肠道菌群与肝癌免疫治疗的研究进展

肠道菌群对人类的健康发挥了重要作用.研究发现,肠道菌群在肿瘤的发生和肿瘤免疫治疗中也起着关键作用.目前,免疫治疗在肝癌治疗领域取得了重要进展.尽管免疫治疗可以提高肝癌患者的生存,但是目前其疗效仍不够满意.调节肠道菌群组成,特别是使有助于免疫治疗效果的菌群在肠道富集,可能会使得肝癌免疫治疗的效果得到提高.本文就肠道菌群与肝癌免疫治疗的相关研究进展进行综述.     

Optimizing radiotherapy with immune checkpoint blockade in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the fifth most common cancer, and its incidence is rapidly increasing in North America and Western Europe as well as South-East Asia. Patients with advanced stage HCC have very poor outcomes;therefore, the discovery of new innovative approaches is urgently needed. Cancer immunotherapy has become a game-changer and revolutionized cancer treatment. A comprehensive understanding of tumor-immune interactions led to the development of immune checkpoint inhibitors (ICIs) as new therapeutic tools, which have been used with great success. Targeting immune checkpoint molecules such as programmed cell death-1 (PD-1) and cytotoxic T lymphocyteassociated protein-4 (CTLA-4) reinvigorates anti-tumor immunity by restoring exhausted T cells. Despite their effectiveness in several types of cancer, of the many immune suppressive mechanisms limit the efficacy of ICI monotherapy. Radiation therapy (RT) is an essential local treatment modality for a broad range of malignancies, and it is currently gaining extensive attention as a promising combination partner with ICIs because of its ability to trigger immunogenic cell death. The efficacy of combination approaches using RT and ICIs has been well documented in numerous preclinical and clinical studies on various types of cancers but not HCC. The application of ICIs has now expanded to HCC, and RT is recognized as a promising modality in HCC. This review will highlight the current roles of PD-1 and CTLA-4 therapies and their combination with RT in the treatment of cancers, including HCC. In addition, this review will discuss the future perspectives of the combination of ICIs and RT in HCC treatment.     

Systemic treatment for unresectable hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is most commonly found in the context of liver cirrhosis and,in rare cases,in a healthy liver.Its prevalence has risen in recent years,particularly in Western nations,due to the increasing frequency of nonalcoholic fatty liver disease.Advanced HCC has a poor prognosis.For many years,the only proven therapy for unresectable HCC (uHCC) was sorafenib,a tyrosine kinase inhibitor.Recently,the synergistic effect of an immune checkpoint inhibitor,atezolizumab,and bevacizu...     

Targeted and immune therapies for hepatocellular carcinoma:Predictions for 2019 and beyond

Systemic therapy for hepatocellular carcinoma(HCC) has markedly advanced since the survival benefit of a molecular targeted agent, sorafenib, were demonstrated in the SHARP and Asia Pacific trials in 2007. Treatment options for patients with advanced HCC increased by sorafenib, and long-term survival for patients with advanced stage HCC has become possible to some extent. However,development of a more potent first-line novel molecular targeted agent replacing sorafenib and a potent second-line agent after disease progression on or intolerant to sorafenib has been warranted because sorafenib lacks tumor shrinking/necrotizing effects and induces relatively severe adverse events such as hand foot skin reaction. Many agents in the 1 st line and 2 nd line setting were attempted to develop between 2007 and 2016, but all of these clinical trials failed.On the other hand, clinical trials of 4 agents(regorafenib, lenvatinib,cabozantinib, and ramucirumab) succeeded in succession in 2017 and 2018, and their use in clinical practice is possible(regorafenib and lenvatinib) or underway(cabozantinib and ramucirumab). Furthermore, all of 5 clinical trials of combination therapy with transcatheter chemoembolization(TACE) plus a molecular targeted agent failed to date, however, the combination of TACE and sorafenib(TACTICS trials) was reported to be successful and presented at ASCO in 2018. Phase 3 clinical trials of immune checkpoint inhibitors and a combination therapy of immune checkpoint inhibitors and molecular targeted agents are also ongoing, which suggests treatment paradigm of HCC in all stages from early,intermediate and advanced stage, is expected to be changed drastically in the very near future.     

Evolution of systemic therapy of advanced hepatocellular carcinoma

Hepatocellular carcinoma （HCC） commonly occurs in hepatitis B endemic areas, especially in Asian countries. HCC is highly refractory to cytotoxic chemotherapy. This resistance is partly related to its tumor biology, pharmacokinetic properties, and both intrinsic and acquired drug resistance. There is no convincing evidence thus far that systemic chemotherapy improves overall survival in advanced HCC patients. Other systemic approaches, such as hormonal therapy and immunotherapy, have also disappointing results. Recently, encouraging results have been shown in using sorafenib in the treatment of advanced HCC patients. In this review, we concisely summarize the evolution of developments in the systemic therapy of advanced 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.     

Current systemic treatment of hepatocellular carcinoma: A review of the literature

Hepatocellular carcinoma (HCC) is the fifth most common form of human cancer worldwide and the third most common cause of cancer-related deaths. The strategies of various treatments for HCC depend on the stage of tumor, the status of patient’s performance and the reserved hepatic function. The Barcelona Clinic Liver Cancer (BCLC) staging system is currently used most for patients with HCC. For example, for patients with BCLC stage 0 (very early stage) and stage A (early stage) HCC, the curable treatment modalities, including resection, transplantation and radiofrequency ablation, are taken into consideration. If the patients are in BCLC stage B (intermediate stage) and stage C (advanced stage) HCC, they may need the palliative transarterial chemoembolization and even the target medication of sorafenib. In addition, symptomatic treatment is always recommended for patients with BCLC stage D (end stage) HCC. In this review, we will attempt to summarize the historical perspective and the current developments of systemic therapies in BCLC stage B and C in HCC.     

