Clinical characteristics and outcome of a cohort of 101 patients with hepatocellular carcinoma

AIM: To conduct a cohort study of 101 patients with hepatocellular carcinoma (HCC) presenting to a tertiary care medical referral center in Germany between 1997 and 1999. METHODS AND RESULTS: Data were retrospectively analyzed by chart review. In 95 cases (72 males and 23 females) sufficient data were available for analysis. Twenty five (29%) of 85 patients were HBsAg or anti HBc positive, 21/85 (25%) were anti HCV positive, and 6/85 (7%) were positive for both HBV and HCV-markers. Age was significantly lower in HBV positive patients than in the other two groups. Thirty one (34%) of 90 patients had histories of alcohol abuse. In 79/94 (84%) patients, cirrhosis was diagnosed. Of these cirrhotic patients, 29/79 (37%) belonged to Child Pugh's group (CHILD) A, 32/79 (40%) to CHILD B, and 18/79 (23%) to CHILD C. AFP was elevated in 61/91 (67%) patients. A single tumor nodule was found in 38/94 (40%), more than one nodule in 31/94 (34%), and 25/94 (26%) had a diffusely infiltrating tumor, i.e. the tumor margins could not be seen on imaging procedures. Portal vein thrombosis was present in 19/94 (20%). Imaging data consistent with lymph node metastases were found in 10/92 (11%), while distant metastases were found in 8/93 (9%). According to Okuda 28/94 (30%) were grouped to stage I, 53/94 (56%) were grouped to stage II, and 13/94 (14%) were grouped to stage II. Survival data were available for 83 patients. The Kaplan-Meier estimate for median survival was 8 4 months. Factors influencing survival were the Okuda score, the presence of portal vein thrombosis, and the presence of ascites. The presence of non complicated liver cirrhosis by itself, distant metastases, or infection with hepatitis viruses did not influence survival. AFP positivity by itself did not influence survival, though patients with an AFP value greater than 100 microg/L did experience shortened survival. Treatment besides tamoxifen or supportive care was associated with prolonged survival. The influence of therapy on survival was most pronounced in Okuda stage II patients. There was longer survival in those Okuda stage II patients who were treated with percutaneous ethanol injection. CONCLUSION: Even in a low incidence area such as Germany, the majority of HCC is caused by viral hepatitis and therefore potentially preventable. Reflecting the high proportion of advanced stage tumors in our patients, the median survival was poor. Patients who received active therapy had a longer survival.     

Hepatocellular cancer: Resection or transplantation

Surgery remains the treatment of choice for hepatocellular carcinoma (HCC). For HCC without underlying cirrhosis resection remains the mainstay treatment option. Prognosis depends on the stage of the tumor. Survival appears to be better for small (less than 5 cm) solitary tumors with negative resection margins and absence of vascular invasion. At present, liver transplantation does not have an established role in the treatment of HCC in a non-cirrhotic liver. Because of the high recurrence rate, it should not be considered for more advanced disease which is not amenable to resection. The surgical approach in cirrhotics depends not only on the stage of the tumor but also on the liver functional reserve. Tumor size, presence of multifocal disease, and vascular invasion determine the risk of HCC recurrence after resection, and the functional stability of the liver determines both resectability and outcome. In societies in which transplantation is not available, small tumors will be treated with liver resection. The outcome in patients with well preserved liver function is relatively good, at least in the medium term. However, recurrent tumor and progressive hepatic decompensation have significant adverse effects on long-term survival. Poor functional reserve may be associated with significant perioperative mortality and lower survival due to progressive liver failure. In our opinion, for small cirrhosis-related HCCs, liver transplantation offers better long-term prospects than resection. Therefore, if liver transplantation is available as an option it should be considered as the treatment of choice, particularly for younger patients with otherwise good life expectancy.     

