (range, 28–76 years), and all patients had performance status 0–2 and Child–Pugh class A or B disease. HCC was etiologically related to HBV in 79.0% of patients. Eleven patients (19.3%) had modified UICC stage III tumors, 11 (19.3%) had stage IVa, and 35 (61.4%) had stage IVb. Following sorafenib monotherapy, 3 patients (5.3%) achieved a partial response and 18 (35.1%) achieved stable disease, with a disease control rate of 40.4%. The median times to progression (TTP) was 9.1 weeks (95% CI 3.4–14.8 weeks). Multivariate analyses showed that serum alpha-fetoprotein (α-FP) ≥400 ng/mL (HR, 2.810; P = 0.023) and the presence of massive intrahepatic tumors (HR, 7.633; P = 0.033) were independent predictors of shorter TTP. The most common grade 3/4 adverse events were hand-foot syndrome (8.8%), diarrhea (7.0%), and skin rash (7.0%). Exacerbation of underlying chronic hepatitis B was not found. Conclusion  Sorafenib monotherapy showed better outcomes with tolerable toxicity in Korean advanced HCC patients, who had intrahepatic nodular tumors and/or metastatic tumors, coupled with low levels of serum α-FP.     

Skin toxicity predicts efficacy to sorafenib in patients with advanced hepatocellular carcinoma

AIM:To study the relationship between adverse events(AEs),efficacy,and nursing intervention for sorafenibtherapy in patients with hepatocellular carcinoma(HCC).METHODS:We enrolled 37 consecutive patients withadvanced HCC who received sorafenib therapy.Relationships among baseline characteristics as well as AEoccurrence and tumor response,overall survival(OS),and treatment duration were analyzed.The nursingintervention program consisted of education regardingself-monitoring and AEs management,and telephoneRESULTS:A total of 37 patients were enrolled in the study,comprising 30 males(81%) with a median age of 71 years.The disease control rate at 3 mo was 41%,and the median OS and treatment duration were 259 and 108 d,respectively.Nursing intervention was given to 24 patients(65%).Every patient exhibited some kinds of AEs,but no patients experienced G4 AEs.Frequently observed AEs G2 included anorexia(57%),skin toxicity(57%),and fatigue(54%).Factors significantly associated with longer OS in multivariate analysis demonstrated that age ≤ 70 years,presence of G2 skin toxicity,and absence of G2 hypoalbuminemia.The disease control rate in patients with G2 skin toxicity was 13/20(65%),which was significantly higher compared with that in patients with no or G1 skin toxicity.Multivariate analysis revealed that nursing intervention and G2 skin toxicity were independent significant predictors for longer treatment duration.CONCLUSION:Skin toxicity was associated with favorable outcomes with sorafenib therapy for advanced HCC.Nursing intervention contributed to better adher-ence,which may improve the efficacy of sorafenib.     

Tolerance and outcomes of sorafenib in elderly patients treated for advanced hepatocellular carcinoma

IntroductionUse of sorafenib remains debated in elderly patients treated for advanced hepatocellular carcinoma (HCC).MethodsThis was a bicentric retrospective study including all patients ≥75 years and treated with sorafenib for advanced HCC between January 2010 and March 2014.ResultsOf the 51 patients included (median age: 78 years, range: 75–92; performance status (PS) 0–1: 98%; cirrhosis: 88.2%; Child–Pugh A: 95.6%) all experienced at least one adverse event (AE). About 2/3 of them (66.7%) had grade 3–4 toxicities, including fatigue (43.1%), hand foot skin syndrome (11.8%), anorexia (9.8%) or diarrhea (9.8%). After adjustment for arterial hypertension, heart failure, other(s) cardiovascular history(ies), and sorafenib dose at baseline, only patients ≥80 years were associated with severe AE (OR: 13.3; p = 0.009). Discontinuation for toxicity was reported in 31 (60.8%) patients, mainly within the 3rd months, especially in those who had PS ≥1 at baseline (OR: 10.4; p = 0.01), or other cardiovascular histories (OR: 30.9; p = 0.016). In this setting, overall survival was significantly reduced (HR: 4.5; p < 0.0001).ConclusionTolerance of Sorafenib seems to be low in elderly, especially for patients aged ≥80 years or with PS ≥1. Starting with reduced dose of sorafenib does not seem to impact results. Some of these patients may truly benefit from the treatment in terms of survival.     

