Рак печени

Заболеваемость и смертность

Рак печени

Заболеваемость и смертность

Рак печени является шестым по распространенности раком и второй лидирующей причиной смертности от рака во всем мире [1]. Самые высокие показатели заболеваемости в восточной и юго-восточной Азии и в северной и западной Африке. Во всем мире гепатоцеллюлярная карцинома (HCC) составляет 70–90% случаев рака печени [1]. Статистические данные компилированы SEER (Surveillance, Epidemiology, and End Results) программой Национального института рака (National Cancer Institute) для категории «рак печени и внутрипеченочных желчных протоков» [2].

По данным Американского онкологического общества (American Cancer Society), в США ежегодно диагностируется приблизительно 40 710 новых случаев рака печени и внутрипеченочных желчных протоков (29 200 мужчин и 11 510 женщин) и происходит приблизительно 28 920 смертей (19 610 мужчин и 9 310 женщин) вследствие этих заболеваний ежегодно [3]. Частота рака печени и внутрипеченочных желчных протоков, в целом, базируется на случаях, диагностированных в период между 2009 и 2013 годами, и составляет примерно 8,4 на 100 000 человек в год. За тот же период возраст-скорректированная смертность была равна 6,1 на 100 000 человек в год, а пожизненный риск развития рака печени и внутрипеченочных желчных протоков — примерно 0,95%. Эти общие статистические данные в значительной степени отражают статистические данные о HCC, на долю которой в Соединенных Штатах приходится 73,8% случаев рака печени и внутрипеченочных желчных протоков [2].

Этиология и факторы риска

Вирусный гепатит

Вирусные гепатиты B (HBV) и C (HCV) вместе являются причиной 74,3% HCC случаев во всем мире [4]. Член семейства Hepadnaviridae ДНК-вирусов, HBV интегрируется в геном хозяина и инициирует репликацию вируса путем обратной транскрипции. Гепатокарциногенез возникает в результате нестабильности генома, вызванной инсерционным мутагенезом, онкогенезом вирусного протеина, а также воспалением и фиброзом, вызванным иммунным ответом хозяина [5]. Показано, что степень репликативной активности HBV коррелирует с повышенным риском HCC [6].  HCV представляет собой РНК-флавивирус, который вызывает хроническое воспаление печени, окислительный стресс и циклы регенерации, пролиферации и фиброза. Эти события вызывают геномные, протеомные и транскриптомные аберрации, которые, в конечном итоге, ведут к HCC. В отличие от HBV, HCC, возникающая в контексте HCV инфекции, практически всегда предшествует циррозу [7]. Было показано, что лечение вирусных гепатитов снижает, но не устраняет риск развития HCC [8].

Алкоголь

Метаболизм алкоголя алкогольдегидразой продуцирует гепатокарциноген ацетальдегид. Хроническое потребление алкоголя результирует в иммуносупрессию и часто сосуществует с пищевой недостаточностью фолата и витамина B12, которые незаменимы для синтеза ДНК и продукции антиоксидантов [9]. Алкоголь сильно потенциирует канцерогенное действие вирусного гепатита, диабета и других гепатотоксинов [9, 10]. Длительное (> 10 лет) воздержание от алкоголя может снижать риск HCС [11].

Неалкогольная жировая болезнь печени

Obesity, hyperlipidemia and insulin resistance comprise the metabolic syndrome which is a risk factor for nonalcoholic fatty liver disease (NAFLD), the most common cause of liver disease in developed countries. NAFLD spans a continuum of progressive hepatic steatosis and dysfunction occurring over decades, leading to nonalcoholic steatohepatitis (NASH) and cirrhosis. HCC arises in 4–27% of patients with NASH following the onset of cirrhosis, although HCC can also occur in the absence of steatohepatitis and fibrosis [12]. NAFLD HCC is typically diagnosed at a more advanced age (median 65–70 years) than HCC due to other causes of liver disease [12, 13]. NASH-induced hepatocarcinogenesis is thought to be driven by the upregulation of insulin-like growth factor signaling, increased oxidative stress, the release of inflammatory cytokines and proangiogenic factors, and the downregulation of anti-inflammatory and antiproliferative tumor suppressors [12–14].

Болезни перегрузки железом и наследственный гемохроматоз

Hereditary hemochromatosis (HH) is caused by C282Y and/orиH63D mutations in the HFE gene. Patients with HH have a 100– 200-fold increased risk of developing HCC, and the overall prevalence is approximately 10% with higher rates reported among those with cirrhosis. Iron overload is strongly associated with HCC, even in the absence of an HFE mutation or cirrhosis. The mechanisms of iron-induced hepatocarcinogenesis include direct mitogenic effects, structural DNA damage, and mutagenesis as a result of oxidative stress, lipid peroxidation, and immunosuppression [15].

Афлатоксины

Aflatoxins are produced by the Aspergillus fungi which grow in the hot, humid climates of south-east Asia and sub-Saharan Africa and are consumed in the form of infected peanuts, grains, and legumes. The main carcinogenic aflatoxin – B1 – induces the formation of DNA adducts leading to missense mutations in p53 and oxidative hepatocytic damage [16]. It is estimated that aflatoxin exposure contributes to 4.6–28.2% of all HCC cases worldwide [17].

Бетель (Betel Quid)

Chewing of betel quid, derived from the areca nut of the Areca catechu palm tree, is a popular practice in southern Asian countries like Taiwan. Chronic betel quid chewing has been implicated in the development of HCC and aerodigestive tract neoplasms. The principal carcinogenic ingredients are nitrosamines and safrole which cause impairments in hepatic detoxification and metabolism, chronic inflammation and oxidative damage, and genetic instability [18, 19].

Дефицит α-1 антитрипсина

The liver glycoprotein alpha-1 antitrypsin (A1AT) is a key mediator in the host response to tissue inflammation and injury. Plasma A1AT deficiency is most commonly caused by Z and/or S mutations in the Pi locus, giving rise to panlobular emphysema, childhood liver disease, cirrhosis and HCC in adults [20, 21]. A1AT deficiency may also potentiate the hepatocarcinogenic effects of infection with HBV or HCV [21]. In addition to HCC, cholangiocarcinoma and mixed HCC-cholangiocarcioma have been reported in association with A1AT deficiency in PiZ heterozygotes [22].

Курение сигарет

The relationship between cigarette smoking, HCC risk, and mortality is controversial and difficult to ascertain given that smoking is often associated with other behaviors that increase HCC and cancer risk in general such as alcohol consumption [11, 23].

Микроцистины

The high incidence of HCC in certain parts of rural China has been linked to the consumption of pond or ditch water contaminated with microcystins, a hepatotoxin produced by blue– green algae [24].

Патогенез

The pathogenesis of HCC is complicated and is the byproduct of intersecting risk factors with diverse mechanisms of hepatocytotoxicity. Hepatocellular injury due to chronic inflammation, oxidative damage, and other stressors causes DNA damage and instability, leading to altered gene expression, dysregulation of metabolic and homeostatic processes, and loss of the normal equilibrium between tumor suppressors and oncogenes, culminating in a final common pathway of carcinogenesis. Key alterations in HCC include TERT promoter mutations or amplification, mutation or deletion of cell cycle regulators including TP53 and CDKN2A, oxidative stress regulators, vascular endothelial growth factor (VEGF) and other angiogenic mediators, MAP kinase and PI3K/Akt/mTOR cascades, and the Wnt/β-catenin axes [25]. The complex molecular taxonomy of HCC has led to challenges in therapeutic targeting, given the myriad interactions between cascades as part of a much larger signaling network.

Предотвращение, скрининг и наблюдение

Primary prevention of HCC consists of a combination of lifestyle and risk factor modifications, and treatment of treatable predisposing conditions. Weight loss and smoking and alcohol cessation have known health benefits that extend beyond reducing HCC incidence and death. Avoidance of hepatotoxins should be encouraged where applicable. Phlebotomy for patients with HH and the use of metformin or thiazolidenediones in diabetic patients have been associated with a decreased risk for HCC, although these have not been officially endorsed as preventive measures [14, 15]. HBV and the subsequent development of HCC can be effectively prevented through adherence to universal vaccination guidelines [26]. Clearance of HBV and HCV as a result of antiviral therapy has been shown to decrease but not completely eliminate the risk of HCC, although its preventive impact in the context of established cirrhosis is uncertain [8].

Surveillance and screening programs for patients with risk factors for HCC can help to decrease mortality (Table 7.1). A study conducted in China randomized approximately 19,000 patients with HBV or chronic hepatitis to screening with ultrasonography and serum AFP every 6 months versus no screening. Despite a compliance rate of only 60% in the screening group, HCC mortality was reduced by 38% [27].

Semiannual monitoring of cirrhotic individuals with a =1.5%/ year risk of developing HCC is considered cost effective and is endorsed by the American and European Associations for the Study of Liver Disease (AASLD, EASL), Asia–Pacific Association for the Study of the Liver and National Comprehensive Cancer Network [28–31]. “At risk” populations who should be screened include patients with HBV or HCV, including those without cirrhosis and who seroconverted or had a sustained virologic response to antivirals. Among HBV patients, there are gender and ethnogeographic differences in predisposition which influence the age at which screening should commence. Native Asian and African carriers of HBV tend to develop HCC at a younger age and earlier screening is therefore recommended [30, 32]. Patients coinfected with HIV and viral hepatitis, and cirrhosis from nonviral etiologies including alcoholic liver disease, NASH, HH, and primary biliary cirrhosis, should also undergo surveillance [28–30]. Screening recommendations for cirrhosis due to autoimmune hepatitis or A1AT deficiency have not been universally endorsed [28–31].

Таблица 7.1. Рекомендации по скринингу/наблюдению гепатоцеллюлярной карциномы.

Кто должен проходить скриннинг

Скрининговые модальности и политика отзыва (recall policies)

Хроническое заболевание печени с циррозом: HCV HBV Stage 4 primary biliary cirrhosis Hemochromatosis α-1-antitrypsin deficiency NAFLD HBV носители+/цирроз: With family history of HCC Asian males ≥40 years old, Asian females ≥50 years old African/North american blacks Benefit of screening/surveillance unclear: HCV without cirrhosis NAFLD without cirrhosis Autoimmune hepatitis with cirrhosis

УЗИ брюшной полости через 6 месяцев AFP не рекомендован AASLD или EASL Если аномальное ультразвуковое исследование: Nodule <1 cm – close follow-up at 3–6 months then at 6 months if stable for a year Nodule 1–2 cm – contrast-enhanced multiphasic cross-sectional imaging or biopsy Nodule >2 cm – contrast-enhanced multiphasic cross-sectional imaging; diagnose as HCC if “radiographic hallmark” present 1

Диагноз

HCC represents an exception to the typical oncologic diagnostic algorithm that mandates histopathologic confirmation of the diagnosis before proceeding with treatment. Imaging has assumed a pivotal role in diagnosing HCC, in some instances obviating the need for a biopsy or tumor marker assessments. The strengths and pitfalls of the noninvasive diagnostic approach, reasons for pursuing a histopathologic diagnosis, and the various imaging and laboratory diagnostic tests in current use are discussed below.