肝细胞癌的分子靶向治疗

分子靶向治疗是近10年来肿瘤治疗领域的重大突破,在肺癌、恶性胃肠间质细胞瘤、恶性淋巴瘤、肠癌、乳腺癌等肿瘤的治疗中已获得很大的成功,尤其HCC的分子靶向治疗在小分子靶向治疗上取得了令人瞩目的新进展,特别是多靶点药物索拉非尼在HCC的靶向治疗中取得的成功,使HCC分子靶向全身治疗有了新的标准。     

Liver transplantation for hepatocellular carcinoma: Korean experience

Hepatocellular carcinoma (HCC) is the second most common cause of male cancer death in Korea, where the major etiology, chronic hepatitis B virus infection, is endemic. With a high incidence of unresectable HCCs and a low cadaveric organ donation rate, the number of adult living-donor liver transplantations (LDLTs) has increased rapidly, by tenfold, over the past 10 years, as an alternative to deceased-donor liver transplantation (DDLT) in Asia, including Korea. Currently, HCC accounts for more than 40% of the indications for adult LDLT as the associated decompensation cirrhosis or unresectable HCC with 2.8% perioperative mortality at our institute. In determining eligibility for LDLT, the Milan criteria, which have a major aim of reducing the wastage of cadaveric liver grafts, still remain the gold standard. Our published results with 168 adult LDLTs show no difference from the results with DDLT for HCC that meets the Milan criteria. However, since a substantial proportion of adult LDLT patients not fulfilling the Milan criteria have been found to survive for longer than expected, and because a live donor organ is a private gift, most LDLT programs in Korea accept HCC patients beyond the Milan criteria, and the reported 3-year survival rates for such patients are approximately 63%. Our new proposal for expanded criteria (Asan criteria; tumor diameter ≤5 cm, number of lesions ≤6, no gross vascular invasion) in LDLT has focused on extending the number limits but keeping the maximum tumor size at 5 cm, because even modest expansion of tumor size limits beyond the Milan criteria adversely affected survival. The overall 5-year patient survival rates were 76.3 and only 18.9% within and beyond the Asan criteria, respectively; these criteria broaden the indications for patient selection and can more accurately identify patients who will benefit from LDLT than the conventional Milan criteria and the University of California at San Francisco criteria. In Asia, where the option for DDLT is minimal or negligible, LDLT with the modest expanded selection criteria will continue to provide a chance of long-term survival for some patients with advanced HCC.     

Hepatocellular carcinoma

Abstract Hepatocellular carcinoma (HCC) has ranked second in cancer mortality in China since the 1990s and is increasing in frequency among males in many countries. Hepatitis B and C viruses, aflatoxin and algal toxin in the contaminated drinking water remain major aetiological factors and hepatitis G virus and transfusion-transmitted virus can not be excluded. A prospective randomized control trial screening for HCC in a high-risk population using alpha fetoprotein (AFP) and ultrasonography has demonstrated a decrease in HCC mortality. Rapidly progressing medical imaging has continuously contributed to the improving treatment results. Surgical resection still plays a major role in influencing prognosis of HCC. Studies on recurrence and metastasis after curative resection have become a key issue for further improvement of the surgical outcome. Regional cancer therapies are progressing rapidly, based on the advances in early diagnosis. The advantages and disadvantages of these are noted. Multimodality combination and sequential treatment has been accepted as an important approach for unresectable HCC and cytoreduction and sequential resection have attracted attention. Conformal radiotherapy has shown important potential for HCC treatment. Intra-arterial chemotherapy has been repeatedly proved effective; however, systemic chemotherapy for HCC remains disappointing. The effects of tamoxifen are questionable, whereas α-interferon has been shown to have significant potential, particularly in prevention of recurrence. All of these treatments have resulted in continuing improvement of HCC prognosis in some centres.     

