肝癌的靶向治疗

肝癌（HCC）是全球最富有挑战性的恶性肿瘤之一。HCC需要综合治疗，目前尚无特效的治疗药物。分子靶向药物的发展，使HCC的全身治疗有了新的希望。阐述了分子靶向药物的现状，多激酶抑制剂、抗血管生成和抗表皮生长因子受体药物在临床上的进展，认为索拉芬尼是晚期HCC的新的标准治疗药物。     

Nutritional and lifestyle correlates of the cancer-protective hormone melatonin

CONTEXT: Despite growing support for melatonin as a promising agent for cancer treatment and possibly cancer prevention, few studies have elucidated factors that influence endogenous melatonin. This overview summarizes dietary and lifestyle factors that have been shown to affect circulating melatonin levels. BIOLOGICAL MECHANISMS: To date, many animal studies and in vitro experiments have illustrated that melatonin possesses oncostatic activity. Mechanisms that are currently being studied include melatonin's activity as an indirect antioxidant and free radical scavenger; its action on the immune system; suppression of fatty acid uptake and metabolism; and its ability to increase the degradation of calmoduline and to induce apoptosis. Studies further suggest that melatonin reduces local estrogen synthesis, through down-regulation of the hypothalamic-pituitary reproductive axis and direct actions of melatonin at the tumor cell level, thus behaving as a SERM. THERAPEUTIC APPLICATIONS: Several small clinical trials have demonstrated that melatonin has some potential, either alone or in combination with standard cancer therapy, to yield favorable responses. Melatonin or its precursor tryptophan have been found in numerous edible plants, but more studies are needed to evaluate the influence of diets rich in tryptophan and melatonin on circulating melatonin levels in humans. Age, BMI, parity, and the use of certain drugs remain the factors that have been associated most consistently with aMT6s levels. DISCUSSION: Further insights into the effects of dietary and lifestyle factors that modulate circulating melatonin levels may provide the basis for novel interventions to exploit melatonin for the prevention and treatment of human diseases.     

Selecting an optimal staging system for hepatocellular carcinoma

BACKGROUND:

Selecting an appropriate staging system is crucial to predict the outcome of patients with hepatocellular carcinoma (HCC). The optimal prognostic model for HCC is under intense debate. This study investigated the prognostic ability of the 5 currently used staging systems, Barcelona Clinic Liver Cancer (BCLC), Cancer of the Liver Italian Program (CLIP), Japan Integrated Scoring (JIS) system, tumor‐node‐metastasis (TNM), and Tokyo score, for HCC.

METHODS:

Between 2002 and 2008, 1713 prospectively enrolled HCC patients were compared for their long‐term survival by using the Akaike information criterion (AIC) according to the staging or scoring methods of these 5 models.

RESULTS:

The mean and median follow‐up duration was 18 and 14 months, respectively. Among all patients, the CLIP staging system had the lowest AIC value in comparison with other systems in the Cox proportional hazards model, followed by the Tokyo score, JIS score, BCLC staging system, and TNM staging system. Patients undergoing curative treatment had a significantly better survival in comparison with patients undergoing noncurative treatment (P < .001). When the predictive accuracy of the staging systems was analyzed according to treatment strategy, the CLIP staging system had the lowest AIC value and remained the best prognostic model in patients undergoing curative (801 patients) and noncurative (912 patients) treatment.

CONCLUSIONS:

The CLIP staging system is the best long‐term prognostic model for HCC in a cohort of patient with early to advanced stage of HCC. Its predictive accuracy is independent of the treatment strategy. Selecting an optimal staging system is helpful in improving the design of future clinical trials. Cancer 2010. © 2010 American Cancer Society.     