Образное обследование

Advances in dynamic contrast-enhanced imaging technology led to the characterization of the “HCC radiologic hallmark” – arterial hyperenhancement followed by venous/delayed phase washout – which is the cornerstone of noninvasive diagnostic criteria for HCC in patients with cirrhosis [28]. The acquisition of high-quality, multiphase contrast-enhanced images via either helical computed tomography (CT) or magnetic resonance imaging (MRI) is key for making an accurate diagnosis.

CT

Multidetector CT (MDCT) scans obtain high-quality, thin-sliced images at a rapid pace and can generate three-dimensional images of tumor vascular anatomy for treatment planning [33]. Triphasic CT scans capturing hepatic arterial, portal venous, and delayed phases have a diagnostic sensitivity and specificity of 89% and 99%, respectively [34].

MRI

On MRI, HCC most commonly appears as a hypointense lesion on T1 that becomes hyperintense on T2, with arterial enhancement and venous washout during dynamic gadolinium-enhanced imaging. Additional features suggestive of HCC include the presence of a fibrous capsule and rapid interval growth [33].

Выполнять ли биопсию?

Постановка диагноза неинвазивно

Guidelines for noninvasive diagnosis were developed to avoid the risks of bleeding and needle tract seeding associated with biopsy. Proponents of the noninvasive approach also cite the difficulty of distinguishing between high-grade dysplastic nodules and early, well-differentiated HCCs pathologically. In the most recent iteration of the AASLD and EASL guidelines, presence of the radiologic hallmark on a single multiphasic cross-sectional imaging modality (helical CT or gadolinium MRI) is sufficient to diagnose tumors >2 cm, and may also be enough to diagnose tumors 1–2 cm in diameter if performed at highvolume tertiary care centers with access to advanced imaging technology [28, 30]. Adherence to these criteria permits the diagnosis of HCC in cirrhotic patients with an overall sensitivity and specificity of approximately 80% and ≥90%, respectively, with gadolinium-MRI being the most sensitive technique [35].

A biopsy is still indicated for nodules arising in noncirrhotic livers and nodules in cirrhotic livers that display an atypical enhancement pattern [28, 30].

Обоснование для биопсии

The yield and accuracy of noninvasive diagnostic criteria are predicated upon the sensitivity and specificity of the imaging modalities used. Even with improved imaging technologies, the accurate distinction of HCC from other malignant or benign lesions remains challenging, especially for small tumors measuring 1–2 cm which are less likely to be hypervascular [36]. Other disease entities (e.g., cholangiocarcinoma, mixed HCCcholangiocarcinoma) can also display the “HCC radiologic hallmark” [37, 38]. Since the treatment and prognosis of these differ significantly from HCC, knowledge of the correct diagnosis is critical and would not otherwise be possible to distinguish without a biopsy. The incidence of needle tract seeding following a liver biopsy for HCC is estimated at 2.7% overall [39], although it is unclear if this is affected by the size of lesion being biopsied [30]. Though not specifically reported, the risks of needle tract seeding and hemorrhage are likely to be low for tumors <2 cm [30]. Thus, clinicians should not be dissuaded from pursuing a biopsy if deemed necessary to make the diagnosis, especially if it might potentially spare patients from exposure to unnecessary invasive or noxious procedures.

Beyond diagnostic purposes, tissue procurement has become increasingly important for the advancement of personalized medicine in oncology. Tumor specimens provide material for genetic and molecular profiling which can facilitate biomarker and therapeutic target discovery, and the elucidation of drug resistance mechanisms.

Опухолевые маркеры

α-фетопротеин сыворотки (AFP) представляет 70 kDa гликопротеин, продуцируемый клетками эндодермального желточного мешка и гепатоцитами во время эмбриогенеза. Он функционирует как транспортная молекула, которая связывается с жирными кислотами, билирубином, стероидами и ксенобиотиками, а также может поддерживать рост-регуляторные и иммуносупрессивные свойства. Поскольку AFP продукция обычно депрессируется у взрослых, повышение сывороточного уровня отражает патологическую синтетическую реактивацию вследствие регенерации печени и/или гепатокарциногенеза [40]. Сывороточные уровни AFP имеют прогностическое значение для HCC [41] и могут использоваться для контроля за течением заболевания и ответа на терапию [41, 42]. AFP менее полезен в качестве диагностического инструмента вследствие его ограниченной специфичности для HCC; хотя уровни AFP ≥ 100 мг/л ассоциированы с 99%-ной специфичностью, это происходит за счет снижения чувствительности в пределах от 17 до 31% [40]. В результате, сывороточный AFP больше не является частью AASLD и EASL диагностических алгоритмов.

Лектин-связанные варианты AFP, такие как lens culinaris agglutinin A-реактивный AFP (AFP-L3) и эритроагглютинирующий фитогемагглютинин (AFP P4 + P5), могут иметь большую чувствительность и специфичность, чем AFP для детекции HCC среди пациентов с циррозом [43], но требуют дальнейшего изучения. Des-γ-карбоксипротромбин (DCP) представляет собой аномальный вариант протромбина, синтезируемый в отсутствие витамина K. Уровни DCP отличают HCC от хронического вирусного гепатита, метастазов в печени и нормальных субъектов и могут быть полезны для мониторинга ответов на терапию [44]. Функционально DCP демонстрирует пропролиферативные и проангиогенные свойства [45, 46]. DCP более чувствителен и специфичен, чем AFP, хотя выявление HCC может быть улучшено комбинацией двух маркеров [40].

Другие биомаркеры: гепаринсульфат протеогликан, глипикан-3 (GPC-3), остеопонтин (OPN), гольджи протеин 73, антиген плоскоклеточной карциномы (SCCA) и microRNA является новыми биомаркерами, которые показали перспективную чувствительность и специфичность либо единично, либо в комбинации с более типичными маркерами в диагностике HCС [40].

Патология

Макроскопическая картина

Макроскопически, HCC представляют разнородные массы варьирующего размера с очаговыми областями кровоизлияния и/или некроза. В отличие от других видов рака, HCC опухоли имеют тенденцию быть мягкими из-за недостаточной десмопластической стромы [47]. Были идентифицированы три основные модели роста: (i) узловая экспансия, представляющая доминантное поражение с сателлитами; (ii) большая одиночная инфильтративная масса со слабыми демаркационными краями, которая обычно наблюдается в нецирротической печени; (iii) диффузное поражение, когда небольшие узелки распределяются по всей печени, напоминая просо. Наличие макроскопической сосудистой инвазии и паттерны инфильтративного роста ассоциированы с плохим прогнозом [48, 49].

Микроскопическая картина

HCC cells are morphologically similar to normal hepatocytes though this varies depending on the degree of differentiation. Cells are polygonal, contain finely granular eosinophilic cytoplasm, large nuclei with prominent nucleoli, and a high nuclear:cytoplasmic ratio. Tumor cells may contain biliary pigments, fat and/or glycogen deposits, and Mallory Denk bodies which are typically associated with alcoholic liver disease. Biliary canaliculi are typically present and are interspersed between cells [47].

Various growth patterns have been documented; the most common is the trabecular pattern consisting of cells arranged in thick cords separated by venous sinusoids. Dilation of biliary canaliculi within the trabeculae or central degeneration of the trabeculae produces the pseudoglandular or acinar pattern. The compact or solid pattern consists of thickened, compressed trabeculae forming a mass [47, 48].

Histological subtypes of HCC include the clear cell variant, characterized by abundant intracellular fat and/or glycogen. Scirrhous HCC is an extremely rare subtype containing abundant fibrous stroma. Sarcomatoid HCC contains spindle-shaped or giant tumor cells. Sclerosing HCC also contains abundant fibrous stroma with densely packed tumor cells [47, 48].

Иммуногистохимия

Иммуноокрашивания HepPar-1 и AFP являются положительными до 90% и 50% HCC, соответственно. Фибриноген, α1-антитрипсин и альбумин могут также окрашиваться положительно в доброкачественных опухолях [47, 48]. Более новые маркеры, включая глипикан-3, протеин теплового шока 70 (hsp70) и глутаминсинтазу, обладают высокой чувствительностью и специфичностью, особенно при использовании в комбинации. Отличие хорошо дифференцированной HCC от диспластических узлов является сложной задачей. Положительность для любых двух из этих трех маркеров имеет чувствительность и специфичность 72% и 100%, соответственно, для дифференциации ранних, низкозлокачественных HCC  от диспластических узелов [50]. Окрашивание для цитокератина, включая AE1 / AE3, CK7 и CK20, вариабельны вследствие слабой экспрессии и считается менее полезным для диагностики HCC.

Polyclonal antiserum to CEA (pCEA) can help to identify bile canaliculi present in normal liver and HCC but not liver metastases [51]. Complete, homogeneous staining for the endothelial marker CD34 across all sinusoidal spaces is also typical for HCC, whereas negative and incomplete staining patterns are more typically seen in normal or cirrhotic liver and benign hepatic lesions, respectively [52].

Молекулярная патология

There is an emerging body of work demonstrating that HCC can be diagnosed using gene expression profiling. Investigators have characterized gene signatures that distinguish between normal and cirrhotic liver, cirrhosis and dysplasia, dysplasia and early HCC, and early and late HCC arising in the context of HCV [53]. The same group has also identified a signature that can predict the presence of vascular invasion with an accuracy rate of 69% [54] which may help to improve prognostication of patients using biopsy material alone. Furthermore, molecularbased subgroups of HCC driven by different biological processes and associated with distinct clinicopathologic phenotypes have been identified [55, 56].

Стадийность

Созданы семь различных систем HCC стадийности, отражающих проблемы охвата биологических, этиологических, этнических и географических факторов, которые влияют на поведение и прогноз болезни.

Опухоль-Узел-Метастаз Система Американского Объединенного Комитета по Раку

The American Joint Committee on Cancer Tumor Node Metastases (TNM) system for hepatocellular carcinoma is a purely anatomical staging system. T, N, and M definitions and stage groupings for the current (8th) edition of this system are shown in Table 7.2 [57].

Таблица 7.2. TNM стадийная система Американского Объединенного Комитета по Раку (American Joint Committee on Cancer, AJCC) для гепатоцеллюлярной карциномы.