肝癌动脉化疗栓塞效果的病理评价

目的研究肝细胞癌经动脉化疗栓塞治疗后癌肿的变化，探索提高疗效的方法。方法对动脉化疗栓塞治疗后行手术的３９例肝癌和１１例对照标本进行坏死程度与包膜、治疗次数、病理类型、分化、血管损伤及淋巴细胞浸润诸因素相关性的分析。结果完全坏死者６例，３０％＿９５％坏死者１４例，仅５％坏死及无坏死者１９例，１１例ＤＳＡ无坏死。癌肿坏死程度与肿癌分化、治疗次数、淋巴细胞浸润无关，而与病理类型、包膜、血管损伤有关。结论肝癌动脉化疗栓塞是中晚期肝癌目前唯一可取的治疗方法。对于有包膜的肝细胞癌，只要治疗能达到癌肿部位，即使一次治疗，也可收到明显的效果。对于如何使每例都达到彻底的癌肿坏死是值得进一步探讨的。     

Role of sorafenib in the treatment of advanced hepatocellular carcinoma: An update

Sorafenib is the first and only p.o. administrated drug currently approved to treat advanced hepatocellular carcinoma (HCC). However, concerns have been raised about sorafenib therapy, including acquired drug resistance. This review provides an overview of sorafenib in the treatment of HCC on the basis of data obtained in the laboratory and in clinical studies. Three underlying mechanisms have been found to support sorafenib therapy. First, sorafenib blocks HCC cell proliferation by inhibiting BRaf and Raf1/c‐Raf serine/threonine kinase phosphorylation in the mitogen‐activated protein kinase pathway. Second, sorafenib induces apoptosis by reducing elF4E phosphorylation and downregulating Mcl‐1 levels in tumor cells. Third, sorafenib prevents tumor‐associated angiogenesis by inactivating vascular endothelial growth factor receptors (VEGFR‐2 and ‐3) and the platelet‐derived growth factor receptor‐β. Clinical trials have demonstrated the effectiveness and relative safety of sorafenib, and thus the drug is used in unresectable HCC. However, many patients may develop acquired resistance to sorafenib, so their response to sorafenib is eventually lost. Sorafenib may induce autophagy, which leads to apoptosis. However, autophagy can also cause drug resistance. Many studies have combined sorafenib with other treatments in an effort to increase its effects, reduce the necessary dose or overcome resistance. It is urgent to study the mechanisms underlying how sorafenib interacts with cellular molecules and other drugs to increase its efficacy and reduce resistance in HCC patients.     

HBx-DNA probe preparation and its application in study of hepatocarcinogenesis

AIM To study the role of HBV especially HBx Open Reading Frame (ORF) in the development of hepatocellular carcinoma (HCC).METHODS HBV 3.2kb fragment was retrieved by digesting recombinant plasmid pBR322-2HBV with EcoR Ⅰ, and HBx 0.59kb fragments by digesting HBV-DNA with BamHⅠ and BglⅡ. These fragments were labelled with digoxigenin to get HBV-DNA and HBx-DNA probes. HBV-DNA was detected in HCC by dot blot and Southern blot hybridization with HBV-DNA probe, so the positive specimens in which HBV-DNA were integrated were selected. HBx-DNA was subsequently detected in the selected specimens with HBx-DNA probe.RESULTS HBV-DNA was detected in 75% HCC, among which integrated type, integrated + free type covered 63.6% and 36.4%. There was no free type. HBx-DNA was detected in 90.5% specimens of integrated type.CONCLUSION Hepatocarcinogenesis was highly related to HBV-DNA integration, and HBV-DNA mainly integrated into chromosome with incomplete virus DNA fragments among which HBx fragment was the predominant one.     

肝细胞癌患者肝移植术后肿瘤复发转移的防治

肝细胞癌(HCC)仍是目前发病率较高的消化道肿瘤,肝移植能从根本上切除肿瘤病灶,是HCC综合治疗方案中的主要手段之一。移植后肿瘤的复发和转移问题,是影响受体长期生存的主要因素。近年来,得益于全球范围的技术改进和经验积累,在HCC的诊疗方面取得了的长足的发展和进步。针对HCC肝移植适应证、复发转移预测、肝移植围手术期干预和术后HCC复发的综合治疗等方面进行探讨。     