超声引导经皮微波治疗原发性肝癌远期疗效评价

目的　评价经皮穿刺微波凝固治疗 (PMCT)原发性肝癌 (HCC)的远期疗效。方法　在超声引导下对 177例HCC患者共 2 6 5个肿瘤灶进行PMCT ,病灶最大直径 1.5～ 8.7cm ,平均4.12± 1.89cm。随访 5～ 74个月 ,定期复查影像 (彩超、CT、MRI)及血清AFP ,184个结节再次穿刺活检。结果　治疗后超声检查显示 ,92 .0 % (2 0 7/ 2 2 5 )的病灶血流消失 ,88.5 % (138/ 15 6 )的病灶增强CT无强化 ,88.9% (32 / 36 )的病灶增强MRI无强化。 184个结节治疗后再活检 ,92 .4% (170 / 184)完全坏死。 6例患者PMCT后外科切除病灶 ,病理显示肿瘤完全坏死 5例 ,大部分坏死 1例。全组 1～ 5年累计生存率分别为 90 .1%、76 .9%、6 8.3%、6 4.2 %和 5 7.8% ,高分化及中分化者的生存曲线均明显好于低分化者 (P <0 .0 5 ) ,中分化与高分化者之间无统计学差异。全组 1～ 5年累计新生病灶率分别为2 6 .1%、37.8%、43.5 %、48.6 %和 5 8.9%。全组无严重并发症。结论　PMCT治疗HCC安全有效 ,可使直径 <5cm的肿块一次原位灭活 ,患者的 5年生存率较高。     

肝切除序贯双管疗法治疗原发性肝癌

 目的　探讨肝癌手术综合治疗及术后复发预防的合理方案。方法　回顾性总结手术治疗316例原发性肝癌，将肝切除的患者分为三组，进行术后无瘤生存率的比较。第一组为单一肝切除组（n＝218），第二组为术前肝动脉化疗栓塞（TACE）+肝切除组（n＝52），第三组为术前TACE+肝切除+术后门静脉化疗组，称为肝切除序贯双管疗法（n＝46）。结果　第一组术后1、3、5年生存率分别为51.2 %、30.0 %和20.5 %，第二组分别为57.2 %、43.0 %、31.5 %，第三组分别为84.0 %、62.5 %和51.0 %。第三组患者与第一组和第二组患者的术后生存率差异均有统计学意义（P＜0.05）。结论　肝切除序贯双管疗法可以提高肝癌患者的生存率，在推迟和预防术后复发方面起到了积极作用。     

经皮微波热凝治疗肝癌的疗效观察

目的 经皮微波肝穿刺对肝癌进行热凝损毁,观察其对肝癌的作用疗效。方法 52例患者在局麻或硬膜外麻醉下,使用2450MHz微波微型穿刺天线,在B超引导下直接经皮穿刺进入肝癌瘤体内,对其进行热凝固。结果 52例患者的97个瘤体中,直径均＜3cm的肿块61个（62．9％）能1次手术热凝损毁,其中57个（93．4％）经CT或MRI检查,并随访6－12个月,提示瘤体热损毁后未见复发;3－5cm的肿块36个（37．1％）,分2次手术,术后6个月CT或MRI检查提示,27个热凝损毁（75．0％）,9个大部分热凝损毁（25．0％）。经皮微波热凝治疗（PMCT）的患者均未见明显的副作用和其他并发症。结论 PMCT治疗肝癌,尤其对直径＜3cm的瘤体疗效可靠,对＞3．5cm或＜5cm的瘤体仍具有大部分或完全热损毁的作用。     

Interaction between cytostatics and nutrients

Cancer patients have the highest prevalence of malnutrition of any group of hospitalized patients. The presence of the tumor alone may lead to reduced intake of different nutrients and treatment modalities such as surgery, chemotherapy and radiation therapy may further exacerbate nutritional disturbances. Dietary manipulation in experimental systems has shown improvement of tumor response to cancer therapy. Drug pharmacokinetics has been shown to be altered by changes in nutritional delivery. This article reviews the present knowledge, from experimental and clinical standpoints, of the potential role of different nutritional factors on the specific cancer treatment. It is obvious that alteration of at least some dietary factors affect the outcome of different forms of cancer treatment. Indeed, although interest in the clinical significance of optimal dietary intake and supplementation during cancer therapy so far remain marginal, accumulating data indicate that this area deserves further research attention.     

