Image-guided locoregional non-intravascular interventional treatments for hepatocellular carcinoma: Current status

Hepatocellular carcinoma (HCC) is one of the most deadly and frequent cancers worldwide, although great advancement in the treatment of this malignancy have been made within the past few decades. It continues to be a major health issue due to an increasing incidence and a poor prognosis. The majority of patients have their HCC diagnosed at an intermediate or advanced stage in theUSA or China. Curative therapy such as surgical resection or liver transplantation is not considered anoption of treatment at these stages.Transarterial chemoembolization (TACE), the most widely used locoregional therapeutic approach, used to be the mainstay of treatment for cases with unresectable cancer entities. However, for those patients with hypovascular tumors or impaired liver function reserve, TACE is a suboptimal treatment option. For example, embolization does not result in complete coverage of a hypovascular tumor, and may rather promotes postoperative tumor recurrence, or leave residual tumor, in these TACE-resistance patients. In addition, TACE carries a higher risk of hepatic decompensation in patients with poor liver function or reserve.Non-vascular interventional locoregional therapies for HCC include radiofrequency ablation (RFA), microwave ablation (MWA), high-intensity focused ultrasound (HIFU), laser-induced thermotherapy (LITT), cryosurgical ablation (CSA), irreversible Electroporation (IRE), percutaneous ethanol injection (PEI), and brachytherapy. Recent advancements in these techniques have significantly improved the treatment efficacy of HCC and expanded the population of patients who qualify for treatment. This review embraces the current status of imaging-guided locoregional non-intravascular interventional treatments for HCCs, with a primary focus on the clinical evaluation and assessment of the efficacy of combined therapies using these interventional techniques.     

Percutaneous image-guided radiofrequency ablation of liver tumors

The development of image-guided percutaneous techniques for local tumor ablation has been one of the major advances in the treatment of liver malignancies. Over the past two decades, several methods for chemical or thermal tumor destruction have been clinically tested. Among these methods, radiofrequency (RF) ablation is currently established as the primary ablative modality at most institutions. RF ablation is accepted as the best therapeutic choice for patients with early-stage hepatocellular carcinoma (HCC) when liver transplantation or surgical resection are not suitable options. In addition, RF ablation is emerging as a viable alternate to surgery for inoperable patients with limited hepatic metastatic disease, especially from colorectal cancer. Several series have shown that RF ablation can result in complete tumor eradication in properly selected candidates, and have provided indirect evidence that the treatment improves survival. In this article, we review technique, indications, and clinical results of percutaneous RF ablation in the treatment of HCC and colorectal hepatic metastases.     

Post-treatment malignant liver lesions. MR imaging

MR imaging is very accurate in the diagnosis and staging of tumors and in surgical planning. MR imaging is also an excellent method for evaluation of the liver after surgical resection, systemic or local tumor therapies, and liver transplantation. It permits early recognition of complications and the presence of recurrent tumor, providing an opportunity to repeat treatment or use alternative treatment. Surgical resection remains the standard therapy for treating liver metastases. The relatively small number of patients who are candidates for curative resection have provided impetus for the implementation and improvement of other techniques. The variety of techniques and the sensitivity for contrast enhancement have made MR imaging an ideal method to follow the response of tumors to various treatment approaches. The appearance of tumor recurrence and the response to treatment are relatively consistently shown on MR images; however, the time course of change in lesion appearance has not been fully elucidated, particularly in the setting of chemotherapy. Evaluating the response to chemotherapy is rendered complex because of the longer duration of the therapy, the types of response that various chemotherapeutic agents engender, the method of action of this therapy and the time of imaging in relation to therapy. The various local therapies share some general principles of action, and many have similar MR imaging findings. Some local therapies are effective only with certain malignancies (e.g., alcohol therapy and HCC), whereas other therapies are more limited because of the size of the tumor kill zone (e.g., interstitial laser therapy). We are in the early stages of using MR imaging to guide local therapies and to monitor response during treatment in real time. This appears to be an important future direction for MR imaging. The role of MR imaging in liver transplantation involves pre- and postoperative investigation of both donors (in the case of living-related transplantation) and recipients. These issues are described further in the section on MR imaging of liver transplantation.     