质子刀放射治疗肝细胞癌的研究进展

随着对正常组织耐受能力的研究的不断深入和放疗技术的发展,针对大部分肝细胞癌（HCC）患者伴有的肝硬化,肿瘤体积大、多发且伴有血管浸润,甚至出现门静脉癌栓等现状,放射治疗便成为HCC降级治疗及辅助治疗的重要手段。其中质子刀（PBT）作为一种较新型的放疗方法取得了较为显著的临床效果。介绍了PBT治疗HCC的生物学特性及其临床疗效和毒性副作用。前期的研究结果表明PBT对于局部照射剂量具有良好的控制作用,可降低对健康肝细胞及周围正常组织的毒性。但目前的临床研究显示PBT应用于HCC也存在着一些禁忌证,值得进一步界定。     

Current controversies surrounding liver transplantation for hepatocellular carcinoma

Liver transplantation (LT) for hepatocellular carcinoma (HCC) has progressed rapidly over the last decade from a futile therapy to the first choice therapy for suitable patients. Excellent outcomes of LT for HCC can be largely attributed to the use of the Milan Criteria, which have restricted LT to patients with early stage tumors. These criteria may be conservative, and it is likely that a subset of patients with tumors beyond these criteria can have acceptable outcomes. However, there is currently insufficient data to accept more liberal criteria as a standard of care, and a higher quality evidence base must be achieved to prevent poor utilization of valuable donor liver resources. In the future, it is probable that more sophisticated selection criteria will emerge incorporating aspects of tumor biology beyond tumor size and number. Dropout from the waiting list due to tumor progression remains a clinical challenge particularly in regions with prolonged waiting times. Priority allocation using HCC MELD points is a practical and transparent solution that has successfully reduced waitlist dropout for HCC patients. Further refinements of the HCC MELD point system are required to ensure equity of access to LT for non‐HCC patients and prioritization of HCC patients with the highest risk of dropout. Improving the evidence base for pre‐LT locoregional therapy to prevent waitlist dropout is an urgent and difficult challenge for the LT community. In the interim transplant clinicians must restrict the use of these therapies to those patients who are most likely to benefit from them.     

Recurrence or metastasis of HCC:predictors, early detection and experimental antiangiogenic therapy

AIM To investigate the predictors for recurrence or metastasis of HCC, and to evaluate the effect of antiangiogenic therapy on the growth of transplantable human HCC in nude mice. METHODS RT-PCR was used to measure the expression of matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor (VEGF) in 56 pairs of nontumorous liver and tumor samples. Sixty blood samples from human HCC were examined by nested RT-PCR to find out AFP mRNA. Recombinant human endostatin and polyclonal antibody against VEGF were administered to treat human HCC transplanted in nude mice. RESULTS Thirty of 56 HCC samples showed stronger expression of MMP-9 in tumorous tissues than in nontumorous tissues. Fifteen of the 26 patients with relative expression level of MMP-9 more than 0.34 developed tumor recurrence or metastasis, whereas only 7 of 30 patients with relative expression level less than 0.34 developed tumor recurrence (P＜0.05).There was no significant difference in the relative expression level of VEGF between patients with postoperative recurrence or metastasis and those without recurrence. AFP mRNA was detectable in 53.3% of patients with HCC. The sensitivity and specificity of AFP mRNA as a marker to detect hematogenous dissemination of HCC cells was 81.8% and 84.4%, respectively. Recombinant human endostatin and polyclonal antibody against VEGF inhibited the growth of transplantable HCC in nude mice by 52.2% and 45.7%, respectively.CONCLUSION MMP-9 expression in HCC correlates with the postoperative recurrence or metastasis of HCC. Patients with high level of MMP-9 expression in HCC are susceptible to metastasis. AFP mRNA could serve as an indicator of hematogenous spreading of HCC cells in circulation and a predictor of recurrence or metastasis of HCC. Antiangiogenesis may be an adjuvant therapy for HCC.     