A new prognostic score system in patients with advanced hepatocellular carcinoma not amendable to locoregional therapy: implication for patient selection in systemic therapy trials

BACKGROUND: Advanced hepatocellular carcinoma (HCC) patients who are not candidates for surgery or locoregional therapy are the focus of clinical trials of systemic therapy, as their overall prognosis remains poor. However, the current prognostic systems cannot reliably select appropriate candidates for systemic therapy trials based on the probability of 3-month survival. In this study, the authors constructed a new prognostic score system, the Advanced Liver Cancer Prognostic System (ALCPS), which can objectively predict the probability of 3-month survival. METHODS: Between 1990 and 2005, 1470 patients with advanced HCC who were not amendable to surgery or locoregional therapy were included in the analysis. The prognostic score system was developed from the multivariate Cox model through a point system and validated in an independent set. Okuda staging and Cancer of the Liver Italian Program (CLIP) score were also applied to the validation set to compare their predictive accuracy. RESULTS: The ALCPS was based on 11 prognostic factors with different weights: ascites, abdominal pain, weight loss, Child-Pugh grade, alkaline phosphatase, total bilirubin, alpha-fetal protein, urea, portal vein thrombosis, tumor size, and presence of lung metastases. It stratified patients in both training and validation sets to different prognostic groups with significant difference in 3-month overall survival (P < .0001). By using the patients in the validation set with known 3-month survival status, the ALCPS showed significantly better predictive power (area under the curve [AUC], 0.77) than Okuda score (AUC, 0.66; P < .001) and CLIP score (AUC, 0.71; P = .002). CONCLUSIONS: The new prognostic system can objectively help the clinicians to select appropriate candidates for evaluation of treatment efficacy in systemic therapy trials for advanced HCC.     

Long‐term outcomes of proton beam therapy in patients with previously untreated hepatocellular carcinoma

Long‐term efficacy of proton beam therapy (PBT) remains unclear for patients with previously untreated hepatocellular carcinoma (HCC). We aimed to study the long‐term outcomes of PBT according to Barcelona Clinic Liver Cancer (BCLC) staging classifications in patients with previously untreated HCC. The major eligibility criteria of this observational study were an Eastern Cooperative Oncology Group performance status (PS) 0–2, Child–Pugh grade A or B, previously untreated HCC covered within an irradiation field, and no massive ascites. A total of 66.0–77.0 GyE was administered in 10–35 fractions. Local tumor control (LTC), defined as no progression in the irradiated field, progression‐free survival (PFS), and overall survival (OS) were assessed according to BCLC staging. From 2002 to 2009 at our institution, 129 patients were eligible. The 5‐year LTC, PFS, and OS rates were 94%, 28%, and 69% for patients with 0/A stage disease (n = 9/21), 87%, 23%, and 66% for patients with B stage disease (n = 34), and 75%, 9%, and 25% for patients with C stage disease (n = 65), respectively. The 5‐year LTC and OS rates of 15 patients with tumor thrombi in major vessels were 90% and 34%, respectively. Multivariate analyses revealed that PS (0 versus 1–2) was a significant prognostic factor for OS. No grade 3 or higher adverse effects were observed. PBT showed favorable long‐term efficacies with mild adverse effects in BCLC stage 0 to C, and can be an alternative treatment for localized HCC especially when accompanied with tumor thrombi. This study was registered with UMIN Clinical Trials Registry (UMIN000025342).     

肝移植治疗晚期原发性肝癌的初步报告

目的 探索晚期肝癌行同种原位肝移植的治疗价值。方法收集我院2000年8月～2002年2月进行的36例肝移植的临床资料,对其中15例晚期肝癌的临床资料进行分析．并对其中手术后出院的13例进行随访。结果 1年生存率85．7％(6／7),有1例6个月内肝癌复发转移而死亡;至2002年2月,无瘤生存10例,最长19个月,最短5个月;带瘤生存2例,1例生存19个月,1例生存10个月。结论 根据我国国情,只要患者经济状况允许,无肝外转移的晚期肝癌仍是目前我国肝移植的适应证。     

规范化肿瘤营养治疗示范病房标准

营养不良在肿瘤患者中发生率高,降低治疗疗效及增加治疗副反应, 因此制定全国规范化肿瘤营养治疗示范病 房标准十分必要。肿瘤营养疗法是遵循肿瘤学原理,运用营养学方法,治疗肿瘤及其并发症,从而改善身体状况及预后的 过程,包括营养诊断、营养治疗、疗效评价三个阶段。而规范化肿瘤营养治疗示范病房是规范实施肿瘤营养疗法,具有示范、 引导作用的单位 [ 含病房、科室和（或）医院]。三级综合医院、有条件的二级综合医院以及所有肿瘤专科医院均要求积极 创建“规范化肿瘤营养治疗示范病房”。在全国范围内建立规范化肿瘤营养治疗示范病房,对于防治肿瘤相关性营养不良, 推动营养治疗的合理应用,提升肿瘤治疗水平,维护患者医疗安全,提高患者生活质量,延长患者生存时间,节约医疗费 用等具有重要意义。     

