分子靶向药物在肝细胞癌治疗中的临床研究进展

肝癌是全球第六大常见的恶性肿瘤,也是第四大肿瘤相关死亡原因,其中肝细胞癌（hepatocellular carcinoma,HCC）占90%,且80%以上的HCC发生在肝炎和肝硬化等患者中。对于HCC的治疗方面,仅20%的HCC患者可进行手术切除、肝脏移植或射频消融治疗,而晚期HCC患者无法进行根治性治疗,其生存率也逐渐下降。近年来,分子靶向药物治疗已成为研究热点,该类药物可通过特异性的与致癌位点靶向结合而发挥抗癌作用。目前,抗HCC的靶向药物主要分为一线药物与二线药物,其中一线药物主要包括索拉非尼、仑伐替尼,二线药物主要包括瑞戈非尼、卡博替尼及雷莫芦单抗等。本文对此类分子靶向药物在HCC治疗中的临床研究进展进行综述。      

肝癌患者口服甲磺酸仑伐替尼不良反应护理

本个案针对中国医学科学院北京协和医学院肿瘤医院深圳医院2020年2月14日收治的1例肝癌口服靶向药(甲磺酸仑伐替尼)引起肛周瘙痒和多处皮损的病例进行分析.患者带肛周皮损入院,与压疮区别后,判断为肝癌患者口服甲磺酸仑伐替尼所致药物不良反应,对症给予治疗与护理.伤口明显好转后,患者出院.此案为新发现的甲磺酸仑伐替尼说明书上...     

厄洛替尼治疗失败后埃克替尼靶向治疗晚期非小细胞肺癌1例报道

厄洛替尼和埃克替尼是一种选择性表皮生长因子受体（epidermal growth factor receptor,EGFR）——酪氨酸激酶抑制剂（tyrosine kinase inhibitor,TKI）,在进展期非小细胞肺癌（NSCLC）中具有靶向治疗作用。靶向药物治疗一般作为二线或三线用药,其治疗失败后很少有行之有效的治疗策略。本文报道1例晚期NSCLC厄洛替尼治疗失败后采用埃克替尼靶向治疗有效的病例。     

晚期肝癌一线治疗的研究进展

肝癌起病隐匿,进展迅速,大多数患者就诊时已失去根治性治疗机会,亟需系统药物治疗。近年来,靶向治疗和免疫治疗迅速发展,使晚期肝癌的一线治疗有了更多的选择。靶向治疗药物包括索拉非尼、仑伐替尼、多纳非尼等,而免疫治疗包括免疫单药治疗和免疫联合治疗。以免疫检查点抑制剂为核心的治疗策略为肝癌患者带来了新的希望,特别是免疫检查点抑制剂联合抗血管生成药物一线治疗肝癌的成功,开启了肝癌的免疫联合治疗模式。在过去20年,晚期肝癌的全身治疗格局发生了重大变化,随着系统治疗方案的增加,合理的治疗顺序及一线治疗的选择对改善患者的预后至关重要。本文就晚期肝癌一线治疗的临床研究进展进行综述。     

仑伐替尼联合局部疗法治疗PD-L1基因阳性门脉癌栓程氏分型Ⅰ~Ⅲ型肝癌疗效观察

目的 比较仑伐替尼联合局部疗法与局部疗法治疗PD-L1基因阳性门脉癌栓程氏分型Ⅰ~Ⅲ型肝癌患者的临床疗效。方法 仑伐替尼联合局部疗法组患者口服仑伐替尼12 mg每天一次（体重≥60 kg）或8 mg每天一次（体重<60 kg）。局部治疗组患者仅行局部治疗。回顾性分析两组患者临床资料和预后。结果 联合组和局部治疗组CR+PR分别为78.1%和53.6%。联合组有效率和疾病控制率均高于局部疗法组（P<0.05）;生存分析结果提示：联合组患者的总生存率高于局部疗法组,差异有统计学意义（P<0.05）。结论 仑伐替尼联合局部疗法治疗PD-L1基因阳性门脉癌栓程氏分型Ⅰ~Ⅲ型肝癌疗效较好,患者总生存率较局部疗法高。     