Assessment of the treatment response of HCC

Surgical hepatectomy or liver transplantation are considered as curative treatment modalities for hepatocellular carcinoma (HCC). However, many patients are not surgical candidates at the time of diagnosis. Great improvements in locoregional therapies including local ablative therapy [radiofrequency (RF) ablation or ethanol ablation] and transarterial techniques (transarterial embolization or transarterial radioembolization) have made possible local control of HCC. For unresectable HCC, a targeted therapy with sorafenib may improve survival. Unlike treatment of other oncologic tumor, the locoregional therapies are mainstay in the treatment of HCC. Therefore, the application of classical criteria such as the World Health Organization (WHO) guideline may not be suitable for accurate treatment response assessment of locoregional therapies or targeted therapy of HCC. An understanding of the imaging features of post-treatment imaging after various treatment modalities for HCC is crucial for treatment response assessment and for determining further therapy. In this article, we review the role of various imaging modalities in assessing treatment response of locoregional therapies and the targeted molecular therapy.     

原发性肝癌的治疗方法与术后肿瘤复发和生活质量的关系

[目的]探讨原发性肝癌(PLC)外科治疗方法与患者术后肿瘤复发和生活质量之间的关联性.[方法]根据治疗方式不同,将358例PLC患者分为两组,肝叶切除组(n=308)和肝移植组(n=50).根据肝功能差异,将肝切除病人分为中重度肝硬化组(n=34)、轻度肝硬化组(n=230)和无肝硬化组(n=44).比较两组患者术后生存率、肿瘤复发率和生活质量.[结果]肝叶切除组1、3、5累积生存率和复发率与肝移植组比较差异无显著性(P>0.05);但中重度肝硬化患者3年、5年生存率低于轻度肝硬化、无肝硬化患者;1、3、5累积生复发率高于轻度、无肝硬化患者,且差异有显著性(P<0.01),轻度与无肝硬化患者组间比较差异无显著性(P>0.05).肝叶切除组患者躯体功能(PH)、心理功能(PS)、症状/副作用(ST)、社会功能(SO)、自我评价及总分均低于肝移植组(P<0.01).PLC患者的手术方法、肝硬化程度与肿瘤复发率和患者的生活质量密切相关.[结论]肝叶切除治疗无硬化或轻度肝硬化PLC与肝移植比较其近远期疗效接近,但中重度肝硬化患者行肝叶切除其肿瘤复发率较高,术后生活质量低.     

肝癌肝移植后亚砷酸化疗的应用

背景：移植后肿瘤复发是影响肝癌肝移植疗效的主要因素,如何防止肝癌肝移植后肿瘤复发是目前肝移植研究的热点问题之一。亚砷酸全身化疗被认为对中晚期肝癌具有一定作用,但在肝移植后的应用还未见报道。目的：观察超出米兰标准的肝癌患者肝移植后应用亚砷酸全身化疗的对肿瘤复发的干预效果。方法：对23例超出米兰标准的肝癌患者肝移植后采用亚砷酸行预防性化疗：静脉滴注10mg/d,连续使用7d后间隔7d,重复4次为1个疗程,患者接受1~4个疗程。观察以上使用亚砷酸化疗患者的生存、肿瘤复发情况,以及化疗不良反应,并与同期16例未使用化疗的肝癌肝移植患者相比较。结果与结论：经过3~32个月随访,共30例患者出现肝癌复发,化疗组16例,非化疗组14例,复发部位最常见于肺部、移植肝及骨骼。化疗组与非化疗组肿瘤复发率差异无显著性意义,但化疗组复发时间明显延迟（P=0.026）;两组6个月、1年生存率差异无显著性意义,化疗组2年生存率显著高于非化疗组（P=0.037）;两组6个月无瘤生存率差异无显著性意义,1年、2年无瘤生存率化疗组显著高于明显非化疗组（P=0.030,0.023）。亚砷酸使用过程中未发现严重不良反应。提示肝癌肝移植患者静脉使用亚砷酸化疗可以延迟肿瘤复发,提高生存率。     

