Multimodality treatment of hepatocellular carcinoma

Abstract By 1996, 2898 patients with pathologically proven hepatocellular carcinoma (HCC) had been treated at the Liver Cancer Institute of Shanghai Medical University. The 5 year survival in the entire series was 36.2%, being increased from 4.8% in 1958–70, 12.2% in 1971–83, to 50.5% in 1984–96 and 274 patients had survived more than 5 years. The increase in the survival rate could be attributed to the decreasing mean tumour diameter (11.7, 10.5 and 9.5 cm, respectively) and multimodality treatment. In addition to small HCC resection (5 year survival 64.9%, n = 735) and large HCC resection (5 year survival 37.4%, n = 1050), the following deserves to be mentioned. First, the 5 year survival of unresectable HCC treated by palliative surgery increased from 0% to 7.2% to 20.0%, which was related to the increase in use of multimodality treatment, particularly in those followed by second-stage resection. Second, cytoreduction and sequential resection is a new field with a significant potential in the treatment of localized unresectable HCC in a cirrhotic liver. Cytoreduction can be achieved by surgery, such as hepatic artery ligation, cannulation, cryosurgery and their combination, and followed by intrahepatic arterial chemoembolization, targeting therapy or regional radiotherapy. Ninety of 647 patients with unresectable HCC so treated had marked shrinkage of tumour and received second-stage resection; the 5 year survival was 71.4%. Third, non-surgical cytoreduction was mainly achieved by transcatheter arterial chemoembolization (TACE); for 70 patients with second-stage resection following TACE, the 5 year survival was 56.0%. Finally, re-resection of subclinical recurrence of tumour after curative HCC resection was performed in 155 patients; the 5 year survival calculated from the first resection was 50.9%, which played an important role in increasing the 5 year survival in the resection group (from 13.0% to 29.5% to 56.2%). It is concluded that multimodality treatment with combined and sequential use of different modalities and repeated use of some modalities is of substantial benefit for localized unresectable HCC.     

Multimodality treatment in hepatocellular carcinoma patients with tumor thrombi in portal vein

AIM To compare the therapeutic effect andsignificances of multimodality treatment forhepatocellular carcinoma (HCC) with tumorthrombi in portal vein (PVTT).METHODS HCC patients (n=147) with tumortrombi in the main portal vein or the first branchof portal vein were divided into four groups bythe several therapeutic methods. There wereconservative treatment group in 18 out ofpatients (group A); and hepatic artery ligation(HAL) and/or hepatic artery infusion (HAI)group in 18 patients (group B), in whompostoberative chemoembolization was doneperiodically; group of removal of HCC with PVTTin 79 (group C) and group of transcatheterhepatic arterial chemoembolization (TACE) orHAI and/or portal vein infusion (PVI) afteroperation in 32 (group D).RESULTS The median survival period was 12months in our series and the 1-, 3-, and 5-yearsurvival rates were 44.3%, 24.5% and 15.2%,respectively. The median survival times were 2,5, 12 and 16 months in group A, B, C and D,respectively. The 1-, 3- and 5-year survival rateswere 5.6%, 0% and 0% in group A; 23.2%,5.6% and 0% in group B; 53.9%, 26.9% and16.6% in group C; 79.3%, 38.9% and 26.8% ingroup D, respectively. Significant differenceappeared in the survival rates among the groups (P<0.05).CONCLUSION Hepatic resection with removalof tumor thrombi and HCC should increase thecurative effects and be encouraged for theprolongation of life span and quality of life forHCC patients with PVTT, whereas the besttherapeutic method for HCC with PVTT is withregional hepatic chemotherapy orchemoemblization after hepatic resection withremoval of tumor thrombi.     