Категория опухоли	Категория лимфоузлов (региональных)	Категория отдаленного метастазирования
Tx = tumor cannot be assessed	Nx = nodes cannot be assessed	Mx = distant metastases cannot be assessed
T0 = none	N0 = no involvement	M0 = none
T1 = solitary tumor, no vascular invasion	N1 = regional nodal metastases	M1 = distant metastases
T1a = solitary tumor ≤2 cm
T1b = solitary tumor >2 cm without vascular invasion
T2 = multiple tumors ≤5 cm or solitary tumor >2 cm with vascular invasion
T3 = multiple tumors, at least one measuring > 5 cm
T4 = ≥1 tumor with major branch portal or hepatic vein invasion
T4 = single or multiple tumors of any size involving major branch of portal or hepatic vein or tumor(s) with direct invasion of adjacent organs other than the gallbladder or with perforation of the visceral peritoneum.

An important limitation of the TNM system is that it does not consider hepatic synthetic function which, as will be discussed later, is a critical determinant of prognosis and treatment options. In addition, the presence of microvascular invasion can only be determined in resected lesions, which may not be an appropriate treatment for some patients [30].

Окуда (Okuda)

The Okuda system assigns patients to one of three stages using four variables: ascites, albumin, bilirubin and tumor size [58]. The Okuda system has been criticized for omitting important tumor-related variables such as size, multiplicity, and portal vein thrombosis (PVT) which limit its prognostic potential in early stage disease [59].

Барселонская Клиническая Стадийность Рака Печени Клиники и алгоритм лечения

The Barcelona Clinic Liver Cancer (BCLC) classification assigns patients to one of five stages (0, A, B, C and D) based on performance status, Child–Pugh score, and tumor extent (Figure 7.1). Prognostic information and treatment recommendations are provided for each stage based on the best available evidence. The BCLC system has been validated in several western cohorts in which HCV is the predominant risk factor [60–62], and has been shown to outperform the Union for International Cancer Control TNM 6th edition and other staging systems to be discussed below. Several limitations of the BCLC system should be noted. First, it has not been validated in Asian populations among whom HBV is endemic and differences in the culture of clinical practice must be considered. Second, the “advanced” or “stage C” category encompasses both portal vein invasion and extrahepatic metastases and may be less discriminatory than other systems which separate these entities [63, 64]. Third, the BCLC system stages patients radiographically but does not provide guidance regarding the management of indeterminate lesions which, depending on how they are interpreted, could impact management and outcome [65]. The prognostic power of the BCLC system may be improved by the integration of molecular biomarkers. Stratification of each BCLC stage by serum VEGF and IGF-1 levels further subdivides patients into better or worse prognostic groups, with the worst outcomes observed amongst those with high VEGF/low IGF-1 levels. In particular, significant survival differences were noted within the BCLC stage C group [66].

Groupe d’Etude et de Traitement du Carcinome Hepatocellulaire (GETCH)

The GETCH considers five variables: performance status, bilirubin, alkaline phosphatase, AFP, portal vein occlusion, which are assigned a weighted score based on Cox regression coefficients. Patients in group A have a score of 0 and are at low risk of death; scores of 1–5 fall within group B intermediate risk; group C includes scores =6 and indicate a high risk of death from HCC [67]. The GETCH has not been externally validated, but did appear to have good predictive ability for the outcomes of patients with advanced HCC in a North American series [64].

 

Рисунок 7.1. Barcelona Clinic Liver Cancer (BCLC) cтадийность и алгоритм лечения.

Рак Печени Итальянской Программы (Cancer of the Liver Italian Program)

The Cancer of the Liver Italian Program (CLIP) score incorporates serum AFP, tumor morphology (uni vs multinodular and tumor occupying =50% vs >50% of liver volume), the presence or absence of PVT, and Child–Pugh score. Each variable is assigned a score of 0, 1, or 2 based on severity and the values are summated. Higher scores reflect more advanced disease and a poorer prognosis [68].

Китайский Университетский Прогностический Индекс (Chinese University Prognostic Index)

The Chinese University Prognostic Index (CUPI) was developed and validated in a cohort of 926 patients from a single center in Hong Kong, 80% of whom had HBV. It includes six variables: symptoms, ascites, AFP, total bilirubin, alkaline phosphatase, and TNM 5th edition stage, each of which is given a weighted value. The sum of the scores classifies patients into low-risk (CUPI score =1), intermediate risk (CUPI 2–7) or high risk (CUPI =8) groups. Comparison of the CUPI with the Okuda, CLIP, and TNM systems within this population showed that the CUPI was more sensitive and predictive of survival, showing significant discrimination throughout the follow-up period [69]. The CUPI was among the staging systems most predictive of survival in a North American patient cohort with advanced HCC [64].

Японская Интегрированная Стадийная Система (Japanese Integrated Staging System)

The Japanese Integrated Staging System (JIS) system combines the Child–Pugh score with the Liver Cancer Study Group of Japan (LCSGJ) TNM classification which is determined by how many of the following criteria are present: solitary tumor, <2 cm in diameter, no vascular invasion (stage I = all three present; stage II = two present; stage III = one present; stage IV = none present). Each category within the Child–Pugh and LCSGJ TNM systems is given a numerical value, and the sum of these generates the JIS score which ranges from 0 to 5. The JIS system has been validated and compared to the CLIP was found to provide superior stratification and prognostication among Japanese patients [70].

There is no single staging system that has been uniformly adopted for the global management and prognostication of HCC. Although the BCLC algorithm has been endorsed by the AASLD and EASL as the reference tool for guiding clinical practice and framing clinical trial design, it has not been validated in nonwestern populations that account for a significant proportion of the global HCC burden. Efforts to improve the prognostic utility of the BCLC and other staging systems by incorporating emerging molecular data remain a work in progress.

Терапия

Оценка соответствия пациента терапии

The management of HCC must consider two equally important and often competing factors: the cancer and the underlying cirrhosis. Hepatic functional reserve is assessed using the Child–Pugh classification system and Model for End Stage Liver Disease (MELD) score.

The Child–Pugh classification measures cirrhosis severity using a composite of three laboratory and two clinical variables. Each variable is assigned a numerical value and the sum of these is used to assign patients to one of three groups: A/well-compensated, B/functional compromise and C/decompensated [71] (see Table 7.3). A strong correlation between Child–Pugh score and survival in cirrhotics has been demonstrated; 2-year survival is approximately 90%, 50%, and 35% for patients in the A, B, and C groups, respectively [72].

The MELD score is calculated using a natural logarithmic equation incorporating international normalized ratio (INR), serum creatinine, and bilirubin [73]. It is primarily used for prioritizing patients on the transplant waiting list; higher scores indicate a higher risk of 3-month mortality.

MELD = 3.8[Ln serum bilirubin (mg/dL)] + 11.2(Ln INR) +  9.6 [Ln serum creatinine (mg/dL) + 6.4

Although objective by virtue of its reliance on laboratory values, the MELD score needs to be interpreted within the clinical context since other factors that could legitimately impact transplant priority may not be reflected by serum markers. Patients with HCC, cholestatic and polycystic liver diseases, cystic fibrosis, and metabolic disorders are granted exception scores that allow them to receive higher priority beyond their native MELD scores [74, 75].

Трансплант

Orthotopic liver transplantation (OLT) is the only potentially curative option for HCC, treating both the malignancy and underlying cirrhosis. Patients are selected for OLT based on liver function and anatomical parameters. The most commonly used tool for determining patient eligibility based on disease extent is the Milan criteria: solitary tumor =5 cm or up to three tumors =3 cm without portal invasion, nodal or distant metastases [76]. Adherence to these criteria has been shown to produce post-OLT 10-year survival rates exceeding 70% [77]. The Milan criteria have been adopted by the United Network for Organ Sharing for liver allocation.

Expanded criteria have been explored in an effort to increase patient eligibility. The University of California San Francisco criteria (solitary tumor =6.5 cm or up to three tumors with a maximum diameter of =4.5 cm, and a summed total tumor diameter =8 cm) and “Up to Seven” rule (meet Milan criteria and sum of largest tumor plus tumor number equals 7) have reported outcomes comparable to the Milan criteria which remains the “gold standard” [78, 79].

“Bridging” therapies such as locoregional ablative measures or resection can help to overcome anatomical and waiting time barriers to OLT via tumor downstaging and/or temporization without compromising outcomes [80, 81]. Tumor resection in individuals with well-compensated cirrhosis may permit the more selective use of OLT; those with high-risk histopathologic features for recurrence (i.e., poor differentiation, vascular invasion, nonencapsulation) may undergo a subsequent pre-emptive transplant while those with low-risk features may reserve OLT as a salvage procedure [80, 81], thus preserving the donor pool for other potential candidates.

Living donor transplants are considered an acceptable alternative to deceased donor organs and have been shown to produce comparable long-term survival outcomes [80]. Donor safety is a key consideration; perioperative morbidity and mortality are reportedly 30–40% and 0.15–0.5%, respectively [82]. Although OLT is potentially curative, patients are committed to lifelong immunosuppression and its attendant risks including secondary malignancies and recurrences which occur in 10–20% of patients [80]. Studies suggest that the commonly used calcineurin inhibitors (e.g., tacrolimus, cyclosporine) may be tumorigenic. mTORbased immunosuppressive regimens may be associated with fewer recurrences and better outcomes [83].

Резекция

Surgery is the cornerstone of care for patients with limited volume HCC and adequate hepatic functional reserve. With modern surgical techniques, 5-year survival ranges from 30–50% and perioperative mortality is 3–5% in cirrhotic patients undergoing hepatectomy [84]. In patients who fall within Milan criteria, 5-year survival outcomes are comparable to those achieved by OLT, approaching 50–70% in some series [85, 86].

Таблица 7.3. Шкала Чайлд-Пью (Child-Pugh).

Точки	1	2	3
Альбумин	>3.5 g/dL	2.8-3.5 g/dL	<2.8 g/dL
Общий билирубин	<2.0 mg/dL	2.0–3.0 mg/dL	>3.0 mg/dL
INR	<1.7	1.7–2.3	>2.3
Клинический асцит	Нет	Mild	Moderate
Энцефалопатия	Нет	Grade 1–2	Grade 3–4

Child–Pugh A, 5–6; Child–Pugh B, 7–9; Child–Pugh C ≥10.

In selecting candidates for resection, both tumor and hepatic functional parameters are considered. The presence of portal hypertension (i.e., portal venous gradient >10 mmHg, varices or splenomegaly with platelets <100,000/mm3, varices) is a major predictor of postoperative hepatic decompensation, and is compounded by the presence of hyperbilirubinema [86]. Recurrence rates are high following resection with up to 70% of patients relapsing by 5 years [86]. A distinction is made between “early” and “late” recurrences occurring =2 years or >2 years after surgery, respectively. While the former entity typically arises from pre-existing intrahepatic micrometastases, the latter entity represents de novo tumors. This hypothesis is supported by geneexpression profiling data from peritumoral liver parenchyma which was shown to be significantly predictive of HCC recurrences >2 years after surgery, but not earlier recurrences [87]. Major clinicopathologic predictors of recurrence include the presence of vascular invasion, tumor multinodularity, and poor differentiation [86]. Where appropriate, recurrent HCC should be aggressively treated using a multimodality approach of repeated resection and/or nonsurgical ablative therapies because long-term survival can still be achieved. Median postrecurrence survival times measured in years have been reported [88, 89].