肝细胞癌的诱导分化治疗

肝细胞癌是最常见的恶性肿瘤之一,虽然其诊断和治疗有不少进展,但其预后仍较差,病死率较高。诱导分化治疗这一概念的提出为肝细胞癌的治疗指明了新的方向。诱导分化治疗在血液系统肿瘤治疗方面获得了成功,其经典范例是全反式维甲酸临床治疗急性早幼粒白血病;但是其在恶性实体肿瘤领域的进展远不如血液系统肿瘤。目前特异性的肝细胞癌诱导分化剂较少,相关的临床应用更是有限。靶向性地针对肿瘤干细胞分化相关的信号转导通路或转录因子进行干预可能起到诱导肝细胞癌分化的效果,例如通过上调与肝细胞分化密切相关的转录因子肝细胞核因子4α（hepatocyte nuclear factor 4α, HNF4α)来诱导肝癌细胞,特别是诱导肝癌干细胞向成熟阶段分化,已初见成效。肿瘤发生发展过程中存在诸多表观遗传学异常改变,如甲基化、乙酰化水平异常或microRNA表达异常,有些改变与肿瘤分化密切相关,干预这些异常改变的药物如组蛋白去乙酰化酶抑制剂对肿瘤起到一定的诱导分化作用。因此,肿瘤干细胞学说的出现及表现遗传学的发展给肝细胞癌诱导分化治疗研究提供了具体的途径。     

Systemic therapy for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is currently the fifth most common solid tumor worldwide and the third leading cause of cancer-related death. Eighty percent of new cases occur in developing countries, but the incidence is rising in economically developed regions including Japan, Western Europe, and the United States. More than 80% of patients present with advanced or unresectable disease, and for those patients who do undergo resection, the recurrence rates can be as high as 50% at 2 years. Thus, a large number of patients will seek systemic therapy. Systemic cytotoxic chemotherapy is largely ineffective and can have significant toxicity in patients with underlying liver dysfunction. Newer biologic agents that target molecular abnormalities common to HCC may improve the clinical outcome in patients with HCC.     

Radiation therapy for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide, and its incidence is on the rise. The primary therapy is resection or liver transplant, but only a minority of patients present with resectable disease. Historically, radiotherapy has not played a significant role in the treatment of liver malignancies because of the low tolerance of the whole liver to radiation. With improvements in 3-dimensional conformal radiotherapy and intensity-modulated radiotherapy, higher doses of radiation can be delivered to target lesions with low doses to the noninvolved liver; thus, experience in the use of radiation for the treatment of focal HCC has increased. At the same time, our understanding of the relationships between radiation dose and volume and the risk of classic radiation-induced liver disease and other toxicities more likely to occur in HCC patients has improved considerably. These developments have led to a body of evidence that now supports the careful use of radiotherapy for unresectable HCC. The rationale for studying radiotherapy in a randomized trial is strong.     

Proton therapy for hepatocellular carcinoma

Proton radiotherapy has seen an increasing role in the treatment of hepatocellular carcinoma(HCC).Historically,external beam radiotherapy has played a very limited role in HCC due to a high incidence of toxicity to surrounding normal structures.The ability to deliver a high dose of radiation to the tumor is a key factor in improving outcomes in HCC.Advances in photon radiotherapy have improved dose conformity and allowed dose escalation to the tumor.However,despite these advances there is still a large volume of normal liver that receives a considerable radiation dose during treatment.Proton beams do not have an exit dose along the beam path once they enter the body.The inherent physical attributes of proton radiotherapy offer a way to maximize tumor control via dose escalation while avoiding excessive radiation to the remaining liver,thus increasing biological effectiveness.In this review we discuss the physical attributes and rationale for proton radiotherapy in HCC.We also review recent literature regarding clinical outcomes of using proton radiotherapy for the treatment of HCC.     