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。     

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.     

Potentiality of immunotherapy against hepatocellular carcinoma

Hepatocellular carcinoma(HCC),the predominant form of primary liver cancer,is the fifth most common cancer worldwide and the second leading cause of cancer-related death. Despite the high incidence,treatment options remain limited for advanced HCC,and as a result prognosis continues to be poor. Current therapeutic options,surgery,chemotherapy and radiotherapy,have only modest efficacy. New treatment modalities to prolong survival and to minimize the risk of adverse response are desperately needed for patients with advanced HCC. Tumor immunotherapy is a promising,novel treatment strategy that may lead to improvements in both treatment-associated toxicity and outcome. The strategies have developed in part through genomic studies that have yielded candidate target molecules and in part through basic biology studies that have defined the pathways and cell types regulating immune response. Here,we summarize the various types of HCC immunotherapy and argue that the newfound field of HCC immunotherapy might provide critical advantages in the effort to improve prognosis of patients with advanced HCC. Already several immunotherapies,such as tumor-associated antigen therapy,immune checkpoint inhibitors and cell transfer immunotherapy,have demonstrated safety and feasibility in HCC patients. Unfortunately,immunotherapy currently has low efficacy in advanced stage HCC patients; overcoming this chal lenge will place immunotherapy at the forefront of HCC treatment,possibly in the near future.     

Immunotherapy for hepatocellular carcinoma: Current status and future perspectives

Hepatocellular carcinoma(HCC) is one of the world’s deadliest and fastestgrowing tumors, with a poor prognosis. HCC develops in the context of chronic liver disease. Curative resection, surgery(liver transplantation), trans-arterial chemoembolization, radioembolization, radiofrequency ablation and chemotherapy are common treatment options for HCC, however, they will only assist a limited percentage of patients. Current treatments for advanced HCC are ineffective and aggravate the underlying live...     

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.     

Targets of immunotherapy for hepatocellular carcinoma: An update

Hepatocellular carcinoma, the most common primary liver cancer, in an immunogenic tumor with a poor prognosis because these tumors are diagnosed at late stages. Although, surgical resection, ablation, liver transplant, and locoregional therapies are available for early stages; however, there are yet no effective treatment for advanced and recurrent tumors. Immune checkpoint inhibitor therapy and adoptive cell transfer therapy has gained the popularity with some positive results because these therapies overcome anergy and systemic immune suppression. However, still there is a lack of an effective treatment and thus there is an unmet need of a novel treatment. At present, the focus of the research is on oncolytic viral therapy and combination therapy where therapies including radiotherapy, immune checkpoint therapy, adoptive cell transfer therapy, and vaccines are combined to get an additive or synergistic effect enhancing the immune response of the liver with a cytotoxic effect on tumor cells. This review discusses the recent key development, the basis of drug resistance, immune evasion, immune tolerance, the available therapies based on stage of the tumor, and the ongoing clinical trials on immune checkpoint inhibitor therapy, adoptive cell transfer therapy, oncolytic viral vaccine therapy, and combination therapy.     

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.     

Sorafenib induced tumor lysis syndrome in an advanced hepatocellular carcinoma patient

A 55-year-old male patient with hepatitis B-related liver cirrhosis was found to have advanced hepatocellular carcinoma. His AFP was initially 9828 μg/L and rapidly dropped to 5597 μg/L in ten days after oral sorafenib treatment. However, he developed acute renal failure, hyperkalemia, and hyperuricemia 30 d after receiving the sorafenib treatment. Tumor lysis syndrome was suspected and intensive hemodialysis was performed. Despite intensive hemodialysis and other supportive therapy, he developed multiple organ failure （liver, renal, and respiratory failure） and metabolic acidosis. The patient expired 13 d after admission.     

Second line systemic therapies for hepatocellular carcinoma: Reasons for the failure

Hepatocellular carcinoma(HCC) is the main cause of death in patients with cirrhosis, with an increasing incidence worldwide. Sorafenib is the choice therapy for advanced HCC. Over time several randomized phase Ⅲ trials have been performed testing sunitinib, brivanib, linifanib and other molecules in head-tohead comparison with Sorafenib as first-line treatment for advanced-stage HCC, but none of these has so far been registered in this setting. Moreover, another feared vacuum arises from the absence of molecules registered as second-line therapy for patients who have failed Sorafenib, representing an urgent unmet medical need. To date all molecules tested as second-line therapies for advanced hepatocellular carcinoma, failed to demonstrate an increased survival compared to placebo. What are the possible reasons for the failure? What we should expect in the near future?     

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...     

Hepatic artery infusion chemotherapy for advanced hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is one of the most common cancers worldwide. Surgery, percutaneous ablation and liver transplantation are the only curative treatment modalities for HCC. However, the majority of patients have unresectable disease at diagnosis. Therefore, effective treatment options for patients with advanced HCC are required. In advanced HCC, according to current international guidelines, sorafenib, a molecular targeted agent, is the standard treatment. However, alternative treatment modalities are required because of the low response rates and unsuitability of molecular agents in real practice. In various treatment modalities, mostly in Asia, hepatic arterial infusion chemotherapy(HAIC) has been applied to advanced HCC with a view to increasing the therapeutic efficacy. HAIC provides direct drug delivery into the tumor feeding vessels and also minimizes systemic toxicities through a greater first-pass effect in the liver. However, the sample sizes of studies on HAIC have been small and large randomized trials are still lacking. In this article, we describe the treatment efficacy of HAIC for advanced stage HCC and discuss future therapeutic possibilities.     

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。