Адъювантная терапия для пациентов, подвергающихся OLT или резекции

Adjuvant transarterial I131-labelled lipiodol and peretinoin – an oral vitamin A derivative – were both shown to decrease the risk of recurrence and prolong survival in randomized studies, but these effects were not durable or borne out in subsequent studies [90–93]. In the post-OLT setting, the I131-labelled monoclonal antibody against the HCC-specific molecule HAb18G/CD147 has shown promise as an adjuvant therapy in a randomized prospective study, though long-term follow-up results are needed [80, 94].

Adjuvant sorafenib was not shown to be effective in the STORM trial which randomized 1114 patients to placebo or sorafenib at standard doses following curative resection or local ablation [95]. Recurrence-free survival was virtually identical in both the sorafenib and placebo arms (33.3 months vs 33.7 months, HR 0.94, P = 0.26). The higher than anticipated proportion of patients on sorafenib who required dose modifications (~90%) and who had discontinued therapy at one year (~50%) may have contributed to the negative results. Sorafenib is currently being evaluated post-OLT in both phase I and II studies (www.clinicaltrials.gov, NCT00844168, NCT01624285). Sorafenib is discussed further later in the chapter.

Taken together, in the absence of data supporting an effective adjuvant strategy, the current standard of care following OLT or resection is expectant management or participation in a clinical trial.

Локорегиональные аблативные терапии

Различные локорегиональные аблативные терапии являются эффективными альтернативами резекции для пациентов, которые имеют противопоказания к хирургии и/или имеют технически нерезектабельную болезнь.

Чрескожная абляция этанолом

Percutaneous ethanol ablation (PEI) with 95% ethanol causes cell death via ischemic and cytotoxic injury. Favored for its lowcost, accessibility, and safety, PEI is highly effective (complete tumor ablation achieved in 98% of cases) and potentially curative with 5, 10, and even 20-year survival rates of 49%, 18%, and 7%, respectively. The best outcomes are achieved in Child–Pugh A or B patients who have one to three tumors with a maximum diameter of ≤3 cm. Although durable local control can be achieved, distant recurrences occur in >50% by 5 years [96].

Радиочастотная абляция

Radiofrequency ablation (RFA) utilizes microwaves to generate thermal energy, resulting in coagulative necrosis. Complete tumor responses are achievable in >90% of cases with a single session of RFA, whereas multiple PEI sessions may be needed to achieve similar results [100]. RFA has replaced PEI as the preferred treatment modality for early stage HCCs at many centers, having been shown to produce superior tumor control and survival [97–99].

The question of whether the results achieved with RFA can rival those of surgery is an active subject of debate [100]. Randomized controlled trials comparing RFA versus resection in patients with limited volume disease (i.e., one to two nodules, maximum diameter <4–5 cm) have arrived at different conclusions [101–103]. RFA efficacy is dependent on tumor size, number, and location. Tumors >4–5 cm are less likely to be adequately contained with the ablation field, and perivascular lesions may be undertreated as a result of thermal dilution by the “heat sink” effect. Superficial tumors may also be suboptimally treated because they can be difficult to visualize, their depth may not be adequately assessed, and there is a risk of damaging adjacent structures. Some of these limitations may be overcome by performing an open as opposed to percutaneous RFA [101]. At the present time, EASL/AASLD guidelines still list surgery as the reference treatment strategy for early stage HCC [28, 30].

Микроволновая абляция

Microwave ablation uses electromagnetic energy to cause thermal ablation. Microwave ablation generates larger heat zones, faster ablation times, and higher intratumoral temperatures which may be able to overcome the heat sink effect associated with perivascular tumors [104, 105]. Retrospective data suggest that microwave ablation and RFA are similarly efficacious in patients with limited disease [106].

Трансартериальные эмболические терапии

Transarterial tumor embolization with chemotherapy-loaded or radiolabelled particles capitalizes on the differences in blood supply to hepatic tumors and normal parenchyma. Because hepatic tumors are primarily supplied by the hepatic artery whereas normal liver is 75% perfused by portal venous circulation, selective tumor targeting can be achieved with relative sparing of the surrounding parenchyma.

• Трансартериальная химиоэмболизация

Conventional transarterial chemoembolization (cTACE) involves the delivery of a chemotherapy–lipiodol (a viscous poppy-seed oil derivative) emulsion followed by embolic particles into the tumor-feeding artery, causing cell death by ischemic and cytotoxic injury. Treatments are delivered every 2–4 months as indicated by tumor response and volume [106]. Doxorubicin, cisplatin, and mitomycin-C are the most commonly employed therapeutic agents, and no particular drug alone or combination has been shown to be superior to the others [107]. cTACE was adopted for the treatment of BCLC stage B HCC on the basis of two randomized, placebo-controlled trials which demonstrated a survival benefit in treatment-naпve patients with good hepatic function, no extrahepatic metastases, or main portal vein involvement [28, 30, 108, 109]. Objective responses are observed in 15–55% of patients, resulting in delayed time to tumor progression and vascular invasion [28, 109]. Recent cohort studies have reported median survival times exceeding 3 years in highly selected patients with Child– Pugh A disease and one to three tumors each =3 cm in diameter [110, 111] – a population that would also be eligible for resection. The presence of more extensive disease and advanced liver dysfunction has been shown to impact outcomes negatively. The main side effects associated with cTACE include postembolization syndrome characterized by pain, nausea, vomiting, fever, and hypertension as well as the potential for liver abscesses, biliary or vascular injury, and tumor rupture in <1% of patients [106].

• Drug-eluting bead TACE

TACE using chemotherapy loaded microspheres – also known as drug-eluting bead (DEB)-TACE – offers several advantages over cTACE including: (i) more precise and accurate drug loading and delivery; (ii) controlled and sustained drug release; and (iii) reduced systemic bioavailability despite high drug doses resulting in decreased systemic toxicities [106, 112]. Doxorubicin-based DEB-TACE and cTACE were compared in the randomized phase II PRECISION V trial [113]. Patients with Child–Pugh C cirrhosis, tumor volume >50%, vascular invasion and/or extrahepatic metastases were excluded. Although DEB-TACE was not superior to cTACE with respect to the primary endpoint of tumor response at 6 months, objective response and disease control rates were higher, and safety and tolerability were significantly improved on the DEB-TACE arm. Disease control rates were significantly better in Child– Pugh B patients with bulkier disease treated with DEB-TACE instead of cTACE [113]. In a recent series which included BCLC A/B patients with an excellent performance status and Child–Pugh = B7 cirrhosis, median survival was 48.5 months and median time to untreatable disease progression was nearly 2 years with DEB-TACE [114]. Although the question of whether survival with DEB-TACE is superior to cTACE has yet to be answered prospectively, a retrospective study of 71 patients reported a significantly longer median survival time in patients treated with DEB-TACE compared to cTACE (610 days and 284 days, P = 0.03) [115].

• Bland transarterial embolization

Whether chemotherapy is necessary to achieve optimal efficacy and durability of outcomes with TACE is unclear. In a retrospective review which included patients with portal vein occlusion and extrahepatic disease treated with transarterial embolization (TAE), median and 3-year survival were 21 months and 33%, respectively. When patients with these characteristics were excluded from the analysis, median and 3-year survival were 40 months and 51%, respectively, similar to those achieved with cTACE [116]. A randomized study reported better local control, time to progression and recurrence-free survival with DEB-TACE compared to TAE, but 1year survival was similar between the arms [117]. Another randomized study reported no differences between DEBTACE and TAE with respect to objective response rate, to progression, progression-free and overall survival, safety, and tolerability [118].

• Трансартериальная радиоэмболизация

Transarterial radioembolization (TARE) replaces chemotherapy-loaded beads with yttrium-90 labelled microparticles, selectively delivering radiation at significantly higher doses than can be attained with external beam radiation (i.e., 222–390 Gy vs 30–50 Gy) [119]. Unlike cTACE and DEB-TACE, TARE can be performed on an outpatient basis and complete ablation can be achieved in a single session. Since vessel occlusion is not necessary for therapeutic efficacy, TARE may be considered for patients with portal vein occlusion who would otherwise be excluded from receiving TACE due to concerns about inducing ischemic hepatitis and hepatic failure [106, 120]. Response rates range from 30 to 50% with TARE, and median survival is approximately 17 months and 10 months in patients with BCLC stage B and C disease, respectively [106]. Although there are no head to head comparisons, several retrospective reviews report favorable outcomes with TARE compared to cTACE/DEB-TACE [106]. The most common side effects associated with TARE include fatigue, ulcer formation due to nontarget microsphere deposition, liver fibrosis, cholecystitis, and radiation pneumonitis especially if pulmonary shunting is present [106, 120].

Taken together, the strongest data demonstrating the efficacy and survival benefit of transarterial embolic therapies come from studies conducted in highly selected patient populations with excellent performance status and liver function, without portal vein involvement or extrahepatic disease. The introduction of newer techniques such as superselective TACE and TARE has made it feasible to treat patients with portal vein involvement, but safety remains a concern.

Внешняя лучевая терапия

Although TARE can overcome the sensitivity of the hepatic parenchyma that has limited the ability to deliver radiation in tumoricidal doses, it is an invasive procedure that may not be appropriate for some patients. Advances in external beam radiation (EBRT) techniques demonstrate feasibility for treating HCC. Retrospective series and uncontrolled studies suggest that EBRT is effective in palliating pain from metastases, can induce meaningful responses in 40–90% of patients including those with PVT, and may be potentially curative in some patients [121, 122]. Prospective studies are examining the role of EBRT as an adjunct to other locoregional as well as systemic therapies.

Системная терапия

Until recent years, there were no effective systemic therapies for HCC not amenable to surgery or nonsurgical locoregional therapies and patients were relegated to best supportive care. “Traditional” cytotoxic as well as endocrine therapies have been extensively explored and are generally considered ineffective in HCC [123–126]. The limited activity of chemotherapy in HCC may be due in part to expression levels of drug-resistance genes [127] as well as the underlying cirrhosis which limits chemotolerance.

Сорафениб

Advances in our understanding of cancer molecular biology and the advent of “targeted” agents which intercept the aberrations that generate and sustain malignant behavior have revolutionized the practice of oncology, and have provided options for malignancies such as HCC that were once considered untreatable. The small molecule multikinase inhibitor – sorafenib – is the prototype targeted agent for HCC, and still remains the only systemic agent known to be effective for this disease.