肝癌肝移植后亚砷酸化疗的应用

背景:移植后肿瘤复发是影响肝癌肝移植疗效的主要因素,如何防止肝癌肝移植后肿瘤复发是目前肝移植研究的热点问题之一.亚砷酸全身化疗被认为对中晚期肝癌具有一定作用,但在肝移植后的应用还未见报道.目的:观察超出米兰标准的肝癌患者肝移植后应用亚砷酸全身化疗的对肿瘤复发的干预效果.方法:对23例超出米兰标准的肝癌患者肝移植后采用亚砷酸行预防性化疗:静脉滴注10 mg/d,连续使用7 d后间隔7 d,重复4次为1个疗程,患者接受1～4个疗程.观察以上使用亚砷酸化疗患者的生存、肿瘤复发情况,以及化疗不良反应,并与同期16例未使用化疗的肝癌肝移植患者相比较.结果与结论:经过3～32个月随访,共30例患者出现肝癌复发,化疗组16例,非化疗组14例,复发部位最常见于肺部、移植肝及骨骼.化疗组与非化疗组肿瘤复发率差异无显著性意义,但化疗组复发时间明显延迟(P=0.026);两组6个月、1年生存率差异无显著性意义,化疗组2年生存率显著高于非化疗组(P=0.037);两组6个月无瘤生存率差异无显著性意义,1年、2年无瘤生存率化疗组显著高于明显非化疗组(P=0.030,0.023).亚砷酸使用过程中未发现严重不良反应.提示肝癌肝移植患者静脉使用亚砷酸化疗可以延迟肿瘤复发,提高生存率.     

“Hepatocellular carcinoma: A life-threatening disease”

An estimated rise in liver cancer incidence will increase to 95374 new cases by 2020. Hepatocellular Carcinoma (HCC), the most common primary malignant tumour of the liver, is considered to be the third leading cause of all cancer-related deaths and fifth common cancer worldwide. The reported data shows that the rate of HCC incidence in male population is three to four times higher compared with the female population. In the United States, HCV-induced liver cancer is increasing very fast because of the lack of proper treatment option. There are various treatment strategies available for HCC like liver transplantation, resection, ablation, embolization and chemotherapy still the prognosis is destitute. If the patient is eligible, liver transplantation is the only therapeutic option that may give around 90% survival rate, but the scarcity of liver donor limits its broad applicability. A sudden address is necessary to develop specific drugs, personalized medicine, for HCC.     

Systemic therapy of hepatocellular carcinoma: Are we making progress?

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third most common cause of cancer deaths. Surgical resection, with or without transplantation, can result in long-term survival. However, surgery can only be performed in about 15% of patients with HCC and the 5-year survival rate is only approximately 33%–50% after potentially curative resection. Percutaneous ethanol injection, radiofrequency ablation, and transarterial chemoembolization are invasive techniques that have shown efficacy in reducing tumor bulk. Similarly, systemic chemotherapy may induce tumor responses, but a survival benefit has not been clearly demonstrated. In addition, the lack of efficacy of antiandrogens, tamoxifen, and single-agent interferon has now been confirmed. Sorafenib is a multikinase inhibitor with antiangiogenic, proapoptotic, and Raf kinase inhibitory activity. In a large, multicenter, randomized, phase 3 trial there was a significant improvement in both time to disease progression and overall survival with sorafenib compared with placebo. Sorafenib is the first agent to demonstrate a consistent improvement in overall survival for patients with advanced HCC. Further studies are required to determine the role of other molecular-targeted therapies, either alone or in combination with sorafenib in patients with advanced HCC. Further studies are also required to determine the role of sorafenib in combination with locoregional therapies (eg, transarterial chemoembolization), and the role of sorafenib as adjuvant therapy following surgery.     