Combined endovascular brachytherapy,sorafenib, and transarterial chemobolization therapy for hepatocellular carcinoma patients with portal vein tumor thrombus

AIM To evaluate the safety and efficacy of combined endovascular brachytherapy(EVBT),transarterial chemoembolization(TACE),and sorafenib to treat hepatocellular carcinoma(HCC) patients with main portal vein tumor thrombus(MPVTT).METHODS This single-center retrospective study involved 68 patients with unresectable HCC or those who were unfit for liver transplantation and percutaneous frequency ablation according to the BCLC classification. All patients had Child-Pugh classification grade A or B,Eastern Cooperative Oncology Group(ECOG)performance status of 0-2,and MPVTT. The patients received either EVBT with stent placement,TACE,and sorafenib(group A,n = 37),or TACE with sorafenib(group B,n = 31). The time to progression(TTP) and overall survival(OS) were evaluated by propensity score analysis.RESULTS In the entire cohort,the 6-,12-,and 24-mo survival rates were 88.9%,54.3%,and 14.1% in group A,and 45.8%,0%,and 0% in group B,respectively(P 0.001). The median TTP and OS were significantly longer in group A than group B(TTP: 9.0 mo vs 3.4 mo,P 0.001; OS: 12.3 mo vs 5.2 mo,P 0.001). In the propensity score-matched cohort,the median OS was longer in group A than in group B(10.3 mo vs 6.0 mo,P 0.001). Similarly,the median TTP was longer in group A than in group B(9.0 mo vs 3.4 mo,P 0.001). Multivariate Cox analysis revealed that the EVBT combined with stent placement,TACE,and sorafenib strategy was an independent predictor of favorable OS(HR = 0.18,P 0.001). CONCLUSION EVBT combined with stent placement,TACE,and sorafenib might be a safe and effective palliative treatment option for MPVTT.     

Antiangiogenic gene therapy for hepatocellular carcinoma using angiostatin gene

Recent studies have reported that antiangiogenic gene delivery into cancer cells inhibits growth of certain tumors in vivo. Hepatocellular carcinoma (HCC) is a hypervascular cancer, and antiangiogenic gene therapy might be suitable for HCC. In the present study, we investigated the antiangiogenic effects of angiostatin gene transduction into HCC both in vitro and in vivo. Angiostatin gene was cloned into a pSecTag2B mammalian expression vector to construct pSecTag2B-ANG. pSecTag2B or pSecTag2B-ANG were transfected into an HCC cell line, PLC/PRF/5, and then stable transfectants were obtained by Zeocin selection. pSecTag2B or pSecTag2B-ANG transfection did not alter the expression of vascular endothelial growth factor (VEGF), a potent angiogenic stimulator, or pigment epithelium-derived factor (PEDF), an angiogenic inhibitor, in PLC/PRF/5 cells. However, conditioned media (CM) derived from pSecTag2B-ANG-transfected PLC/PRF/5 cells (CM-ANG) suppressed the proliferation and migration of human umbilical vein endothelial cells (HUVEC) by 35% and 50%, respectively, relative to their effects on nontransfected cells. In in vivo experiments, pSecTag2B-ANG stable transfected (CM-Mock) and nontransfected cells (CM-N) were mixed at various proportions and the mixed cells were subcutaneously implanted into athymic mice. Suppression of tumor growth was noted in mice implanted with angiostatin gene-transfected cells, and such suppression was proportional with the percentage of transfected cells. Analysis of the vascular density in these tumors showed that the tumor growth suppression effect of angiostatin gene correlated with suppression of tumor vascularity. In conclusion, antiangiogenic gene therapy using angiostatin gene is potentially suitable for the treatment of patients with HCC.     

肝癌的非手术治疗

肝癌患者病情复杂,宜根据病变的具体情况和各种治疗方法的不同特点和适应证选择最佳方案。治疗方法的选择应依据肿瘤的大小和数目、肿瘤侵袭的部位和范围、静脉癌栓和远处转移情况、患者肝功能代偿程度以及全身状况(年龄、心肺功     

原发性肝癌的非手术治疗

原发性肝癌（下简称肝癌）主要是肝细胞癌，少数是胆管细胞癌。我国是肝癌高发地区，其恶性程度高，进展快，治疗棘手，预后差。外科手术切除或肝移植是最有效的治疗，但绝大多数病例属于中晚期或有严重的肝硬化，而不适合外科手术治疗^[1]，因而非手术治疗适用于大多数病例或与外科手术相结合提高治疗效果^[1,2]。     

