Combination of interventional therapies in hepatocellular carcinoma

Many interventional techniques aimed at achieving nonsurgical ablation of hepatocellular carcinoma have been developed and clinically tested over the last decade. Percutaneous image-guided therapies such as ethanol injection and radiofrequency thermal ablation provide an effective means for treating hepatocellular carcinoma lesions smaller than 3 cm, but do not ensure successful ablation of larger tumors. In view of the limitations of available interventional therapies, there is currently a focus on a multimodality strategy for the treatment of large hepatocellular carcinomas. Combination of transcatheter arterial chemoembolization and ethanol injection overcomes the weakness of each of the two procedures, enhancing local therapeutic effect and long-term survival. More recently, a new technique for single-session ablation of large hepatocellular carcinoma lesions has been devised by combining transcatheter hepatic arterial balloon occlusion/embolization and radiofrequency treatment. This combined approach substantially increases the thermal necrosis volume that can be created with respect to the conventional radiofrequency technique, as a result of the reduction of heat loss caused by convection. In a pilot multicentric clinical trial performed in 62 patients, successful ablation of hepatocellular carcinoma lesions ranging 3.5-8.5 cm in diameter was achieved in 82% of cases in the absence of major complications. This new technique seems to have the potential to replace other interventional methods for the treatment of large hepatocellular carcinoma.     

Non-surgical therapies of hepatocellular carcinoma

Early detection of hepatocellular carcinoma (HCC) through surveillance programmes allows potentially curative therapies such as resection, liver transplantation and percutaneous ablation to be applied in 40% of the patients. In non-surgical candidates, percutaneous treatments are the best therapeutic approach, and may improve survival in patients with well preserved liver function and small tumours that achieve initial complete response. Applying these criteria 5-year survival rates above 50% are achieved. Radio frequency thermal ablation provides slightly better objective response rates than ethanol injection, but no survival advantages have been reported. At more advanced stages, only chemoembolization has been shown to improve survival in well-selected candidates.     

Nonpercutaneous therapies of hepatocellular carcinoma

Treatment of hepatocellular carcinoma depends largely on local resources, the stage of the disease and the presence of cirrhosis, but is limited overall by the lack of efficient chemotherapy. Hepatic resection is the treatment of choice for the few patients with hepatocellular carcinoma and normal liver. Five-year survival without recurrence in patients with a tumor of mean diameter 8 cm was 33%. Liver transplantation is the best chance for cure in patients with cirrhosis and a single small tumor, but its widespread application is limited by a number of obstacles, including cost. Tumor size and number, and liver status were common guidelines for selecting patients. Five-year survival of transplant patients was > 50%, compared to 0% in historical untreated controls. Patients with well-preserved liver function and a small tumor at the periphery could equally benefit from hepatic resection, although cirrhosis entails the risk of morbidity due to portal hypertension and development of de-novo tumors. Another major drawback of hepatic resection is the early spread of tumor cells, facilitating early tumor recurrence after operation. For patients with compensated cirrhosis and a small tumor who were hardly eligible for surgery, transcatheter arterial chemoembolization appeared to be a cost-saving and effective treatment modality. Transcatheter arterial chemoembolization has been largely employed also for the palliative treatment of patients with large tumors, but the benefits on survival are doubtful. Conventional radiotherapy with external irradiation was not effective against hepatocellular carcinoma.     

Future therapies for hepatocellular carcinoma

A large proportion of patients with advanced hepatocellular carcinoma (HCC) lack effective therapy. Due to chemoresistance, hope has focused on other approaches including targeted therapies, immune stimulants, and the emerging area of gene therapy. Increasing efforts in basic and clinical development of these approaches will hopefully result in more efficient therapies against HCC.     