Mechanisms of resistance to sorafenib and the corresponding strategies in hepatocellular carcinoma

Sorafenib, the unique drug as first-line treatment for advanced hepatocellular carcinoma (HCC), has opened a window of hope after searching for effective agents to combat HCC for decades. However, the overall outcomes are far from satisfactory. One of the explanations is the genetic heterogeneity of HCC, which has led to identifying predictive biomarkers for primary resistance to sorafenib, and then applying the concept of personalized medicine, or seeking therapeutic strategies such as combining sorafenib with other anticancer agents. Some of the combinations have demonstrated a better effectiveness than sorafenib alone, with good tolerance. The acquired resistance to sorafenib has also drawn attention. As a multikinase inhibitor, sorafenib targets several cellular signaling pathways but simultaneously or sequentially the addiction switches and compensatory pathways are activated. Several mechanisms are involved in the acquired resistance to sorafenib, such as crosstalks involving PI3K/Akt and JAK-STAT pathways, hypoxia-inducible pathways, epithelial-mesenchymal transition, etc . Based on the investigated mechanisms,some other molecular targeted drugs have been applied as second-line treatment for treat HCC after the failure of sorafenib therapy and more are under evaluation in clinical trials. However, the exact mechanisms accounting for sorafenib resistance remains unclear. Further investigation on the crosstalk and relationship of associated pathways will better our understanding of the mechanisms and help to find effective strategies for overcoming sorafenib resistance in HCC.     

Assessment of response to sorafenib in advanced hepatocellular carcinoma using perfusion computed tomography: Results of a pilot study

AimsThis prospective pilot study investigated the feasibility of perfusion computed tomography parameters as surrogate markers of angiogenesis and early response following sorafenib administration in patients with advanced hepatocellular carcinoma.MethodsTen patients were evaluated with perfusion computed tomography before starting sorafenib and after 3 months. Blood flow, blood volume, mean transit time, hepatic arterial fraction, and permeability surface-product were compared in tumour lesions and in hepatic parenchyma at baseline and at follow-up. Correlation between these parameters and changes in alpha-fetoprotein levels was calculated.ResultsAt baseline, blood volume, blood flow, hepatic arterial fraction and permeability surface values were higher in lesions compared to those in hepatic parenchyma, while mean transit time was lower (p < 0.05). After sorafenib treatment, only mean transit time was significantly increased versus baseline (p < 0.05). At follow-up, plasma alpha-fetoprotein levels decreased in all patients. At follow-up, an inverse correlation was observed between baseline mean transit time and changes in alpha-fetoprotein (r = ?0.6685, p = 0.0125), as well as a correlation between baseline blood flow and alpha-fetoprotein (r = 0.6476, p = 0.0167).ConclusionThis pilot study suggests that after sorafenib treatment an increase in mean transit time observed in tumour lesions is inversely correlated with alpha-fetoprotein reductions after therapy. Mean transit time may represent a possible marker of response irrespectively of alpha-fetoprotein values.     

Neoadjuvant sorafenib combined with gemcitabine plus oxaliplatin in advanced hepatocellular carcinoma

This paper reports the first case of a patient with hepatocellular carcinoma with lymph node metastasis treated by sorafenib combined with gemcitabine plus oxaliplatin,with a partial response and normalization of α fetoprotein,which allowed curative surgery.The potential synergy between these three drugs needs to be confirmed,and is currently being investigated in a randomized phase Ⅱ trial.     