Sorafenib inhibits Raf, Flt-3, c-Kit, RET, VEGFR and PDGFRassociated kinases though its primary mechanism of action is believed to be antiangiogenic [128]. Following promising results in a single arm phase II trial [129], the multicenter phase III SHARP and Asia–Pacific trials showed that sorafenib significantly improved time to progression and overall survival in advanced HCC patients compared to placebo [130, 131], ultimately leading to its approval for HCC by the FDA. Notably, although the hazard ratios for survival were virtually identical in both trials (0.69 and 0.68), the median survival times with sorafenib were 10.7 months and 6.5 months in the SHARP and Asia–Pacific trials, respectively [130, 131]. The disparity in survival may be attributable to differences in liver disease etiology; in the SHARP study, approximately 30% and 20% of patients had HCV and HBV as their underlying risk factor whereas 70% of patients on the Asia–Pacific trial had HBV [130, 131]. A pattern of improved outcomes with sorafenib in HCV compared to HBV patients has been reported in several retrospective series, and in a subgroup analysis from a phase III trial of sorafenib versus sunitinib [132–134]. A potential explanation for the apparent differences in sensitivity based on viral etiology may relate to the activation of Raf-1 – a target of sorafenib – by HCV core protein, thus sensitizing infected cells [135].

The most common grade 3–4 side effects associated with sorafenib are hypertension, fatigue, abdominal pain, diarrhea, hand–foot skin reaction, and liver dysfunction which occur in 2–11% of patients [130, 131]. It should be noted that in both trials, >95% of patients had Child–Pugh A disease. Since sorafenib is hepatically metabolized, tolerance in individuals with liver dysfunction is a concern, with shorter survival times and a higher risk of hepatic decompensation in Child–Pugh B compared to A patients [136]. Similar findings were reported in the phase IV GIDEON study [137]. A phase I study of sorafenib in patients with renal and hepatic dysfunction has shown serum total bilirubin and albumin levels to be key variables in determining sorafenib tolerance; dose reductions are needed in those with a bilirubin >1.5 х the upper limit of normal and/or albumin <2.5 mg/dL [138].

Комбинации сорафениба

The combination of sorafenib and doxorubicin showed promising activity in a randomized phase II study [139]. Patients on the combination arm experienced a significant improvement in median time to progression (6.4 months vs 2.8 months, P = 0.02), and median survival compared to doxorubicin alone (13.7 months vs 6.5 months, P = 0.006). Sorafenib +/doxorubicin is currently being assessed in a multicenter phase III trial (www.clinicaltrials. gov, NCT01272557).

Combined modality therapy with cTACE or DEB-TACE and sorafenib has been evaluated in several studies. TACE-induced hypoxia and ischemia generate a rise in VEGF that peaks 24 h postprocedure before progressively declining over subsequent days [140]. Post-TACE VEGF peaks have been associated with

the development of distant metastases [141]. It was hypothesized that sorafenib might abrogate the rise in VEGF, translating into delayed time to progression and longer survival. Although feasible and safe [142], the combination of TACE and sorafenib has not been shown to improve outcomes in two randomized studies conducted in patients with BCLC stage B disease [143, 144]. TACE +/sorafenib continues to be evaluated in a phase III cooperative group trial that will include patients with branch/ lobar but not main portal vein involvement (www.clinicaltrials. gov, NCT01004978).

Clinical trials combining sorafenib with newer locoregional modalities such as TARE (www.clinicaltrials.gov, NCT01135056, NCT01126645) and external beam radiation techniques (www. clinicaltrials.gov, NCT01328223, NCT01618253, NCT01141478, NCT01319942) are currently underway at several centers worldwide.

Терапия второй линии

In the phase III RESORCE trial, regorafenib, a multikinase inhibitor of KIT, RET, PDGFR, RAF kinases, VEGFR1-3 and TIE-2, increased overall survival compared to placebo (10.6 months vs 7.8 months, HR 0.62, P <0.001) in patients who had progressed on sorafenib [145]. Progression-free survival, as well as objective response and disease control rates were also improved on regorafenib. Although grade =3 adverse events such as hand–foot skin reaction, fatigue, diarrhea, and hypertension were more frequent with regorafenib, patient-reported quality of life was similar to that reported with placebo [146].

Другие агенты

• Блокада рецептора эпидермального фактора роста

Anti-epidermal growth factor receptor (EGFR) small molecule tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs) including gefitnib, erlotinib, lapatinib, and cetuximab have each been studied in single arm phase II trials [147–153]. While erlotinib appeared to have a disease stabilizing effect in 40–50% of patients [147, 148], as a group these agents do not appear to have clinically relevant activity. The phase III SEARCH study comparing sorafenib plus erlotinib versus sorafenib did not demonstrate any statistically significant differences in survival or time to progression [154]. Predictive biomarkers characterized in colorectal and lung malignancies such as activating KRAS and EGFR mutations have not been robustly explored in HCC.

• Insulin-like growth factor-1 receptor

The insulin-like growth factor-1 receptor mAb cixutumumab was inactive in HCC and caused grade 3/4 hyperglycemia in 46% of patients in a phase II study [155]. Results from phase I and II studies of other anti-insulin-like growth factor-1 receptor antibodies are pending (www.clinicaltrials.gov, NCT00956436, NCT01334710).

• c-Met и фактор роста гепатоцитов

Anti c-Met agents have shown promising activity in sorafenibrefractory HCC. A randomized phase II study of the c-Met TKI tivantinib reported a statistically significant improvement in median time to progression over placebo in sorafenib-refractory HCC, particularly in patients with high as opposed to low tumor c-Met expression by immunohistochemistry [156]. A randomized phase II discontinuation study of the dual c-Met/ VEGFR-2 antibody cabozantinib reported a tumor regression rate and median progression-free and overall survival times of 78%, 4.4 months and 15.1 months, respectively [157].

• MAP киназный путь

Data on the activity of agents targeting Ras, Raf, and Mek in HCC are sparse and have not shown any compelling signals of activity [158]. A phase II study of selumetinib, a Mek 1/2 inhibitor, was terminated for inefficacy [159] but a phase I/II combination study with sorafenib is ongoing (www.clinicaltrials.gov, NCT01029418).

• PI3K/Akt/mTOR путь

mTOR inhibitors have garnered interest in HCC as immunosuppressants post-OLT and for the treatment of established HCC. Several retrospective series indicate that mTOR-based immunosuppressive agents are associated with lower recurrence rates and better survival post-OLT [82]. However, a recent phase III trial of second-line everolimus failed to improve outcomes over placebo in sorafenib-refractory HCC [160].

• Anti-angiogenic agents

Agents targeting VEGF or its receptor include bevacizumab, ramucirumab, and cediranib. Bevacizumab showed promising single agent activity, but 11% of patients had a grade =3 hemorrhagic event including one fatal variceal bleed [161]. A phase II study of first-line bevacizumab and erlotinib reported an objective response rate of 24% and median progressionfree and overall survival were 7.2 months and 13.7 months, respectively [162]. A phase III trial of bevacizumab/erlotinib versus sorafenib has been launched (www.clinicaltrials.gov, NCT00881751).

Ramucirumab, an anti-VEGFR2 mAb, was evaluated in second-line post-sorafenib patients in the phase III REACH study [163]. In the overall study population, ramucirumab did not significantly improve overall survival compared to placebo (9.2 months vs 7.6 months, HR 0.87, P = 0.14). However, among patients with a baseline AFP >400 ng/mL, survival was significantly improved with ramucirumab versus placebo (7.8 months vs 4.2 months, HR 0.67, P = 0.006). The relationship between baseline elevated AFP and response to ramucirumab in secondline post-sorafenib progression is currently being studied in the ongoing phase III REACH-2 study (www.clinicaltrials.gov, NCT02435433).

The bFGF inhibitor brivanib was evaluated in two phase III studies as first-line therapy versus sorafenib and in sorafenibrefractory HCC – both were negative [164, 165]. Linifanib is a dual VEGFR/PDGFR TKI that was evaluated against sorafenib in a phase III trial. Although survival outcomes were comparable, the predefined superiority and noninferiority thresholds for linifanib were not met [166].

Sunitinib is a multikinase inhibitor with a spectrum similar to sorafenib. Based on several phase II trials showing modest activity [167–169], a phase III Asian trial of sunitinib versus sorafenib was launched. Compared to sorafenib, sunitinib was more toxic and survival outcomes were inferior [170].

• Immunotherapy

The immune checkpoint inhibitor, nivolumab, has shown promising activity in a phase I/II study conducted in patients with advanced HCC, approximately 70% of whom had previously received sorafenib [171]. Objective responses were observed in 19% of patients including two complete responses, and occurred in both hepatitis-infected and uninfected patients. An interim analysis of the study reported a median response duration of nearly 2 years, median survival was 15 months, and 48% of patients were still alive at 18 months [172]. Antiviral responses in hepatitis C infected patients were also reported. A phase III trial of first-line nivolumab versus sorafenib in advanced HCC is currently recruiting (www.clinicaltrials. gov, NCT02576509).

Оценка ответа на терапию для HCС

The RECIST (Response Evaluation Criteria in Solid Tumors) guidelines are the most commonly used metric for assessing the effects of antineoplastic therapy on malignant diseases. RECIST guidelines use changes in unidimensional measurements to determine whether patients are responding to or progressing on therapy [173].

Conventional RECIST guidelines are considered inadequate for capturing responses to therapies with antiangiogenic properties (i.e., sorafenib, transarterial therapies) in HCC. In the phase II and III studies of sorafenib, only 2–3% of patients had partial responses by RECIST – seemingly incongruous with the reported survival benefit [129–131]. Modified response assessment tools evaluate changes in tumor vascularity and/or necrosis which may be more sensitive markers of therapeutic activity. In the initial phase II study of sorafenib, the ratio of central necrosis to tumor volume was associated with clinical benefit [129, 174]. Modified RECIST guidelines, endorsed by EASL and the AASLD, measure changes in the size of arterially enhancing (i.e., viable) areas within a tumor instead of the entire tumor [175]. These novel techniques require validation.

Наблюдение и выживаемость

Given the high propensity for HCC to return post-treatment and the rarity of true “cures” even after radical therapies like OLT and surgery, all patients need to be closely monitored for recurrences. The NCCN guidelines recommend serial imaging and AFP levels every 3–6 months during the first 2 years following surgery or transplant, then every 6–12 months thereafter [31].

Заключение

HCC is a heterogeneous and complex disease entity that, in its advanced stages, remains recalcitrant to the ongoing endeavor to develop effective therapies beyond sorafenib. Therapies tailored to specific biomarker-enriched populations may hold the best promise for the next breakthrough. In addition to continued research efforts, prevention and early detection are key measures for combating HCC.