超声造影评估肝脏肿瘤微波消融边界的研究进展

微波消融（microwave ablation，MWA）以其微创、疗效好等特点已广泛应用于肝脏肿瘤的治疗，而消融未达到安全边界会造成治疗不彻底的后果，容易引起肿瘤复发，因此消融术后评估消融边界（ablation margin，AM）是治疗中不可或缺的环节。而超声造影（contrast-enhanced ultrasound，CEUS）具有经济、实时、无放射性、无肾毒性等优点，可作为评估AM的重要方法。本文就超声造影评估肝脏肿瘤微波消融边界的研究进展做一综述。     

New perspectives and strategy research biomarkers for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. Cirrhosis caused by hepatitis B virus, hepatitis C virus or chronic alcohol intake is associated with major risk. Systematic screening for HCC of asymptomatic patients with cirrhosis is needed for earlier detection of small tumors requiring treatment (liver transplantation, surgical resection, percutaneous techniques). The recommended screening strategy among cirrhotic patients is based on regular liver ultrasonography associated with serum alpha-fetoprotein (AFP) assay. As the performance of AFP is not satisfactory, additional tumoral markers are proposed (des-gamma-carboxyprothrombin, glycosylated AFP-L3 fraction). Currently, diagnosis of HCC in cirrhotic patients includes non-invasive tests (imaging after contrast administration, AFP assay); diagnostic biopsy is performed when imaging is limited. After treatment, tumor recurrence is assessed by regular follow-up (AFP assay and imaging). Despite the lack of accurate markers, recent developments in genomic and proteomic approaches will allow the discovery of new biomarkers for primary tumors, as well as for recurrence. This review summarizes the current state of biomarkers for screening, diagnosis and follow-up of HCC, and highlights new perspectives in the field.     

Imaging tumor response following liver-directed intra-arterial therapy

Liver-directed intra-arterial therapies are palliative treatment options for patients with unresectable liver cancer; their use has also resulted in patients being downstaged leading to curative resection and transplantation. These intra-arterial therapies include transarterial embolization, conventional transarterial chemoembolization (TACE), drug-eluting bead TACE and radioembolization. Assessment of imaging response following these liver-directed intra-arterial therapies is challenging but pivotal for patient management. Size measurements based on computed tomography or magnetic resonance imaging (MRI) have been traditionally used to assess tumor response to therapy. However, these anatomic changes lag behind functional changes and may require months to occur. Further, these intra-arterial therapies cause acute tumor necrosis, which may result in a paradoxical increase in tumor size on early follow-up imaging despite complete cell death or necrosis. This concept is unique comparing to changes seen following systemic chemotherapy. The recent development of functional imaging techniques including diffusion-weighted MRI (DW MRI) and positron emission tomography (PET) allow for early assessment of treatment response and even prediction of overall tumor response to intra-arterial therapies. Although the results of DW MRI and PET studies are promising, the impact of these imaging modalities to assess treatment response has been limited without standardized protocols. The aim of this review article is to delineate the best practice for assessing tumor response in patients with primary or secondary hepatic malignancies undergoing intra-arterial therapies.     

The progression of hepatitis B- and C-infections to chronic liver disease and hepatocellular carcinoma: presentation, diagnosis, screening, prevention, and treatment of hepatocellular carcinoma

Much information has been gained in the diagnosis and treatment of HCC during the last 15 years. Ever improving imaging technology has made nonhistologic diagnostic criteria possible, albeit controversial. Liver transplantation, resection, and RFA are considered curative options. Yet, HCC incidence is steadily rising because of limited progress on disease prevention. Accurate and cost-effective screening is necessary. Presently, only 10% to 15% of HCC patients present with a curative stage of disease. Because the field of HCC is rapidly changing, patients with HCC should be referred to liver centers with a full array of services, from surgical to oncologic. The prognosis for HCC patients will surely improve with a multi-disciplinary approach to care and further clinical research. Better screening and prevention of recurrence should eventually improve survival. It is hoped that antiviral treatment studies will lower the risk of HCC, and that these changes will occur soon enough to help the many patients at risk for or diagnosed with HCC over the next several years.     