免疫检查点抑制剂治疗晚期肝癌的研究进展

肝细胞癌(hepatocellular carcinoma,HCC)是中国发病率和死亡率较高的恶性肿瘤之一,大多数患者确诊时已进入晚期.酪氨酸激酶抑制剂索拉非尼和仑伐替尼是中晚期HCC的一线治疗药物,但疗效十分有限.近年来,针对程序性死亡受体-1(programmed cell death protein-1,PD-1...     

中晚期肝细胞癌介入及系统治疗的现状与研究进展

肝细胞癌(HCC)是我国发病率及死亡率位居前列的常见恶性肿瘤, 大部分患者就诊时已处于中晚期。介入治疗是HCC局部治疗的最主要手段, CalliSpheres载药微球作为一种新型介入材料, 比传统经导管肝动脉化疗栓塞术的碘油具有明显优势, 肝动脉灌注化疗对肿瘤有更高的缓解率及转化成功率;目前一系列靶向药物如仑伐替尼、多纳非尼、阿帕替尼, 相继获批用于晚期HCC的治疗;免疫检查点抑制剂在晚期HCC治疗中取得了突破性进展, 各种新药不断涌现, 各种治疗药物组合的临床研究也不断进步。探讨近期介入、靶向及免疫治疗在中晚期HCC治疗的最新应用及临床研究进展, 以期为HCC治疗提供决策参考。     

阿伐曲泊帕治疗仑伐替尼相关重型再生障碍性贫血一例并文献复习

目的:探讨阿伐曲泊帕对仑伐替尼相关重型再生障碍性贫血（SAA）的疗效及安全性。方法:回顾性分析南京医科大学第一附属医院收治的1例仑伐替尼相关SAA患者的临床资料。总结治疗过程，分析阿伐曲泊帕治疗结果，并进行文献复习。结果:该例SAA患者肝癌骨转移后使用仑伐替尼和短程局部放疗后出现骨髓衰竭，确诊SAA。应用他克莫司、西罗莫司后血象无改善。接受阿伐曲泊帕40 mg/d治疗4周后，三系造血恢复，脱离输血。结论:阿伐曲泊帕成功治疗1例仑伐替尼相关SAA，耐受性良好，值得临床继续积累相关病例。     

仑伐替尼治疗恶性实体瘤的研究进展

仑伐替尼（lenvatinib）是日本卫材（Eisai）公司研发并生产的一种多靶点酪氨酸激酶抑制剂（tyrosine kinase inhibitor,TKI）,可抑制多条影响血管生成和细胞增殖的重要通路,包括血管内皮生长因子受体（vascular endothelial growth factor receptor,VEGFR）1~3、成纤维细胞生长因子受体（fibroblast growth factor receptor,FGFR）1~4、血小板衍生生长因子受体α 及原癌基因RET和KIT。这些信号通路已在之前的研究中被证实与多种恶性肿瘤的发生发展及不良预后相关,仑伐替尼可以通过阻断以上通路发挥抑制肿瘤生长的作用。在目前临床所使用的已知的激酶抑制剂中,仑伐替尼是唯一同时对VEGFR和FGFR有抑制作用的TKI类药物。在一系列临床试验中,仑伐替尼对多种实体瘤的单药治疗效果也得到了进一步的临床证实,与其他药物联合治疗的临床试验也在不断开展。本文论述近年来仑伐替尼在甲状腺癌、肝细胞癌、肾细胞癌、子宫内膜癌、非小细胞肺癌以及恶性黑色素瘤等实体瘤治疗中的研究进展。     