基因治疗在肝癌中的应用

肝癌是一种高度恶性的肿瘤，目前首选的治疗方法仍然是手术切除，但复发率高。因此，对于肝癌的治疗更多考虑综合治疗。作为第4类新治疗模式的生物治疗显示出较好的前景，为当前肝癌治疗研究热点之一。为此本刊特约请从事相关研究的专家对肝癌生物治疗现状和前景进行笔谈。     

肝癌综合介入治疗的现状

原发性肝癌恶性程度很高，大多数患者就诊时已无外科手术指征，即使能进行外科手术切除，术后肿瘤复发率亦较高。采用肝动脉插管化疗、栓塞方法（transcatheter arterial chemoembolization，TACE）亦称介入疗法，治疗不能手术切除的肝癌和术后复发的肝癌，取得了良好的效果。介入疗法已被公认为治疗不能手术切除和术后复发肝癌的首选方法，但肝癌介入治疗后复发、转移问题仍未解决，影响了其远期生存率。越来越多的学者认识到对肝癌采用综合介入治疗的必要性和重要性。     

Locoregional therapy for hepatocellular carcinoma

Locoregional therapies for hepatocellular carcinoma have progressed greatly in the last 30 years, beginning with the introduction of chemoembolization. Embolization techniques have evolved with the use of drug-eluting beads and radioembolization with yttrium-90. In the last 10 years, several new ablation techniques were developed including radiofrequency ablation, microwave ablation, cryoablation, laser ablation, and irreversible electroporation. Isolated or in combination, these techniques have already shown that they can improve patient survival and/or provide acceptable palliation.     

Immune therapy for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death worldwide. Currently, there are no treatment options available for a large number of these patients. One of the mechanisms that may contribute to tumor growth is the lack of an effective immune response toward viral antigens or other tumor-associated antigens (TAAs). Immunotherapy has been tested as a potential therapeutic option for these patients. Several methods of immune modulation for augmenting antitumor immunity are being explored and have been shown to be effective in suppressing HCC growth in animal models. Activation of HCC-specific response can be accomplished by targeting hepatitis B or C viral antigens, alpha-fetoprotein, or other TAAs. This review summarizes part of the recent data on the use of adoptive transfer of immunity against viral antigens, oral immune modulation against TAAs, and the use of pulsed innate immune cells and gut adjuvants for the suppression of HCC; it reviews some additional new immunotherapeutic approaches.     

原发性肝癌伴门脉癌栓综合诊治的研究进展

原发性肝细胞癌（HCC）是较常见的消化道恶性肿瘤之一，其死亡率居我国恶性肿瘤的第二位，而伴有门脉癌栓（PVTT）的肝癌因易发生肝内及远处转移，被认为是预后差的主要指标之一，生存期为2．4～2．7个月。虽然HCC合并门脉癌栓是预后不良的标志，但在肝功能及一般情况允许的情况下，仍可尝试多种治疗方法以提高此类患者的生存率，综合治疗在该病的治疗中起着重要的作用。     

Rapid intrahepatic tumor seeding after percutaneous ethanol injection therapy for hepatocellular carcinoma

A 73-year-old man with hepatocellular carcinoma (HCC) had been treated repeatedly with transcatheter arterial embolization (TAE) and percutaneous ethanol injection therapy (PEIT) since 2000. HCC recurrence near the intrahepatic left portal vein was treated by PEIT in 2004. The patient complained of fatigue and upper abdominal pain 28 days later. Abdominocentesis and abdominal computed tomography demonstrated rupture of the recurrent HCC and multiple intrahepatic recurrences. We successfully performed emergency TAE, but the patient died of liver failure. Rapid seeding of multiple intrahepatic tumors after PEIT is a rare event, but such a possibility must be kept in mind.     