Indicators of sorafenib efficacy in patients with advanced hepatocellular carcinoma

AIM: To determine significant indicators for the efficacy of sorafenib in patients with advanced hepatocellular carcinoma (HCC).METHODS: A total of 46 patients with Barcelona Clinic Liver Cancer stage C who received sorafenib for more than 30 d at the Iizuka Hospital from June 2009 to December 2012 were enrolled in this study. Multivariate and univariate analyses were performed to evaluate the associations of hepatic function according to Child-Pugh grade, location and size of the largest tumor and adverse events of sorafenib treatment, such as hand-foot syndrome (HFS), hypertension, diarrhea, and alopecia, with the efficacy of treatment, as measured by overall survival (OS) and time to progression (TTP).RESULTS: Patients included 39 men and 7 women whose ages ranged from 48 to 85 years (70.6 ± 9.6 years). HCC was classified according to etiology as follows: hepatitis C virus (n = 26), hepatitis B virus (n = 9), and other (n = 11). Liver function in patients was categorized as Child-Pugh grade A (n = 30) or B (n = 16). Tumors were categorized by size [< 5 cm (n = 33) or >5 cm (n = 13)] and the location of the largest tumor was used to categorize patients with intrahepatic (n = 28) or extrahepatic (n = 18) HCC. HFS, hypertension, diarrhea, and alopecia were present in 22 (47.8%), 19 (41.3%), 15 (32.6%) and 7 patients (15.2%), respectively. The median OS of all patients was 373 d and the median TTP was 112 d. The etiology of HCC did not correlate with the median OS and TPP. The median OS of patients with tumors < 5 cm was significantly longer than those with larger tumors (496 vs 245 d; HR = 0.19, 95%CI: 0.07-0.48; P < 0.01). According to the results of a multivariate analysis, the size of the largest tumor affected OS (HR = 0.22, 95%CI: 0.08-0.59; P < 0.01). The median TTP was significantly longer in patients with extrahepatic compared to intrahepatic major HCC (224 vs 98 d; HR = 0.32; 95%CI: 0.14-0.67; P < 0.01). The median TTP of patients with HFS was significantly longer than those without it (195 d vs 83 d; HR = 0.41, 95%CI: 0.20-0.82; P < 0.05), and the median TTP was significantly longer in patients with hypertension (195 d vs 84 d; HR = 0.43, 95%CI: 0.21-0.84; P < 0.05). According to the results of the multivariate analysis, extrahepatic major HCC (HR = 0.36, P < 0.01) and HFS (HR = 0.44, P < 0.05) prolonged TTP.CONCLUSION: Extrahepatic major HCC and HFS are associated with prolonged TTP and are useful indicators for judging the efficacy of sorafenib treatment.     

Complete remission of advanced hepatocellular carcinoma by radiofrequency ablation after sorafenib therapy

Sorafenib,a potent multikinase inhibitor,lead to a significant improvement in progression free survival and overall survival in patients with advanced hepatocellular carcinoma(HCC).Though sorafenib has proven its efficacy in advanced stage HCC,there are limitedreports on the role of sorafenib allowing for curative treatment by down-staging.We herein report a case of advanced HCC with vascular invasion,which showed treatment response by sorafenib therapy as to allow for radiofrequency ablation as curative treatment.The patient was followed-up for 6 mo without recurrence with continued sorafenib therapy.     

Chemotherapy for advanced hepatocellular carcinoma in the sorafenib age

The kinase inhibitor sorafenib is the only systemic therapy proven to have a positive effect on survival of patients with advanced hepatocellular carcinoma(HCC).After development of sorafenib and its introduction as a therapeutic agent used in the clinic,several critical questions have been raised.Clinical parameters and biomarkers predicting sorafenib efficacy are the most important issues that need to be elucidated.Although it is difficult to know the responders in advance using conventional characteristics of patients,there are specific serum cytokines and/or gene amplification in tumor tissues that have been reported to predict efficacy of sorafenib.Risk and benefits of continuation of sorafenib beyond radiological progression is another issue to consider because no other standard therapy for advanced HCC as yet exists.In addition,effectiveness of the expanded application of sorafenib is still controversial,although a few studies have shed some light on combinational treatment with sorafenib for intermediate-stage HCC.Recently,over 50 relevant drugs have been developed and are currently under investigation.The efficacy of some of these drugs has been extensively examined,but none have demonstrated any superiority over sorafenib,so far.However,there are several drugs that have shown efficacy for treatment after sorafenib failure,and these are proceeding to further studies.To address these issues and questions,we have done extensive literature review and summarize the most current status of therapeutic application of sorafenib.     

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.     