Targeted therapies for hepatocellular carcinoma

Unlike most solid tumors, the incidence and mortality of hepatocellular carcinoma (HCC) have increased in the United States and Europe in the past decade. Most patients are diagnosed at advanced stages, so there is an urgent need for new systemic therapies. Sorafenib, a tyrosine kinase inhibitor (TKI), has shown clinical efficacy in patients with HCC. Studies in patients with lung, breast, or colorectal cancers have indicated that the genetic heterogeneity of cancer cells within a tumor affect its response to therapeutics designed to target specific molecules. When tumor progression requires alterations in specific oncogenes (oncogene addiction), drugs that selectively block their products might slow tumor growth. However, no specific oncogene addictions are yet known to be implicated in HCC progression, so it is important to improve our understanding of its molecular pathogenesis. There are currently many clinical trials evaluating TKIs for HCC, including those tested in combination with (eg, erlotinib) or compared with (eg, linifanib) sorafenib as a first-line therapy. For patients who do not respond or are intolerant to sorafenib, TKIs such as brivanib, everolimus, and monoclonal antibodies (eg, ramucirumab) are being tested as second-line therapies. There are early stage trials investigating the efficacy for up to 60 reagents for HCC. Together, these studies might change the management strategy for HCC, and combination therapies might be developed for patients with advanced HCC. Identification of oncogenes that mediate tumor progression, and trials that monitor their products as biomarkers, might lead to personalized therapy; reagents that interfere with signaling pathways required for HCC progression might be used to treat selected populations, and thereby maximize the efficacy and cost benefit.     

Molecular targeted therapies in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a complex and heterogeneous tumor with several genomic alterations. There is evidence of aberrant activation of several signaling cascades such as epidermal growth factor receptor (EGFR), Ras/extracellular signal-regulated kinase, phosphoinositol 3-kinase/mammalian target of rapamycin (mTOR), hepatocyte growth factor/mesenchymal-epithelial transition factor, Wnt, Hedgehog, and apoptotic signaling. Recently a multikinase inhibitor, sorafenib, has shown survival benefits in patients with advanced HCC. This advancement represents a breakthrough in the treatment of this complex disease and proves that molecular therapies can be effective in HCC. It is becoming apparent, however, that to overcome the complexity of genomic aberrations in HCC, combination therapies will be critical. Phase II studies have tested drugs blocking EGFR, vascular endothelial growth factor/platelet-derived growth factor receptor, and mTOR signaling. No relevant data has been produced so far in combination therapies. Future research is expected to identify new compounds to block important undruggable pathways, such as Wnt signaling, and to identify new oncogenes as targets for therapies through novel high-throughput technologies. Recent guidelines have established a new frame for the design of clinical trials in HCC. Randomized phase II trials with a time-to-progression endpoint are proposed as pivotal for capturing benefits from novel drugs. Survival remains the main endpoint to measure effectiveness in phase III studies. Patients assigned to the control arm should receive standard-of-care therapy, that is, chemoembolization for patients with intermediate-stage disease and sorafenib for patients with advanced-stage disease. Biomarkers and molecular imaging should be part of the trials, in order to optimize the enrichment of study populations and identify drug responders. Ultimately, a molecular classification of HCC based on genome-wide investigations and identification of patient subclasses according to drug responsiveness will lead to a more personalized medicine.     

几种不同治疗手段对原发性肝癌的疗效比较研究

目的对原发性肝癌儿种不同治疗手段疗效进行比较分析,为临床合理化治疗方案的确定提供参考与帮助.方法我院1999年6月至2003年6月收治原发性肝癌病例中80例分为A组:单纯手术组;B组:手术切除 植入式肝动脉化疗泵化疗组;C组:单纯肿瘤内注射无水酒精组;D组:股动脉穿刺介入治疗组.对不同治疗手段疗效进行比较分析.结果治疗后A、B、C、D四组1年生存率分别为60.13%、71.26%、43.15%、42.78%,2年生存率分别为46.52%、51.38%,26.64%,25.83%.A、B组术后1年复发率分别为60.33%,49.28%,术后2年复发率分别为76.59%,61.24%.结论对原发性肝癌的治疗以手术切除病灶加化疗的综合治疗效果最佳,单纯手术切除较荷瘤的其他治疗手段效果好,但对无法手术切除的病例肿瘤局部用药的治疗手段仍具有一定的控制效果.     