盘点2009年晚期肾癌治疗新进展

自2005年美国FDA批准索拉非尼用于晚期肾细胞癌的治疗以来,晚期肾癌的治疗疗效发生了划时代的巨变,揭开了晚期肾癌靶向治疗的序幕。近年来,治疗肾癌的靶向药物层出不穷,在过去的1年里,不仅原有的4个靶向药物（索拉非尼、索坦、贝伐单抗、替西罗莫司）临床研究继续得到关注,而且又有2个新的靶向药物得到批准。     

Clinical outcomes and influencing factors of PD-1/PD-L1 in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) has an increasing incidence worldwide, and the global 5-year survival rate ranges from 5–30%. In China, HCC seriously threatens the nation''s health; the incidence of HCC ranks fourth among all theriomas, and the mortality rate is the third highest worldwide. The main therapies for HCC are surgical treatment or liver transplantation; however, most patients with HCC will experience postoperative recurrence or metastasis, eventually resulting in mortality. As for advanced or unresectable HCC, the current appropriate treatment strategy is transarterial chemoembolization; however, limited therapeutic effect and natural or acquired drug resistance affect the efficacy of this approach. Previous studies have demonstrated that PD-L1 expression on host cells and myeloid cells plays an important role in PD-L1 blocked-mediated tumor regression. Thus, further research on programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) is required. Countries including the United States, France, Britain and China have developed PD-1/PD-L1 blockers, including nivolumab, pembrolizumab, cemiplimab, atezolizumab, avelumab, durvalumab, toripalimab, sintilimab and camrelizumab. Notably, all of these blockers have therapeutic effect and influencing factors in HCC. Factors that influence the clinical outcome of PD-1 have also been discovered, such as inflammatory genes, specific receptors and signaling pathways. The discovery of these factors will help to identify novel methods, such as combination treatment, to decrease the influence of other factors on the efficacy of PD-1/PD-L1. Sorafenib and lenvatinib have been approved for first-line treatment for patients with advanced HCC. When first-line treatment frequently fails, pembrolizumab and ipilimumab plus nivolumab are used following sorafenib (but not lenvatinib) treatment in advanced HCC. Thus, tumor immunotherapy using PD-1/PD-L1 blockers exhibits promising outcomes for the treatment of HCC, and more novel PD-1/PD-L1 inhibitors are being developed to fight against this disease. The present review discusses the clinical results and influencing factors of PD-1/PD-L1 inhibitors in HCC to provide insight into the development and optimization of PD-1/PD-L1 inhibitors in the treatment of HCC.     

Prospect of lenvatinib for unresectable hepatocellular carcinoma in the new era of systemic chemotherapy

The phase III clinical trial of the novel molecular targeted agent (MTA) lenvatinib for patients with advanced hepatocellular carcinoma (HCC) (REFLECT trial) found that lenvatinib was non-inferior to sorafenib in overall survival. Recently, the efficacy of multiple MTAs, including lenvatinib, in practice has been reported, and therapeutic strategies for Barcelona Clinic Liver Cancer (BCLC) intermediate stage HCC are undergoing major changes. Based on these results, lenvatinib could be recommended for patients with transcatheter arterial chemoembolization (TACE)-refractory, ALBI grade 1, within the up-to-seven criteria in the BCLC intermediate stage. Lenvatinib provides a more favorable outcome than TACE, even in cases with large or multinodular HCC beyond the up-to-seven criteria with Child-Pugh grade A. When patients meet the definitions of TACE-refractory or TACE-unsuitable, switching to systemic chemotherapy, including lenvatinib, is for favorable for preserving liver function. If initial treatment, including MTA, has a significant therapeutic effect and downstaging of HCC is obtained, additional TACE or surgical resection should be considered. Lenvatinib also has a therapeutic effect for poorly differentiated type and non-simple nodular type HCC thanks to the survival-prolonging effect of this drug. Furthermore, a significant therapeutic effect is expected in tumors with more than 50% liver involvement or main portal vein invasion, which have traditionally been considered to have a poor prognosis in patients. This suggests that at the start of lenvatinib treatment, HCC patients with ALBI grade 1 may be able to maintain liver functional reserve.     