超声引导经皮双极射频消融治疗肝癌的局部疗效观察

目的观察超声引导经皮双极射频消融治疗肝癌的局部疗效。方法选取我院2012年5月~2013年10月收治、以治愈性治疗为目的的24例肝癌患者32个病灶,对所有患者均采取超声引导下经皮双极射频消融进行治疗,术后1个月观察患者影像学(超声造影、增强CT或增强MRI)检查结果,以评价局部疗效,以后每3个月随访一次,以观察患者复发情况。结果病灶完全消融(CA)率96.9%(31/32),其中最大径3cm病灶CA率为100%(27/27),最大径≥3cm病灶CA率为80%(4/5);原发性肝癌完全CA率95.7%(22/23),转移性肝癌CA率100%(9/9)。所有患者均未出现严重并发症及与手术相关的死亡。随访2~19个月,局部复发率为6.3%(2/32)远处复发率为33.3%(8/24)。结论超声引导下经皮双极射频消融治疗肝癌安全可靠、局部疗效确切,对小肝癌尤其明显。     

A multicenter,randomized, observation-controlled clinical trial to evaluate the efficacy and safety of thymalfasin adjuvant therapy in patients with HBV-related HCC after curative resection – first announcement of the protocol

Hepatocellular carcinoma (HCC), the third leading cause of cancer-related death worldwide, is a disease of immune microenvironment. Chronic Hepatitis B virus (HBV) infection, also an immune-related disease, is the major etiological factor for HCC especially in Asia. As an immune regulator, which has pleiotropic activities on T cells, nature killer cells and dendritic cells and so on, the efficacy of thymalfasin on HCC patients has been proven by several pilot studies as an adjuvant therapy. Combination of thymalfasin significantly improved survival and prolonged the time to tumor recurrence in patients who received transcatheter arterial chemoembolization after tumor resection. An improvement in patients’ immunity has also been demonstrated. However, there is no large-scale randomized controlled study so far in resectable HCC patients. To confirm the role of thymalfasin adjuvant therapy in patients with HBV-related HCC after curative resection, a large-scale multicenter randomized controlled trial has been planned in China to investigate the effect of thymalfasin (1.6 mg twice a week for 12 months) on 2-year recurrence-free survival rate and tumor immune microenvironment. Here is the first announcement of the study protocol (ClinialTrials.gov Identifier: NCT02281266).     

Intraoperative ultrasound patterns predict recurrences after surgical treatments for hepatocellular carcinoma

IntroductionHepatocellular carcinoma (HCC) is associated with a high incidence of postoperative recurrence, despite high rates of complete necrosis with radiofrequency ablation (RFA) and curative hepatic resections (HR). The aim of this study was to identify intraoperative ultrasound patterns observed during HR or RFA that predicting intrahepatic HCC recurrence.Materials and methodsFrom January 1997 through August 2008, we treated 377 patients with HCC (158 with HR and 219 with surgical RFA). All patients underwent intraoperative ultrasound (IOUS) examination. Primary HCCs was classified according to diameter, HCC pattern (nodular or infiltrative), echogenicity (hyper- or hypo-), echotexture (homogeneous or inhomogeneous), capsular invasion, mosaic pattern, nodule-in-nodule appearance, and infiltration of portal vessels. Number of HCC nodules was also considered. Comparisons between the groups of possible factors for intrahepatic recurrence of treated tumors were performed using the Kaplan–Meier method and compared using the log-rank test.ResultsPatients were followed for 9–127 months (median: 18.6 months), and intrahepatic recurrence was observed in 198 (52.5%). In 138 patients (36.5%), recurrences were located in different segments with respect to the primary tumor. In 60 HCC tumors (16%), local recurrences were found in the same segment as the primary tumor. At univariate analysis, primary HCC echogenicity and mosaic pattern were the only factors not significant associated with intrahepatic recurrences.ConclusionIOUS is an accurate staging tool for use during “surgical” resection or RFA. This study shows that IOUS patterns can also be used to estimate the risk of post-treatment HCC recurrence. In patients at high risk for this outcome, closer follow-up and use of adjuvant therapies could be useful.     