Emerging curative-intent minimally-invasive therapies for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the most common cause of liver malignancy and the fourth leading cause of cancer deaths universally. Cure can be achieved for early stage HCC, which is defined as 3 or fewer lesions less than or equal to 3 cm in the setting of Child-Pugh A or B and an ECOG of 0. Patients outside of these criteria who can be down-staged with loco-regional therapies to resection or liver transplantation (LT) also achieve curative outcomes. Traditionally, surgical resection, LT, and ablation are considered curative therapies for early HCC. However, results from recently conducted LEGACY study and DOSISPHERE trial demonstrate that transarterial radio-embolization has curative outcomes for early HCC, leading to its recent incorporation into the Barcelona clinic liver criteria guidelines for early HCC. This review is based on current evidence for curative-intent loco-regional therapies including radioembolization for early-stage HCC.     

Salvage locoregional therapies for recurrent hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is the second most common cause of cancerrelated death worldwide. Despite the advent of screening efforts and algorithms to stratify patients into appropriate treatment strategies, recurrence rates remain high. In contrast to first-line treatment for HCC, which relies on several factors, including clinical staging, tumor burden, and liver function, there is no consensus or general treatment recommendations for recurrent HCC(R-HCC). Locoregional therapies include a s...     

Treatment of hepatocellular carcinoma by percutaneous interventional methods

In the treatment of early and intermediate hepatocellular carcinoma the range of indications for percutaneous ablation techniques is becoming wider than surgery or intra-arterial therapies. Indeed, whereas for some years only patients with up to three small tumors were treated, with the introduction of the single-session technique performed under general anesthesia, even patients with more advanced disease are now being treated. Although it is understood that partial resection assures the highest local control, the survival rates after surgery are roughly comparable with percutaneous ethanol injection. The explanation is due to a balance among advantages and disadvantages of the two therapies. Percutaneous ethanol injection survival curves are better than curves of resected patients who present adverse prognostic factors, and this means that surgery needs a better selection of the patients. Indications for both of these therapies are reported. An open question remains about the choice between percutaneous ethanol injection and other new ablation procedures. In our department we currently use radiofrequency ablation in the majority of patients but consider percutaneous ethanol injection and segmental transarterial chemoembolization complementary, and use them according to the features of the disease and the response. Evaluation of their therapeutic efficacy, techniques and results are reported.     

原发性肝细胞癌介入治疗的现状与进展

临床对原发性肝细胞癌(HCC)的治疗已取得了长足进步,其中以介入放射学为主的综合治疗在整个治疗中占据重要地位.HCC的介入治疗方法主要包括以肝动脉化疗栓塞(TACE)为代表的血管内介入治疗和以局部消融为主的非血管介入治疗,而介入结合靶向治疗更进一步丰富了HCC介入治疗的内涵.本文将分别从HCC介入治疗的不同方法、原理、...     

局部消融在肝细胞癌治疗中的应用

手术切除和肝移植被认为是肝细胞癌(HCC)根治性治疗手段,但仅有10%~20%的HCC患者能接受这些治疗。近些年来,射频消融、微波消融、冷冻消融及新近出现的不可逆电穿孔消融等局部治疗方法逐渐成为无法手术患者的替代治疗。除了局部控制肿瘤生长改善预后外,消融技术还有助于肿瘤降级以便二次切除。重点介绍了射频消融及联合其他治疗手段治疗HCC的进展,对射频消融与其他局部消融进行了比较,简述了智能导航技术在辅助消融中的应用,认为随着影像医学的发展以及其他相关领域的进步,未来消融技术在临床应用中将更加广泛。     

Therapeutic radiological interventional procedures in hepatocellular carcinoma.