Charged-particle therapy for hepatocellular carcinoma

Historically, the use of external-beam radiotherapy for hepatocellular carcinoma (HCC) has been limited by toxicity to the uninvolved liver and surrounding structures. Advances in photon radiotherapy have improved dose conformality to the tumor and facilitated dose escalation, a key contributor to improved HCC radiation treatment outcomes. However, despite these advances in photon radiotherapy, significant volumes of liver still receive low doses of radiation that can preclude dose escalation, particularly in patients with limited functional liver reserves. By capitalizing on the lack of exit dose along the beam path beyond the tumor and higher biological effectiveness, charged-particle therapy offers the promise of maximizing tumor control via dose escalation without excessive liver toxicity. In this review, we discuss the distinctive biophysical attributes of both proton and carbon ion radiotherapy, particularly as they pertain to treatment of HCC. We also review the available literature regarding clinical outcomes and the toxicity of using charged particles for the treatment of HCC.     

Liver transplantation for unresectable malignancies: Beyond hepatocellular carcinoma

Indications for liver transplantation have expanded over the past few decades owing to improved outcomes and better understanding of underlying pathologies. In particular, there has been a growing interest in the field of transplant oncology in recent years that has led to considerable developments which have pushed the boundaries of malignant indications for liver transplantation beyond hepatocellular carcinoma (HCC). In this article, we review and summarise the published evidence for liver transplantation in non-HCC primary and metastatic liver malignancies and highlight ongoing clinical trials that address unresolved questions therein. We also examine the current technical, immunological and oncological challenges that face liver transplantation in this growing field and explore potential approaches to overcome these barriers.     

Cancer stem cells in hepatocellular carcinoma: Recent progress and perspective

Although the “cancer stem cell (CSC)” hypothesis was first proposed roughly 50 years ago, recent progress in stem cell biology and technologies has successfully achieved the identification of CSCs in a variety of cancers. CSCs are defined as a minor population which possesses a prominent ability to generate new tumors that faithfully reproduce the phenotype of original tumors in xenotransplant assays. Additionally, CSCs are able to self-renew and generate differentiated progenies to organize a hierarchical cell system in a similar fashion to normal stem cells. Although not all types of cancer follow the CSC theory, it provides an attractive cellular mechanism to account for the therapeutic resistance and recurrence of the disease. A minor population with CSC properties has been detected in a number of established hepatocellular carcinoma (HCC) cell lines and extensive analyses characterizing the CSC system in primary HCC samples are now ongoing. Considering that HCC has high rates of recurrence and mortality, novel therapeutic approaches are urgently required. Although the clinical relevance of CSCs remains elusive, deep understanding of the cellular organization of HCC may allow us to develop therapies targeting specific cell types such as CSCs.     

Diabetes mellitus is associated with increased mortality in patients receiving curative therapy for hepatocellular carcinoma

Background.

Diabetes mellitus (DM) is closely associated with hepatocarcinogenesis. This study explores the prognostic impact of DM in patients who received curative therapy for localized hepatocellular carcinoma (HCC).

Methods.

Patients who had been diagnosed with stage I or II HCC in 2003 and 2004 and received surgical resection or local ablation therapy were identified from the population-based Taiwan National Cancer Registry. Data pertaining to DM and other comorbidities were retrieved from the Taiwan National Health Insurance database. Liver cancer-specific survival (LCS), liver disease-related survival (LDS) and overall survival (OS) rates were compared between patients with and without DM. The presence of other comorbidities and tumor status were adjusted using multivariate analysis.

Results.

A total of 931 patients who fulfilled the study criteria were analyzed; 185 (20%) of them had DM (type 1 or type 2). The LCS, LDS, and OS rates were significantly worse for patients with DM than patients without DM (all p < .001). After adjusting for age, sex, tumor stage, treatment, and the presence of other comorbidities, DM remained an independent predictor of poorer LCS (hazard ratio [HR] = 1.57; p < .001), LDS (HR = 1.70; p < .001), and OS (HR = 1.69; p < .001). The associations between DM and mortality were consistent among subgroups, irrespective of tumor size, stage, treatment modality, and liver cirrhosis.

Conclusions.

DM is an independent factor for poorer prognosis in patients who received curative therapy for localized HCC.