Comparison of the safety and prognosis of sequential regorafenib after sorafenib and lenvatinib treatment failure in patients with unresectable hepatocellular carcinoma: a retrospective cohort study

BackgroundThere is lack of studies on sequential regorafenib after sorafenib and lenvatinib treatment failure in patients with unresectable hepatocellular carcinoma (HCC). This study was to explore the safety and prognosis of sequential regorafenib after sorafenib and lenvatinib failure in HCC patients.MethodsThis study was a retrospective, real-world study that included 50 HCC patients who received sequential regrafinib after sorafenib and lenvatinib failure. The safety and prognosis of two groups were compared.ResultsThe incidence of all grade and III/IV adverse events were 68% and 24%. According to Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 and modified (m) RECIST standards, the objective response rates (ORRs) after receiving regorafenib were 14.0% and 22.0%, respectively. The disease control rates (DCRs) were 62.0% and 60.0%, respectively. Based on different first-line targeted drugs, 50 patients were divided into sorafenib (n=22) and lenvatinib group (n=28). There was no differences between two groups except age and bilirubin. And there was no differences in other treatments before or after regorafenib. The baseline between two groups was basically same and had good comparability. There was no difference in incidence of all grade and III/IV adverse events, ORR and DCR between two groups (P>0.05). On long-term prognosis, total overall survival (TOS) in sorafenib and lenvatinib group were 23.0 (95% CI: 15.1–30.9) vs. 29.7 (95% CI: 21.4–38.1) months. The difference was statistically significant (P=0.041). Besides, regorafenib overall survival (ROS) in sorafenib and lenvatinib group were 11.7 (95% CI: 7.1–16.3) vs. 15.9 (95% CI: 8.3–23.5) months. The difference was statistically significant ( P=0.045). The regorafenib progression-free survival (RPFS) was 5.6 (95% CI: 1.9–9.2) vs. 8.0 (95% CI: 5.1–10.9) months in sorafenib and lenvatinib group, respectively, and difference was not statistically significant (P=0.380).ConclusionsRegorafenib is an effective drug for second-line treatment of HCC, with fewer severe adverse events, ORR and DCR was 14–22% and 62–60%, respectively. Both TOS and ROS in lenvatinib group were better than those in sorafenib group. For HCC patients whose first-line targeted drug is lenvatinib, it is safe and effective to accept regorafenib after disease progresses.     

Systemic Treatment of Patients with Advanced,Unresectable Hepatocellular Carcinoma: Emergence of Therapies

To date, sorafenib, a multiple tyrosine kinase inhibitor, is the only systemic agent approved by the FDA in the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC). Several other tyrosine kinase-inhibiting agents have been investigated in the first-line setting, either alone (sunitinib, brivanib, linifanib, and lenvatinib) or in combination with sorafenib (erlotinib and doxorubicin) in phase 3 trials. However, none of these studies demonstrated an improvement in survival over sorafenib. Many agents have also been tested in patients with HCC whose disease has progressed on sorafenib, but regorafenib is the only one to have demonstrated efficacy in this setting in a randomized, phase 3 trial. There were no clear survival benefits shown with everolimus, brivanib, or ramucirumab as second-line therapy. Nivolumab has also shown promising efficacy in patients with HCC who progressed on sorafenib, which was recently granted approval by the FDA, although larger confirmative trials may be considered. The treatment landscape for patients with advanced unresectable hepatocellular tumors has remained fairly static for the past 10 years, with multiple failed trials yield little change in the way these patients might be treated. However, recent findings for regorafenib, lenvatinib, and nivolumab have led to the most significant changes in the treatment paradigm in years.     