Role of anti-angiogenesis therapy in the management of hepatocellular carcinoma: The jury is still out

As the leading cause of disease-related deaths, cancer is a major public health threat worldwide. Surgical resection is still the first-line therapy for patients with early-stage cancers. However, postoperative relapse and metastasis remain the cause of 90% of deaths of patients with solid organ malignancies, including hepatocellular carcinoma (HCC). With the rapid development of molecular biology techniques in recent years, molecularly targeted therapies using monoclonal antibodies, small molecules, and vaccines have become a milestone in cancer therapeutic by significantly improving the survival of cancer patients, and have opened a window of hope for patients with advanced cancer. Hypervascularization is a major characteristic of HCC. It has been reported that anti-angiogenic treatments, which inhibit blood vessel formation, are highly effective for treating HCC. However, the efficacy and safety of anti-angiogenesis therapies remain controversial. Sorafenib is an oral multikinase inhibitor with anti-proliferative and anti-angiogenic effects and is the first molecular target drug approved for the treatment of advanced HCC. While sorafenib has shown promising therapeutic effects, substantial evidence of primary and acquired resistance to sorafenib has been reported. Numerous clinical trials have been conducted to evaluate a large number of molecularly targeted drugs for treating HCC, but most drugs exhibited less efficacy and/or higher toxicity compared to sorafenib. Therefore, understanding the mechanism(s) underlying sorafenib resistance of cancer cells is highlighted for efficiently treating HCC. This concise review aims to provide an overview of anti-angiogenesis therapy in the management of HCC and to discuss the common mechanisms of resistance to anti-angiogenesis therapies.     

Combining antiangiogenic therapy with immunotherapy exerts better therapeutical effects on large tumors in a woodchuck hepatoma model

Cytokine and antiangiogenic gene therapies have proved effective in implanted hepatocellular carcinoma (HCC) models in which small tumor burdens were established in small rodents. These models, however, may not reflect human HCCs, which are frequently detected at a stage when tumors are large and multifocal. In addition, HCC in patients is often associated with viral hepatitis. To investigate the effectiveness of a mixture type of gene therapy strategy on large tumor burdens, we used the woodchuck model in which woodchuck hepatitis virus-induced HCCs are large and multifocal, simulating the conditions in humans. Adenoviruses encoding antiangiogenic factors (pigment epithelium-derived factor and endostatin) or cytokines (GM-CSF and IL-12) were delivered via the hepatic artery separately or in combination into woodchuck livers bearing HCCs. Our results showed that the mixture type of strategy, which contained two cytokines and two antiangiogenic factors, had better antitumor effects on large tumors as compared with monotherapy either with antiangiogenic or cytokine genes. The immunotherapy recruited significant levels of CD3⁺ T cells that infiltrated the tumors, whereas the antiangiogenesis-based therapy significantly reduced tumor vasculature. The mixture type of gene therapy achieved both effects. In addition, it induced high levels of natural killer cells and apoptotic cells and reduced the levels of immunosuppressive effectors in the tumor regions. Hence, antiangiogenic therapy may provide the advantage of reducing immune tolerance in large tumors, making them more vulnerable to the immune reactions. Our study implies that in the future, the combination therapy may prove effective for the treatment of patients with advanced HCC.     

5-氟脲嘧啶腹腔化疗预防裸鼠人结肠癌细胞肝转移研究

目的探索预防大肠癌根治术后肝转移局部区域性辅助化疗新途径.方法利用裸鼠人结肠癌细胞肝转移模型观察术后早期大剂量大容积5-氟脲嘧啶腹腔化疗预防裸鼠经睥接种的人结肠癌细胞肝转移的疗效.结果术后早期5-氟脲嘧啶40 mg/生理盐水40 ml/kg,1次/d,连续2 d 的腹腔化疗可使裸鼠肝转移发生率降低40%,平均每只裸鼠肝转移瘤数目减少50.89%,平均每只裸鼠生存时间延长48.21%.结论腹腔化疗是一个预防大肠癌根治术后肝转移有效的辅助化疗新途径.     