BACKGROUND: To improve the survival rate of patients with hepatocellular carcinoma (HCC) in whom surgery is not possible, various methods have been developed employing angiographic and percutaneous techniques. We analyzed our experience with various percutaneous therapeutic interventional techniques done for HCC in our center. METHODS: Sixty-one patients with inoperable HCC (mean age 48.9 [SD 13.8] y; 47 men) were treated between January 1997 and December 2000 by transcatheter arterial chemoembolization (TACE) alone (22), TACE with percutaneous alcohol injection (PEI) (20), transcatheter arterial embolization (TAE) with steel coils and gel foam for gastrointestinal bleed (7), percutaneous radiofrequency ablation (1), percutaneous preoperative right portal vein embolization (3) and percutaneous preoperative tumor embolization to reduce blood loss at surgery (8). RESULTS: In 42 patients treated by TACE and PEI and TACE alone, tumor necrosis was scored; over 50% necrosis was seen only after six and nine months in both treatment groups. The survival rates after six and nine months and the median survival were similar in the two groups. Of 7 cases treated with TAE with steel coils and gel foam, the gastrointestinal bleeding stopped in four; in the other three, bleeding did not stop completely although less transfusion was required. In the patient treated by radiofrequency ablation, follow-up contrast-enhanced CT did not show enhancing tumor mass. We noted left lobe enlargement after percutaneous preoperative right portal vein embolization, prior to right hepatectomy. CONCLUSION: In patients with HCC not amenable to surgical intervention, a variety of percutaneous therapeutic interventional techniques may be used.     

Japanese experience in ablation therapies for hepatocellular carcinoma

In the treatment of hepatocellular carcinoma, only 20–30% of patients are candidates for surgery. Still worse, even after curative surgical resection, 80% of patients develop recurrence within 5 years. Thus, various non-surgical therapies have developed. Among them, image-guided local ablation therapies, such as percutaneous ethanol injection, microwave coagulation and radiofrequency ablation, have been widely used for small hepatocellular carcinoma, because they are potentially curative, minimally invasive and easily repeatable. Percutaneous ethanol injection was a standard therapy. However, there has been a drastic shift from ethanol injection to radiofrequency ablation in recent years. In Japan, 1500 institutes have already introduced radiofrequency ablation in the treatment of liver tumors and the cool-tip electrode system has an 80% share of the market. Radiofrequency ablation can achieve complete tumor necrosis in most cases.Long-term survival seems considerably good, and complications are not frequent in radiofrequency ablation. Randomized controlled trials have proved that radiofrequency ablation is superior to ethanol injection in the treatment of small hepatocellular carcinoma from the viewpoint of, not only treatment response, but also long-term survival. Radiofrequency ablation seems feasible, efficacious and considerably safe. Radiofrequency ablation will be more widely performed in the treatment of primary and metastatic liver tumors in Japan.     

Antiviral therapies for hepatitis B virus-related hepatocellular carcinoma

Chronic hepatitis B virus(HBV) infection is a critical risk factor for the carcinogenesis and progression of hepatocellular carcinoma(HCC). It promotes HCC development by inducing liver fibrogenesis, genetic and epigenetic alterations, and the expression of active viral-coded proteins. Effective antiviral treatments inhibit the replication of HBV, reduce serum viral load and accelerate hepatitis B e antigen serum conversion. Timely initiation of antiviral treatment is not only essential for preventing the incidence of HCC in chronic hepatitis B patients, but also important for reducing HBV reactivation, improving liver function, reducing or delaying HCC recurrence, and prolonging overall survival of HBV-related HCC patients after curative and palliative therapies. The selection of antiviral drugs, monitoring of indicators such as HBV DNA and hepatitis B surface antigen, and timely rescue treatment when necessary, are essential in antiviral therapies for HBVrelated HCC.     

各种介入治疗肝癌方法临床评价

<正>介入治疗作为治疗中晚期肝癌的主要手段[1],可分为经血管介入技术和非血管介入技术。1经血管介入技术1.1经肝动脉介入技术可分为选择性肝动脉灌注(TAI)、选择性肝动脉栓塞(TAE)、选择性肝动脉化疗栓塞(TACE)。目前,临床应用以TACE为主,在治疗不能手术切除和术后复发的肝癌患者中已被公认为首选疗法,其治疗原发性和转移性肝癌,尤其是局限性肝癌可获得较好的疗效[2]。传统观念认为,TACE可应用于外科手术前和术     