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。     

Complete response to sorafenib in a patient with recurrent hepatocellular carcinoma

Partial hepatectomy is still the treatment of choice aiming at a cure for patients with hepatocellular carcinoma (HCC), provided that the patient can tolerate the treatment. For patients with multiple recurrent HCC after partial hepatectomy which cannot be treated by re-hepatectomy or local ablative therapy, the prognosis is extremely poor. Sorafenib is a molecular-targeted agent which has been demonstrated in two global phase III randomized controlled trials to show survival benefit for advanced HCC. Here, we present a 56-year-old patient with HCC who showed complete clinical response after sorafenib was used for tumor recurrence which developed 3 mo after partial hepatectomy. There was no evidence of progression of disease for 60 mo till now after continuous treatment with sorafenib.     

根治性肝切除联合索拉非尼治疗肝细胞癌的研究进展

根治性肝切除仍然是肝细胞癌(hepatocellularcarcinoma,HCC)的主要治疗手段,但术后转移复发导致肝切除的疗效进入瓶颈期.探索术后复发的治疗措施是有效延长患者生存时间的重要课题.目前,以经皮肝动脉化疗栓塞为代表的多种治疗措施已在临床广泛开展,但尚缺乏大规模、多中心随机对照临床试验的循证医学证据.分子靶向药物索拉非尼的出现为改善HCC预后开辟了新局面,对于已接受过根治性肝切除治疗的HCC患者,索拉非尼可能是一种有效的辅助治疗方法,值得深入探索.     

Adjuvant sorafenib in hepatocellular carcinoma: A cautionary comment of STORM trial

Recurrence rate of hepatocellular carcinoma (HCC) is very high even after curative surgery, and no postoperative therapies have been definitively shown to prevent HCC recurrence. Sorafenib is proved to be effective for advanced HCC by two large randomized controlled trials in 2008 and 2009. Therefore it stands to reason to expect that adjuvant sorafenib may improve post-surgery outcomes of patients with HCC. However, many questions still exist about the value of sorafenib for patients with HCC after surgery or transarterial chemoembolization. In this editorial, we complehensively reviewed the safety and efficacy of adjuvant sorafenib for patients with hepatocellar carcinoma after surgery or transarterial chemoembolization. We emphasized the positive and negative role of sorafenib.     

Sustained treatment response of metastatic hepatocellular carcinoma with bevacizumab and sorafenib

The overall survival for patients with advanced hepatocellular carcinoma(HCC)is still limited.Although the multi-kinase inhibitor sorafenib has recently been approved for this disease,response rates are still low and patients often face dose-limiting toxicities which lead to a reduction in prognosis and treatment success.We here report a patient with metastasized HCC who shows a sustained response for more than 30 mo to sorafenib therapy after failure of a first line therapy with gemcitabine,oxaliplatin and...     

Assessment of clinical and radiological response to sorafenib in hepatocellular carcinoma patients

Sorafenib is an effective anti-angiogenic treatment forhepatocellular carcinoma(HCC). The assessment of tumor progression in patients treated with sorafenib is crucial to help identify potentially-resistant patients,avoiding unnecessary toxicities. Traditional methods to assess tumor progression are based on variations in tumor size and provide unreliable results in patients treated with sorafenib. New methods to assess tumor progression such as the modified Response Evaluation Criteria in Solid Tumors or European Association for the Study of Liver criteria are based on imaging to measure the vascularization and tumor volume(viable or necrotic). These however fail especially when the tumor response results in irregular development of necrotic tissue. Newer assessment techniques focus on the evaluation of tumor volume,density or perfusion. Perfusion computed tomography and Dynamic ContrastEnhanced-UltraS ound can measure the vascularization of HCC lesions and help predict tumor response to antiangiogenic therapies. Mean Transit Time is a possible predictive biomarker to measure tumor response. Volumetric techniques are reliable,reproducible and time-efficient and can help measure minimal changes in viable tumor or necrotic tissue,allowing the prompt identification of non-responders. Volume ratio may be a reproducible biomarker for tumor response. Larger trials are needed to confirm the use of these techniques in the prediction of response to sorafenib.     

Hepatic arterial infusion of oxaliplatin plus fluorouracil/leucovorin vs. sorafenib for advanced hepatocellular carcinoma

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