Adjuvant therapy in pancreatic cancer

The outlook for patients with pancreatic cancer has been grim. There have been major advances in the surgical treatment of pancreatic cancer, leading to a dramatic reduction in post-operative mortality from the development of high volume specialized centres. This stimulated the study of adjuvant and neoadjuvant treatments in pancreatic cancer including chemoradiotherapy and chemotherapy. Initial protocols have been based on the original but rather small GITSG study first reported in 1985. There have been two large European trials totalling over 600 patients (EORTC and ESPAC-1) that do not support the use of chemoradiation as adjuvant therapy. A second major finding from the ESPAC-1 trial (541 patients randomized) was some but not conclusive evidence for a survival benefit associated with chemotherapy. A third major finding from the ESPAC-1 trial was that the quality of life was not affected by the use of adjuvant treatments compared to surgery alone. The ESPAC-3 trial aims to assess the definitive use of adjuvant chemotherapy in a randomized controlled trial of 990 patients.     

Reappraisal of surgical treatment of small hepatocellular carcinomas in cirrhosis: Clinicopathological study of resection or transplantation

Thirty-two patients with hepatocellular carcinoma (HCC) occurring in individuals with cirrhosis had a potentially curative surgical procedure. Twenty-two had segmental hepatic resections (HR), and 10 underwent orthotopic liver transplantation (OLTx). The diagnosis of hepatic malignancy was established in each case preoperatively, and each case was studied intraoperatively by means of sonography. Postoperatively each surgical specimen was examined pathologically with attention to the possibility of intrahepatic tumor spread. Twenty-three of the 32 patients had single small HCC lesion (<5 cm diameter) identified preoperatively. Sixteen of these underwent HR and seven underwent OLTx. Multiple additional neoplastic lesions were found in 19% of the 16 HR cases and in 14% of those undergoing OLTx when the resection specimens were examined pathologically. Vascular invasion was present in 43% of the OLTx patients and in 25% of the HR patients. Subtotal hepatic resection for small HCC occurring in cirrhosis has produced few long-term survivals. Both pre- and intraoperative sonography have been shown to underestimate the extent and distribution of these tumors. Based upon this experience that (1) vascular spread occurs often in HCC and (2) a high risk of postoperative hepatic failure can be expected after HR in cirrhotic individuals, OLTx is the most rational surgical procedure for such cases as it has the potential to cure.     

HBx-DNA probe preparation and its application in study of hepatocarcinogenesis

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Developing better treatments in hepatocellular carcinoma

The marked heterogeneity of hepatocellular carcinoma (HCC), particularly with regard to the etiology and severity of the underlying cirrhosis, makes clinical trial design in this disease very challenging. In addition, despite the global burden of HCC, there have been relatively few randomized studies. The major advance in medical therapy in HCC has been the benefit of sorafenib, as demonstrated in two Phase III studies. However, the benefit is small, and new therapies to augment or replace sorafenib are urgently needed. These newer therapies, as well as the progress made in two important areas – clinical trial design and molecular characterization – are the subject of this article.     

Immunotherapy for hepatocellular carcinoma:Current and future

Hepatocellular carcinoma(HCC) arises on the background of chronic liver disease. Despite the development of effective anti-viral therapeutics HCC is continuing to rise, in part driven by the epidemic of non-alcoholic fatty liver disease. Many patients present with advanced disease out with the criteria for transplant, resection or even locoregional therapy. Currently available therapeutics for HCC are effective in a small minority of individuals. However,there has been a major global interest in immunotherapies for cancer and although HCC has lagged behind other cancers, great opportunities now exist for treating HCC with newer and more sophisticated agents. Whilst checkpoint inhibitors are at the forefront of this revolution, other therapeutics such as inhibitory cytokine blockade, oncolytic viruses, adoptive cellular therapies and vaccines are emerging. Broadly these may be categorized as either boosting existing immune response or stimulating de novo immune response. Although some of these agents have shown promising results as monotherapy in early phase trials it may well be that their future role will be as combination therapy,either in combination with one another or in combination with treatment modalities such as locoregional therapy. Together these agents are likely to generate new and exciting opportunities for treating HCC, which are summarized in this review.