Current status of first-line therapy,anti-angiogenic therapy and its combinations of other agents for unresectable hepatocellular carcinoma

Globally, hepatocellular carcinoma (HCC) is a frequently diagnosed malignancy with rapidly increasing incidence and mortality rates. Unfortunately, many of these patients are diagnosed in the advanced stages when locoregional treatments are not appropriate. Before 2008, no effective drug treatments existed to prolong survival, until the breakthrough multi-tyrosine kinase inhibitor (TKI) sorafenib was developed. It remained the standard treatment option for advanced HCC for 10 years, with a battery of other candidate drugs in clinical trials failing to produce similar efficacy results. In 2018, the REFLECT trial introduced another multi-TKI, lenvatinib, which has non-inferior overall survival compared with sorafenib. Thus, offering patients and their treating physicians two effective treatment options. Recently, immunotherapy-based drugs, such as atezolizumab and bevacizumab, have shown promising results in patients with unresectable HCC. This review summarizes clinical trial and real-world data studies of sorafenib and lenvatinib in patients with unresectable HCC. We offer guidance on the optimal choice between the two treatments and discuss the potential of immunotherapy-based combination; when more data become available, this will likely make the choice between sorafenib and lenvatinib somewhat obsolete.     

索拉非尼治疗肝细胞癌的现状

在我国肝细胞癌有较高的发病率、术后复发率和病死率。肝细胞癌对放化疗不敏感,尤其是进展期肝细胞癌尚缺乏有效的治疗手段。索拉非尼是第一个用于肝细胞癌临床治疗的分子靶向药物,是肝细胞癌药物治疗的里程碑。然而,在临床应用中存在耐药现象。因此,探究索拉非尼的耐药机制、寻找耐药的分子标记物有重要意义。本文对索拉非尼治疗肝细胞癌的现状进行综述。     

含奥沙利铂化疗方案治疗晚期原发性肝细胞癌的研究进展

索拉非尼是目前唯一被多国批准的治疗晚期原发性肝细胞癌（HCC）的分子靶向药物,但其对生存期改善有限,最终出现病情进展。近几年,含奥沙利铂的化疗方案显示出良好的临床疗效,且患者耐受性可,为晚期 HCC 患者提供了新的治疗选择。     

Traitement systémique du carcinome hépatocellulaire

Systemic cytotoxic treatments provide marginal benefit in unresectable or metastatic HCC. With the arrival of molecularly targeted agents, there has been renewed interest in developing novel systemic treatments for HCC. For the first time, results of a phase III randomized, placebo-controlled trial were recently presented in which sorafenib demonstrated improved survival in patients with advanced HCC. Therefore, sorafenib is now the new standard for the first-line treatment of advanced HCC. The identification of predictive factors and the search for new molecules remain major challenges for this poor prognostic disease.     

Targeting the eicosanoid pathway in hepatocellular carcinoma

Liver cancer has variable incidence worldwide and high mortality. Histologically, the most common subtype of liver cancer is hepatocellular carcinoma (HCC). Approximately 30-40% of HCC patients are diagnosed at an advanced stage, and at present, there are limited treatment options for such patients. The current first-line therapy with tyrosine kinase inhibitors, sorafenib or lenvatinib, prolongs survival by a median of about 2.5-3 months after which the disease normally progresses. Additionally, many patients discontinue the use of tyrosine kinase inhibitors due to toxicity or may not be suitable candidates due to co-morbidity or frailty. It is, therefore, imperative to identify novel therapeutic targets for advanced HCC patients. Persistent injury to the liver as a result of insults such as hepatitis B or C viral (HBV or HCV) infections, alcohol abuse, and non-alcoholic fatty liver disease (NAFLD), results in chronic inflammation, which progresses to hepatic fibrosis and later, cirrhosis, provides the conditions for initiation of HCC. One of the key pathways studied for its role in inflammation and carcinogenesis is the eicosanoid pathway. In this review, we briefly outline the eicosanoid pathway, describe the mechanisms by which some pathway members either facilitate or counter the development of liver diseases, with the focus on NAFLD/hepatic fibrosis/cirrhosis, and HCC. We describe the link between the eicosanoid pathway, inflammation and these liver diseases, and identify components of the eicosanoid pathway that may be used as potential therapeutic targets in HCC.