Литература

1 Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. Ca Cancer J Clin 2015;65(2):87–108.

2 Howlader N, Noone AM, Krapcho M, et al. (eds). SEER Cancer Statistics Review, 1975–2013, National Cancer Institute. Bethesda, MD, http://seer.cancer. gov/csr/1975_2013/, based on November 2015 SEER data submission, posted to the SEER web site, April 2016.

3 Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin 2017;67(1):7–30.

4 Plummer M, de Martel C, Vignat J, et al. Global burden of cancers attributable to infections in 2012: a synthetic analysis. Lancet Global Health 2016;4(9):e609–16.

5 Pollicino T, Saitta C, Raimondo G. Hepatocellular carcinoma: the point of view of the hepatitis B virus. Carcinogenesis 2011;32(8):1122–32.

6 Chen CJ, Yang HI, Su J. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 2006;295(1):65–73.

7 Yamashita T, Honda M, Kaneko S. Molecular mechanisms of hepatocarcinogenesis in chronic hepatitis C virus infection. J Gastroenterol Hepatol 2011;26(6):960–4.

8 Shen YC, Hsu C, Cheng CC, et al. A critical evaluation of the preventive effect of antiviral therapy on the development of hepatocellular carcinoma in patients with chronic hepatitis C or B: a novel approach by using meta-regression. Oncology 2012;82(5):275–89.

9 Voigt MD. Alcohol in hepatocellular carcinoma. Clin Liver Dis 2005;9(1):151–69.

10 Hassan MM, Hwang LY, Hatten CJ, et al. Risk factors for hepatocellular carcinoma: synergism of alcohol with viral hepatitis and diabetes mellitus. Hepatology 2002;36(5):1206–13.

11 Shih WL, Chang HC, Liaw YF, et al. Influences of tobacco and alcohol use on hepatocellular carcinoma survival. Int J Cancer 2012;131(11):2612–21.

12 Starley BQ, Calcagno CJ, Harrison SA. Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection. Hepatology 2010;51(5):1820–32.

13 Siegel AB, Zhu AX. Metabolic syndrome and hepatocellular carcinoma: two growing epidemics with a potential link. Cancer 2009:115:5651–61.

14 Baffy G, Brunt EM, Caldwell SH. Hepatocellular carcinoma in non-alcoholic fatty liver disease: an emerging menace. J Hepatol 2012;56(6):1384–91.

15 Kowdley KV. Iron, hemochromatosis, and hepatocellular carcinoma. Gastroenterology 2004;127(5 Suppl 1):S79–86.

16 Wu HC, Santella R. The role of aflatoxins in hepatocellular carcinoma. Hepat Mon 2012;12(10 HCC):e723.

17 Liu Y, Wu F. Global burden of aflatoxin-induced hepatocellular carcinoma: a risk assessment. Environ Health Perspect 2010;118(6):818–24.

18 Tsai JF, Jeng JE, Chuang LY, et al. Habitual betel quid chewing and risk for hepatocellular carcinoma complicating cirrhosis. Medicine (Baltimore) 2004;83(3):176–87.

19 Chung Y-T, Chan C-L, Wu C-C, et al. Safrole-DNA adduct in hepatocellular carcinoma associated with betel quid chewing. Toxicol Lett 2008;183:21–7.

20 Topic A, Ljujic Am, Radojkovic D. Alpha-1-antitrypsin in pathogenesis of hepatocellular carcinoma. Hepat Mon 2012;12(10 HCC):e7042.

21 Carrell RW, Lomas DA. Alpha-1-antitrypsin deficiency – a model for conformational diseases. N Engl J Med 2002;346(1):45–53.

22 Zhou H, Fischer HP. Liver carcinoma in PiZ alpha-1antitrypsin deficiency. Am J Surg Pathol 1998;22(6):742–8.

23 Siegel AB, Conner K, Wang S, et al. Smoking and hepatocellular carcinoma mortality. Exp Ther Med 2012;3(1):124–8.

24 Ueno Y, Nagata S, Tsutsumi T, et al. Detection of microcystins, a blue-green algal hepatotoxin, in drinking water sampled in Haimen and Fusui, endemic areas of primary liver cancer in China, by highly sensitive immunoassay. Carcinogenesis 1996;17:1317–21.

25 Llovet JM, Zucman-Rossi J, Pikarsky E, et al. Hepatocellular carcinoma. Nat Rev Dis Primers 2016;2:16018.

26 Chang MH, You SL, Chen CJ, et al. Decreased incidence of hepatocellular carcinoma in hepatitis B vaccines: a 20 year follow-up study. J Natl Cancer Inst 2009;101:1348–55.

27 Zhang BH, Yang BH, Tang ZY. Randomized controlled trial of screening for hepatocellular carcinoma. J Cancer Res Clin Oncol 2004;130(7):417–22.

28 European Association for the Study of the Liver, European Organization for Research and Treatment of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 2012;56(4):908–43.

29 Della Corte C, Colombo M. Surveillance for hepatocellular carcinoma. Semin Oncol 2012;39(4):384–98.

30 Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology 2011;53(3):1020–2.

31 Hepatobiliary Cancers Version 1.2013. NCCN Guidelines. National Comprehensive Cancer Network. 21 May 2013. Accessed 22 May 2013.

32 Kew MC, Macerollo P. Effect of age on the etiologic role of the hepatitis B virus in hepatocellular carcinoma in blacks. Gastroenterology 1988;94(2):439–42.

33 Ayyappan AP, Jhaveri KS. CT and MRI of hepatocellular carcinoma: an update. Expert Rev Anticancer Ther 2010;10(4):507–19.

34 Lim JH, Choi D, Kim SH. Detection of hepatocellular carcinoma: value of adding delayed phase imaging to dualphase helical CT. Am J Roentgenol 2002;179:67–73.

35 Leoni S, Piscaglia F, Golfieri R, et al. The impact of vascular and nonvascular findings on the invasive diagnosis of small hepatocellular carcinoma based on the EASL and AASLD criteria. Am J Gastroenterol 2010;105(3):599–609.

36 Bolondi L, Gaiani S, Celli N, et al. Characterization of small nodules in cirrhosis by assessment of vascularity: the problem of hypovascular hepatocellular carcinoma. Hepatology 2005;42(1):27–34.

37 Sanada Y, Shiozaki S, Aoki H, et al. A clinical study of 11 cases of combined hepatocellular-cholangiocarcinoma assessment of enhancement patterns on dynamic computed tomography before resection. Hepatol Res 2005;32:185–95.

38 Rimola J, Forner A, Reig M, et al. Cholangiocarcinoma in cirrhosis; absence of contrast washout in delayed phases by magnetic resonance imaging avoids misdiagnosis of hepatocellular carcinoma. Hepatology 2009;50:791–8.

39 Silva MA, Hegab B, Hyde C, et al. Needle track seeding following biopsy of liver lesions in the diagnosis of hepatocellular cancer: a systematic review and meta-analysis. Gut 2008;57:1592–6.

40 El Makarem MA. An overview of biomarkers for the diagnosis of hepatocellular carcinoma. Hepat Mon 2012;12(10 HCC):e6122.

41 Tyson GL, Duan Z, Kramer JR, et al. Level of alpha-fetoprotein predicts mortality among patients with hepatitis C-related hepatocellular carcinoma. Clin Gastroenterol Hepatol 2011;9(11):989–94.

42 Yau T, Yao TJ, Chan P, et al. The significance of early alphafetoprotein level changes in predicting clinical and survival benefits in advanced hepatocellular carcinoma patients receiving sorafenib. Oncologist 2011;16(9):1270–9.

43 Sterling RK, Jeffers L, Gordon F, et al. Clinical utility of AFP-L3% measurement in North American patients with HCV-related cirrhosis. Am J Gastroenterol 2007;102(10):2196–205.

44 Liebman HA, Furie BC, Tong MJ, et al. Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma. N Engl J Med 1984;310(22):1427–31.

45 Suzuki M, Shiraha H, Fujikawa T, et al. Des–gammacarboxyprothrombin is a potential autologous growth factor for hepatocellular carcinoma. J Biol Chem 2005;280(8):6409–15.

46 Fujikawa T, Shiraha H, Ueda N, et al. Des-gamma-carboxyl prothrombin-promoted vascular endoethelial cell proliferation and migration. J Biol Chem 2007;282(12):8741–8.

47 Goodman ZD. Neoplasms of the liver. Mod Pathol 2007;20 Suppl 1:S49–60.

48 Paradis V. Histopathology of hepatocellular carcinoma. Recent Results Cancer Res 2013;190:21–32.

49 Okuda K, Peters RL, Simson IW. Gross anatomic features of hepatocellular carcinoma from three disparate geographic areas: proposal of new classification. Cancer 1983;54:2165–73.

50 Tremosini S, Forner A, Boix L, et al. Prospective validation of an immunohistochemical panel (glypican 3, heat shock protein 70 and glutamine synthetase) in liver biopsies for diagnosis of very early hepatocellular carcinoma. Gut 2012;61(10):1481–7.

51 Wolber RA, Greene CA, Dupuis BA. Polyclonal carcinoembryonic antigen staining in the cytologic differential diagnosis of primary and metastatic hepatic malignancies. Acta Cytol 1991;35(2):215–20.

52 Coston WM, Leora S, Lau SK, et al. Distinction of hepatocellular carcinoma from benign hepatic mimickers using glypican-3 and CD34 immunohistochemistry. Am J Surg Pathol 2008;32(3):433–44.

53 Wurmbach E, Chen YB, Khitrov G, et al. Genome-wide molecular profiles of HCV-induced dysplasia and hepatocellular carcinoma. Hepatology 2007;45(4):938–47.

54 Minguez B, Hoshida Y, Villanueva A, et al. Gene-expression signature of vascular invasion in hepatocellular carcinoma. J Hepatol 2011;55(6):1325–31.

55 Hoshida Y, Nijman SMB, Kobayashi M, et al. Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma. Cancer Res 2009;69(18):7385–92.

56 Toffanin S, Hoshida Y, Lachenmayer A, et al. MicroRNAbased classification of hepatocellular carcinoma and oncogenic role of miR-517a. Gastroenterology 2011;140(5):1618–28.

57 Abou-Alfa GK, Pawlik TM, Shindoh J, Vauthey JN. Liver. In: MB Amin, SB Edge, FL Greene, et al. (eds) AJCC Cancer Staging Manual, Eighth Edition. New York: Springer Nature, 2017.

58 Okuda K, Ohtsuki T, Obata H, et al. Natural history of hepatocellular carcinoma and prognosis in relation to treatment. Study of 850 patients. Cancer 1985;56(4):918–28.