大肝癌的消融治疗

肝癌是我国最常见的恶性肿瘤之一,当单个肿瘤直径大于5 cm时定义为大肝癌。大肝癌具有肿瘤恶性程度高、易出现肿瘤转移和血管浸润等特点,增加了治疗的难度。外科切除是大肝癌首选的治疗方案,但仅有20%~30%的患者符合手术治疗要求。对于不可切除的大肝癌国内外指南推荐经肝动脉化疗栓塞术(TACE)作为治疗方案,TACE可以控制肿瘤进展并延长患者生存时间,但反复多次的TACE治疗疗效有限,且对患者肝功能造成严重损害,单独的TACE治疗已无法满足临床需求。随着肿瘤消融技术如射频、微波和冷冻消融等不断发展,TACE联合肿瘤消融治疗已成为大肝癌治疗中的一个重要治疗手段。然而目前国内外关于大肝癌消融治疗的疗效仍有较多的争议,因此如何选择合适的消融时机,减少消融术后残留,降低消融术后肿瘤的复发,最终使患者生存获益是目前临床和科研仍需继续探讨的难题。针对以上内容,综述并分析了大肝癌消融治疗的现况、困境及未来发展趋势。     

Local injection therapy for hepatocellular carcinoma

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world and ranks the third most common cause of cancer-related death. Surgical resection, liver transplantation and percutaneous ablation are generally considered the only curative treatment for early stage HCC. Besides the limitations of insufficient organ donors and a long waiting time for liver transplantation, however, resection is applied only to patients with good hepatic reserve and localized tumors, with a resectability of 30%. DATA SOURCES: Local ablation therapy, which is minimally invasive but contributes to the significant improvement of survival in patients with unresectable tumor, hasbeen widely used in treating small HCC. Among the techniques of local therapy, percutaneous ethanol injection (PEI) with a complete response in 80% of HCCs less than 3 cm has been accepted as an alternative to surgery in patients with small HCC. Moreover, percutaneous hepatic quantified ethanol injection (PHQEI) or PEI according to the standard criteria has been confirmed to benefit patients with HCC, especially when quantified ethanol is given at a short interval (QESI, the interval was 2-3 days). RESULT: Several limitations related to local percutaneous methods may result in incomplete therapeutic effect in case of larger HCC nodules (>3 cm). CONCLUSION: The combined use of different methods according to the clinical status of patients or tumors may be essential to the effective treatment of HCC.     

局部消融治疗超适应证范围肝癌的现状

肝癌是常见恶性肿瘤之一,我国肝癌发病率占全世界的54％.肝癌的治疗方法主要有手术切除、肝移植、血管介入疗法、局部消融、放疗、化疗、生物及免疫治疗、分子靶向药物、中医中药等.局部消融术操作简单、安全有效、创伤小,在临床中发挥越来越重要作用.     

Microwave coagulation therapy for hepatocellular carcinoma

The efficacy and safety of microwave coagulation therapy (MCT) in patients with hepatocellular carcinoma (HCC) and impaired hepatic reserve were studied. Preoperative background factors, postoperative results, and prognostic factors were compared in 51 patients who underwent hepatic resection (HR group) and 38 patients who underwent microwave coagulation therapy (MCT group). Before surgery, measures of hepatic function, including level of albumin (P = 0.0072), prothrombin time (P < 0.0001), hepaplastin test (P = 0.0088), and the radioactivity of technetium‐99m galactosyl‐human serum albumin 15 min in the liver after injection divided by that in both liver and heart (P < 0.0001) were significantly lower in the MCT group than in the HR group. The indocyanine green dye retention rate at 15 min was significantly greater (P < 0.0001) in the MCT group than in the HR group, and a significant difference was noted in Child‐Pugh grade between the groups (P < 0.0001). Operative time (P = 0.0014) and blood loss during surgery (P = 0.0005) were significantly lower in the MCT group than in the HR group. In contrast, no significant differences were recognized between the groups in the changes in postoperative liver function, or in the rates of morbidity, mortality, local recurrence, and survival. Moreover, the type of treatment (HR or MCT) was not a prognostic factor. The results indicate that MCT can be used safely as an alternative to hepatic resection in patients with poor liver function without reducing the efficacy of local control.