Magnetic resonance of focal liver lesions in hepatic cirrhosis and chronic hepatitis.

Detection of focal liver nodules in patients with cirrhosis continues to be a radiologic challenge despite progressive advances in liver imaging in the past 2 decades. Patients with hepatic cirrhosis have a high predisposition to develop hepatocellular carcinoma (HCC), and the early detection and diagnosis of this tumor is very important because the most effective treatment is surgical resection, transplantation, or local ablation therapy when the tumor is small. Cirrhotic livers are mainly composed of fibrosis, together with a broad spectrum of focal nodular lesions ranging from regenerative nodules to premalignant dysplastic nodules to overt HCC. Awareness of such lesions and interpretation of imaging studies in these patients requires a critical review to detect subtle tumors, and a thorough understanding of the imaging appearance of the malignant and benign masses that can occur in the cirrhotic liver. Although the recent advances in liver imaging techniques, especially computed tomography (CT) and magnetic resonance (MR), have facilitated the detection and characterization of focal liver nodules in cirrhotic patients, discriminating between HCC and precancerous nodules remains problematic with all available imaging techniques. Nevertheless, MR imaging appears to have more potential than other imaging techniques in the study of cirrhotic patients and MR may be more appropriate than the other imaging modalities for the detection of small HCCs. In this article we review the imaging characteristics of nodular focal lesions that arise in cirrhotic livers, with special attention to MR imaging features.     

原位肝移植治疗原发性肝癌

背景:肝移植可完整切除病肝,远期疗效优于肝切除,其5年存活率可达70%H1.此外,肝移植还可避免在肝功能不良的情况下肝切除带来的术后肝功能不全的严重风险.目的:回顾性分析原发性肝癌原位肝移植治疗效果及意义.方法:对解放军南京军区福州总医院肝胆外科1980-03/2008-12因原发性肝癌行原位肝移植术患者75例术后生存及肿瘤复发情况进行总结分析.结果与结论:75例患者术后1,2,3年的总体生存率及无瘤生存率分别为:86.6%,66.70%.53.3%及65.2%,53.9%,34.1%,平均生存时间25个月.其中符合Milan标准的手术患者术后1,2,3年的总体生存率及无瘤生存率分别为:88.4%,72.5%,57.9%及77.6%,62.3%,51.8%,平均生存时间39个月.超出Milan标准的6例患者均在术后1年内出现肿瘤的复发,有2例患者在术后1年内死亡,术后1年生存率为66.7%.其余4例患者于术后2年内相继死亡.平均生存时间14个月.提示原位肝移植是原发性肝癌的有效治疗方法之一,选择符合Milan标准的原发性肝癌患者行肝移植手术治疗将会取得最佳疗效.     

干扰素治疗原发性肝癌的临床疗效观察

目的探讨干扰素治疗原发性肝癌的疗效。方法对2006年9月～2010年8月在本科行根治性切除术后72例原发性肝癌患者的治疗效果进行回顾性分析。结果本研究中,行根治性手术切除术后再应用干扰素的患者中,2年内总的复发/转移率53.57%(15/28),2年生存率50.00%(14/28);接受单纯根治性手术切除治疗的患者2年内总的复发/转移率68.18%(30/44),2年生存率29.55%(13/44)。根治性切除联合干扰素治疗原发性肝癌的治疗效果明显优于单纯行根治性手术切除。结论干扰素可减少肝癌患者根治性切除术后的复发与转移,提高生存率。     

肝癌切除疗效分析112例报告

目的：分析原发性肝癌手术切除的方法及效果。方法：对手术切除的原发性肝癌112例从肿瘤部位、大小、人肝血流阻断、切除方式、失血量、手术时间等方面进行分析。结果：手术切除率26.23%,手术死亡率0.89%,5年生存率18.75%,10年生存率仅2例。结论：原发性肝癌患者就诊时多数已为中晚期或大肝癌,手术切除后疗效较差。提高生存率关键是：小肝癌的切除、切除方式、术后TACE、复发再切除及术后生物治疗等。