原发性肝癌经动脉化疗栓塞术后的CT评价

目的探讨CT评价原发性肝癌TACE术后的临床应用价值。材料和方法回顾分析100例原发性肝癌TACE术后的临床与影像检查资料。结果100例中巨块型70例，肿块最大径8-15cm，结节型30例，肿块最大径3．3—7．0cm。经1次TACE治疗者48例，经2次TACE治疗者52例。观察期内所有病人均存活。30例结节型肝癌TACE术后CT表现为完全型28例，斑片型2例，70例巨块型肝癌TACE术后CT表现为完全型20例，斑片型40例，稀少型10例。30例结节型肝癌经1次TACE后完全缓解28例，部分缓解2例（经再次TACE后完全缓解），70例巨块型肝癌经1次TACE后20例完全缓解，部分缓解40例（其中22例经再次TACE后12例完全缓解），进展10例。结节型肝癌与巨块型肝癌TACE术后的CT表现及近期疗效有显著性差异（P〈0．05）。结论CT是评价原发性肝癌TACE疗效的有效方法。结节型肝癌TACE后CT表现以完全型为主，近期疗效好，巨块型肝癌TACE后可表现为完全型、斑片型及稀少型，斑片型、稀少型TACE近期疗效不如完全型，需再次TACE治疗或选择其他治疗方法。     

提高肝癌介入治疗的疗效

由于我国是肝炎大国,肝癌发病率居高不下,每年约10万人死于肝癌,尽管作为肝癌首选治疗方法的手术切除,随着外科技术以及麻醉和护理手段的进步,肝癌的手术适应症不断放宽,手术范围几甚达到解剖学极限,但由于肝癌的特殊病理特点,患者早期常无症状,发现时多至中晚期,能手术切除者仅占10%～15%.而肝移植治疗地位虽已显现,但恐难成为主流.随着20世纪80年代影像医学的迅猛发展,为肝癌局部治疗打开了发展的空间.以血管介入治疗的经皮肝动脉栓塞化疗（transarterial chemoembolization,TACE）,非血管介入的经皮无水乙醇注射治疗（percutaneous ethanol injection,PEI）为代表,射频冷冻、激光、微波、高频率聚焦超声等局部治疗方法,已成为多学科处理、多模式联合应用即综合治疗肝癌的重要环节.然而目前所倡导的综合治疗模式在临床实践中却常各自为政,缺乏系统化和规范化,各种治疗手段被盲目扩大化,甚至达到了滥用的程度,本文就提高肝癌介入治疗疗效作一述评.     

肝癌微创介入治疗进展

原发性肝癌的治疗方法一直是许多学者研究的重点,近年来尽管新兴治疗方法层出不穷,但由于病变多发生于进展期肝病或肝硬化的基础上,因此目前原发性肝癌仍然是一种难治性恶性肿瘤。在治疗方面,外科手术切除及肝移植虽是根治性治疗方法,但由于移植相关问题的复杂性及原发性肝癌本身的隐匿性,使得上述两种治疗方法并不能适用于大多数患者。近些年,随着设备和技术水平的提高,原发性肝癌的微创介入治疗得到了越来越多的重视,其中应用最为广泛的就是肝动脉化疗栓塞术(TACE)和组织消融术(TA)。该文主要讨论上述两种介入疗法联合应用治疗原发性肝癌的有效性、可行性,以及近年来介入治疗在原发性肝癌治疗领域的研究进展。     

肝细胞癌介入治疗的现状与展望

肝细胞癌（HCC）是全球最难治疗的恶性肿瘤之一,全球每年约有65万患者死于HCC。虽然其治疗手段繁多,但疗效仍不令人满意。目前,以经导管肝动脉化疗栓塞术（TACE）为代表的介入治疗已成为中晚期肝癌患者的主要治疗手段。介绍了经皮无水酒精注射、射频消融术、局部氩氦冷冻治疗、放射性粒子植入术等局部介入治疗的发展,以及与生物、基因治疗的联合应用,使综合介入治疗成为HCC最主要的非手术治疗模式。指出随着个体化、规范化的综合介入治疗手段的应用和推广,HCC的整体疗效将得到进一步提高。