59 Kudo M, Chung H, Osaki Y. Prognostic staging system for hepatocellular carcinoma (CLIP): its value and limitations, and a proposal for a new staging system, the Japan Integrated Staging Score (JIS score). J Gastroenterol 2003;38(3):207–15.

60 Marrero JA, Fontana RJ, Barrat A, et al. Prognosis of hepatocellular carcinoma: comparison of 7 staging systems in an American cohort. Hepatology 2005;41(4):707–16.

61 Cillo U, Vitale A, Grigoletto F, et al. Prospective validation of the Barcelona Clinic Liver Cancer staging system. J Hepatol 2006;44(4):723–31.

62 Guglielmi A, Ruzzenente A, Pachera S, et al. Comparison of seven staging systems in cirrhotic patients with hepatocellular carcinoma in a cohort of patients who underwent radiofrequency ablation with complete response. Am J Gastroenterol 2008;103(3):597–604

63 Han KH, Kudo M, Ye SL, et al. Asian consensus workshop report: expert consensus guideline for the management of intermediate and advanced hepatocellular carcinoma in Asia. Oncology 2011;81(Suppl 1):158–64.

64 Huitzil-Melendez FD, Capanu M, O’Reilly EM, et al. Advanced hepatocellular carcinoma: which staging systems best predict prognosis? J Clin Oncol 2010;28(17):2889–95.

65 Kim SE, Lee HC, Kim KM, et al. Applicability of the BCLC staging system to patients with hepatocellular carcinoma in Korea: analysis at a single center with a liver transplant center. Korean J Hepatol 2011;17(2):113–119.

66 Kaseb AO, Morris JS, Hassan MM, et al. Clinical and prognostic implications of plasma insulin-like growth factor-1 and vascular endothelial growth factor in patients with hepatocellular carcinoma. J Clin Oncol 2011;29(29):3892–9.

67 Chevret S, Trinchet JC, Mathieu D, et al. A new prognostic classification for predicting survival in patients with hepatocellular carcinoma. Groupe d’Etude et de Traitement du Carcinoma Hepatocellulaire. J Hepatol 1999;31(1):133–41.

68 A new prognostic system for hepatocellular carcinoma: a retrospective study of 435 patients: the Cancer of the Liver Italian Program (CLIP) investigators. Hepatology 1998;28(3):751–5.

69 Leung TW, Tang AM, Zee B, et al. Construction of the Chinese University Prognostic Index for hepatocellular carcinoma and comparison with the TNM staging system, the Okuda staging system, and the Cancer of the Liver Italian Program staging system: a study based on 926 patients. Cancer 2002;94(6):1760–9.

70 Kudo M, Chung H, Haji S, et al. Validation of a new prognostic staging system for hepatocellular carcinoma: the JIS score compared with the CLIP score. Hepatology 2004;40(6):1396–405.

71 Pugh RN, Murray-Lyon IM, Dawson JL, et al. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973;60(8):646–9.

72 Albers I, Hartmann H, Bircher J, Creutzfeldt W. Superiority of the Child-Pugh classification to quantitative liver function tests for assessing prognosis of liver cirrhosis. Scand J Gastroenterol 1989;24(3):269–76.

73 Malinchoc M, Kamath PS, Gordon FD, et al. A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic hunts. Hepatology 2000;31(4):864–71.

74 Quante M, Benckert C, Thelen A, Jonas S. Experience since MELD implementation: how does the new system deliver? Int J Hepatol 2012;2012:264015.

75 Asrani SK, Kim WR. Model for end stage liver disease: end of the first decade. Clin Liver Dis 2011;15(4):685–98.

76 Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;334(11):693–9.

77 Mazzaferro V, Chun YS, Poon RTP, et al. Liver transplantation for hepatocellular carcinoma. Ann Surg Oncol 2008;15(4):1001–7.

78 Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology 2001;6:1394–403.

79 Mazzaferro V, Llovet JM, Miceli R, et al. Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis. Lancet Oncol 2009;10(1):35–43.

80 Melloul E, Lesurtel M, Carr BI, Clavien PA. Developments in liver transplantation for hepatocellular carcinoma. Semin Oncol 2012;39(4):510–21.

81 Fuks D, Dokmak S, Paradis V, et al. Benefit of initial resection of hepatocellular carcinoma followed by transplantation in case of recurrence: an intention-to-treat analysis. Hepatology 2012;55:132–40.

82 Trotter JF, Adam R, Lo CM, Kenison J. Documented deaths of hepatic lobe donors for living donor liver transplantation. Liver Transpl 2006;12:1485–8.

83 Treiber G. mTOR inhibitors for hepatocellular carcinoma: a forward-moving target. Expert Rev Anticancer Ther 2009;9(2):247–61.

84 Song T, Ip E, Fong Y. Hepatocellular carcinoma: current surgical management. Gastroenterology 2004;127: S248–60.

85 Dhir M, Lyden ER, Smith LM, Are C. Comparison of outcomes of transplantation and resection in patients with early hepatocellular carcinoma: a meta-analysis. HPB (Oxford) 2012;14(9):635–45.

86 Llovet JM, Schwartz M, Mazzaferro M. Resection and liver transplantation for hepatocellular carcinoma. Semin Liver Dis 2005;25(2):181–200.

87 Hoshida Y, Villanueva A, Kobayashi M, et al. Gene expression in fixed tissues and outcome in hepatocellular carcinoma. N Engl J Med 2008;359(19):1995–2004.

88 Shrager B, Jibara GA, Schwartz M, Roayaie S. Resection of hepatocellular carcinoma without cirrhosis. Ann Surg 2012;255(6):1135–43.

89 Roayaie S, Schwartz JD, Sung MW, et al. Recurrence of hepatocellular carcinoma after liver transplant: patterns and prognosis. Liver Transpl 2004;10(4):534–40.

90 Lau WY, Lai EC, Leung TW, Yu SC. Adjuvant intraarterial iodine-131-labeled lipiodol for resectable hepatocellular carcinoma: a prospective randomized trial – update on 5-year and 10-year survival. Ann Surg 2008;247(1):43–8.

91 Muto Y, Moriwaki H, Ninomiya M, et al. Prevention of second primary tumors by an acyclic retinoid, polyprenoic acid, in patients with hepatocellular

carcinoma. Hepatoma Prevention Study Group. N Engl J Med 1996;334(24):1561–7.

92 Muto Y, Moriwaki H, Saito A. Prevention of second primary tumors by an acyclic retinoid in patients with hepatocellular carcinoma. N Engl J Med 1999;340(13):1046–7.

93 Okita K, Matsui O, Kumada K, et al. Effect of peretinoin on recurrence of hepatocellular carcinoma (HCC): results of a phase II/III randomized placebo-controlled trial. J Clin Oncol 2010;28(suppl; abstr 4024):15s.

94 Xu J, Shen ZY, Chen XG, et al. A randomized controlled trial of Licartin for preventing hepatoma recurrence after liver transplantation. Hepatology 2007;45(2):269–76.

95 Bruix J, Takayama T, Mazzaferro V, et al. Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomized, double-blind, placebocontrolled trial. Lancet Oncol 2015:16(13):1344–54.

96 Shiina S, Tateishi R, Imamura M, et al. Percutaneous ethanol injection for hepatocellular carcinoma: 20-year outcome and prognostic factors. Liver Int 2012;32(9):1434–42.

97 Lencioni RA, Allgaier HP, Cioni D, et al. Small hepatocellular carcinoma in cirrhosis: randomized comparison of radiofrequency thermal ablation versus percutaneous ethanol injection. Radiology 2003;228(1):235–40.

98 Bouza C, Lopez-Cuadrado T, Alcazar R, et al. Meta-analysis of percutaneous radiofrequency ablation versus ethanol injection in hepatocellular carcinoma. BMC Gastroenterol 2009;9:31.

99 Orlando A, Leandro G, Olivo M, et al. Radiofrequency thermal ablation vs. percutaneous ethanol injection for small hepatocellular carcinoma in cirrhosis: meta-analysis of randomized controlled trials. Am J Gastroenterol 2009;104(2):514–24.

100 Livraghi T, Meloni F, Di Stasi M, et al. Sustained complete response and complications rates after radiofrequency ablation of very early hepatocellular carcinoma in cirrhosis: is resection still the treatment of choice? Hepatology 2008;47:82–9.

101 Feng K, Yan J, Li X, et al. A randomized controlled trial of radiofrequency ablation and surgical resection in the treatment of small hepatocellular carcinoma. J Hepatol 2012;57(4):794–802.

102 Chen MS, Li JQ, Zheng Y, et al. A prospective randomized trial comparing percutaneous local ablative therapy and partial hepatectomy for small hepatocellular carcinoma. Ann Surg 2006;243:321–8.

103 Huang J, Yan L, Cheng Z, et al. A randomized trial comparing radiofrequency ablation and surgical resection for HCC conforming to the Milan criteria. Ann Surg 2010;252(6):903–12.

104 Bhardwaj N, Strickland AD, Ahmad F, et al. Liver ablation techniques: a review. Surgical Endoscopy 2010;24(2):254–65.

105 Ding J, Jin X, Liu J, et al. Comparison of two different thermal techniques for the treatment of hepatocellular carcinoma. Eur J Radiol 2013;82(9):1379–84.

106 Salem R, Lewandowski RJ. Chemoembolization and radioembolization for hepatocellular carcinoma. Clin Gastroenterol Hepatol 2013;11(6):604–11.

107 Marelli L, Stigliano R, Triantos C, et al. Transarterial therapy for hepatocellular carcinoma: which technique is more effective? A systematic review of cohort and randomized studies. Cardiovasc Intervent Radiol 2007;30(1):6–25.

108 Lo C-M, Ngan H, Tso W-K, et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology 2002;35:1164–71.

109 Llovet JM, Real MI, Montana X, et al. Arterial embolization or chemoembolization versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomized controlled trial. Lancet 2002;359:1734–9.

110 Lewandowski RJ, Mulcahy MF, Kulik LM, et al. Chemoembolization for hepatocellular carcinoma: comprehensive imaging and survival analysis in a 172 patient cohort. Radiology 2010;255(3):955–65.

111 Takayasu K, Arii S, Kudo M, et al. Superselective transarterial chemoembolization for hepatocellular carcinoma. Validation of treatment algorithm proposed by Japanese guidelines. J Hepatol 2012;56(4):886–92.

112 Lewis AL, Gonzalez, MV, Lloyd AW, et al. DC bead: in vitro characterization of a drug-delivery device for transarterial chemoembolization. J Vasc Interv Radiol 2006;17(2 Pt 1):335–42.

113 Lammer J, Malagari K, Vogl T, et al. Prospective randomized study of doxorubicin-eluting-bead embolization in the treatment of hepatocellular carcinoma: results of the PRECISION V study. Cardiovasc Intervent Radiol 2010;33(1):41–52.

114 Burrel M, Reig M, Forner A, et al. Survival of patients with hepatocellular carcinoma treated by transarterial chemoembolisation (TACE) using Drug Eluting Beads. Implications for clinical practice and trial design. J Hepatol 2012;56(6):1330–5.

115 Dhanasekaran R, Kooby DA, Staley CA, et al. Comparison of conventional transarterial chemoembolization (TACE) and chemoembolization with doxorubicin drug eluting beads (DEB) for unresectable hepatocellular carcinoma (HCC). J Surg Oncol 2010;101(6):476–80.

116 Maluccio MA, Covey AM, Porat LB, et al. Transcatheter arterial embolization with only particles for the treatment of unresectable hepatocellular carcinoma. J Vasc Interv Radiol 2008;19(6):862–9.

117 Malagari K, Pomoni M, Kelekis A, et al. Prospective randomized comparison of chemoembolization with doxorubicin-eluting beads and bland embolization with BeadBlock for hepatocellular carcinoma. Cardiovasc Intervent Radiol 2010;33(3):541–51.

118 Brown KT, Gonen M, Do KG, et al. A randomized single blind controlled trial of beads versus doxorubicin-eluting beads for arterial embolization of hepatocellular carcinoma (HCC). 2013 Gastrointestinal Cancers Symposium. J Clin Oncol 2012;30 (suppl 34; abstr 143).

119 Young JY, Rhee TK, Atassi B, et al. Radiation dose limits and liver toxicities resulting from multiple yttrium-90 radioembolization treatments for hepatocellular carcinoma. J Vasc Interv Radiol 2007;18(11):1375–82.

120 Kulik LM, Carr BI, Mulcahy MF, et al. Safety and efficacy of 90Y radiotherapy for hepatocellular carcinoma with and without portal thrombosis. Hepatology 2008;47(1):71–81.

121 Hawkins MS, Dawson LA. Radiation therapy for hepatocellular carcinoma: from palliation to cure. Cancer 2006;106(8):1653–63.

122 Kim YJ, Chung SM, Choi BO, Kay CS. Hepatocellular carcinoma with portal vein tumor thrombosis: improved treatment outcomes with external beam radiation therapy. Hepatol Res 2011;41(9):813–24.

123 Olweny CL, Toya T, Katongole-Mbedde E, et al. Treatment of hepatocellular carcinoma with adriamycin. Cancer 1975;36:1250–7.

124 Yeo W, Lam KC, Zee B, et al. A randomized phase III study of doxorubicin versus cisplatin/interferon-alpha2B/ doxorubicin/fluorouracil (PIAF) combination chemotherapy for unresectable hepatocellular carcinoma. J Natl Cancer Inst 2005;97(20):1532–8.

125 Nowak A, Findlay M, Culjak G, Stockler M. Tamoxifen for hepatocellular carcinoma. Cochrane Database Syst Rev 2004;(3):CD001024.

126 Guo TK, Hao XY, Ma B, et al. Octreotide for advanced hepatocellular carcinoma: a meta-analysis of randomized controlled trials. J Cancer Res Clin Oncol 2009;135(12):1685–92.

127 Huang CC, Wu MC, Xu GW, et al. Overexpression of the MDR1 gene and p-glycoprotein in human hepatocellular carcinoma. J Natl Cancer Inst 1992;84(4):262–4.

128 Wilhelm SM, Carter C, Tang L, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/ MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 2004;64(19):7099–109.

129 Abou-Alfa GK, Schwartz L, Ricci S, et al. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol 2006;24(26):4293–300.

130 Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359(4):378–90.

131 Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, doubleblind, placebo-controlled trial. Lancet Oncol 2009;10(1):25–34.

132 Huitzil-Melendez FD, Saltz LB, Song J, et al. Retrospective analysis of outcome in hepatocellular carcinoma patients with hepatitis C versus B treated with sorafenib. 2007 Gastrointestinal Cancers Symposium, abstract 173.

133 Bruix J, Raoul JL, Sherman M, et al. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: subanalyses of a phase III trial. J Hepatol 2012;57(4):821–9.

134 Cheng AL, Kang Y, Lin D, et al. Phase III study of sunitinib versus sorafenib in advanced hepatocellular carcinoma. J Clin Oncol 2011;29(suppl; abstr 4000).

135 Aoki H, Hayashi J, Moriyama M, et al. Hepatitis C virus core protein interacts with 14-3-3 protein and activates the kinase Raf-1. J Virol 2000;74(4):1736–41.

136 Abou-Alfa GK, Amadori D, Santoro A, et al. Safety and efficacy of sorafenib in patients with hepatocellular carcinoma (HCC) and Child-Pugh A versus B cirrhosis. Gastrointest Cancer Res 2011;4(2):40–4.

137 Marrero JA, Lencioni R, Kudo M, et al. Global investigation of therapeutic decisions in hepatocellular carcinoma and of its treatment with sorafenib (GIDEON): clinical findings in patients with liver dysfunction. J Clin Oncol 29:2011(suppl; abstr 4001).

138 Miller AA, Murry DJ, Owzar K, et al. Phase I and pharmacokinetic study of sorafenib in patients with hepatic or renal dysfunction: CALGB 60301. J Clin Oncol 2009;27(11):1800–5.

139 Abou-Alfa GK, Johnson P, Knox JJ, et al. Doxorubicin plus sorafenib vs doxorubicin alone in patients with advanced hepatocellular carcinoma: a randomized trial. JAMA 2010;304(19):2154–60.

140 Li X, Feng GS, Zheng CS, et al. Expression of plasma vascular endothelial growth factor in patients with hepatocellular carcinoma and effect of transcatheter arterial chemoembolization therapy on plasma vascular endothelial growth factor level. World J Gastroenterol 2004;10:2878–82.

141 Xiong ZP, Yang SR, Liang ZY, et al. Association between vascular endothelial growth factor and metastasis after transcatheter arterial chemoembolization in patients with hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int 2004;3(3):386–90.

142 Pawlik TM, Reyes DK, Cosgrove D, et al. Phase II trial of sorafenib combined with concurrent trans-arterial embolization with doxorubicin-eluting beads for hepatocellular carcinoma. J Clin Oncol 2011;29(30):3960–7.

143 Kudo M, Imanaka K, Chida N, et al. Phase III study of sorafenib after transarterial chemoembolization in Japanese and Korean patients with unresectable hepatocellular carcinoma. Eur J Cancer 2011;47(14):2117–27.

144 Lencioni R, Llovet JM, Han G, et al. Sorafenib or placebo in combination with transarterial chemoembolization (TACE) with doxorubicin-eluting beads (DEBDOX) for intermediatestage hepatocellular carcinoma (HCC): phase II, randomized, double-blind SPACE trial. J Clin Oncol 2012;30(suppl 4; abstr LBA154).

145 Bruix J, Merle P, Granito A, et al. Efficacy and safety of regorafenib versus placebo in patients with hepatocellular carcinoma (HCC) progressing on sorafenib: results of the international, randomized phase 3 RESORCE trial. 2016 World Congress on GI Cancer, Barcelona, Spain, abstract LBA03.

146 Bruix J, Merle P, Granito A, et al. Efficacy, safety, and health-related quality of life (HRQoL) of regorafenib in patients with hepatocellular carcinoma (HCC) progressing on sorafenib: Results of the international double-blind phase 3 RESORCE trial. 2016 ESMO Congress, Copenhagen, Denmark, abstract LBA28.

147 Philip PA, Mahoney MR, Allmer C, et al. Phase II study of Erlotinib (OSI-774) in patients with advanced hepatocellular cancer. J Clin Oncol 2005;23:6657–63.

148 Thomas MB, Chadha R, Glover K, et al. Phase 2 study of erlotinib in patients with unresectable hepatocellular carcinoma. Cancer 2007;110:1059–67.

149 O’Dwyer PJ, Biantonio BJ, Levy DE, et al. Gefitinib in advanced unresectable hepatocellular carcinoma: results from the Eastern Cooperative Oncology Group’s Study E1203. 2006 ASCO Annual Meeting Proceedings Part I. J Clin Oncol 2006;24(18S, June 20 Supplement):4143.

150 Ramanathan RK, Belani CP, Singh DA, et al. A phase II study of lapatinib in patients with advanced biliary tree and hepatocellular cancer. Cancer Chemother Pharmacol 2009;64(4):777–83.

151 Bekaii-Saab T, Markowitz J, Prescott N, et al. A multiinstitutional phase II study of the efficacy and tolerability of lapatinib in patients with advanced hepatocellular carcinoma. Clin Cancer Res 2009;15:5895–901.

152 Zhu AX, Stuart K, Blaszkowsky LS, et al. Phase 2 study of cetuximab in patients with advanced hepatocellular carcinoma. Cancer 2007;110(3):581–9.

153 Gruenwald V, Wilkens L, Gebel M, et al. A phase II openlabel study of cetuximab in unresectable hepatocellular carcinoma: final results. 2007 ASCO Annual Meeting Proceedings Part I. J Clin Oncol 2007;25(18S June 20 Supplement):4598.

154 Zhu A, Rosmorduc O, Evans J, et al. SEARCH: a phase III, randomized, double-blind, placebo-controlled trial of sorafenib plus erlotinib in patients with hepatocellular carcinoma (HCC). Ann Oncol 2012;23(Suppl. 9).

155 Abou-Alfa GK, Gansukh B, Chou JF, et al. Phase II study of cixutumumab (IMC-A12, NSC742460; C) in hepatocellular carcinoma (HCC). J Clin Oncol 2011;29(suppl; abstr 4043).

156 Santoro A, Rimassa L, Borbath I, et al. Tivantinib for second-line treatment of advanced hepatocellular carcinoma: a randomized, placebo-controlled phase 2 study. Lancet Oncol 2013;14(1):55–63.

157 Verslype C, Cohn AL, Kelley RK, et al. Activity of cabozantinib (XL184) in hepatocellular carcinoma: results from a randomized phase II discontinuation study. J Clin Oncol 2012;30(suppl; abstr 4007).

158 Ang C, Owen D, Abou-Alfa GK. Systemic therapy in advanced HCC. In: Clinical Interventional Radiology. Elsevier. In press.

159 O’Neil BH, Goff LW, Kauh JS, et al. Phase II study of the mitogen-activated protein kinase 1/2 inhibitor selumetinib in patients with advanced hepatocellular carcinoma. J Clin Oncol 2011;29(17):2350–6.

160 Novartis study of Afinitor in advanced liver cancer does not meet primary endpoint of overall survival. Novartis media release 2013 August 7. http://www.novartis.com/newsroom/ media-releases/en/2013/1721562.shtml (accessed 27 August 2013).

161 Siegel AB, Cohen EL, Ocean A, et al. Phase II trial evaluating clinical and biologic effects of bevacizumab in advanced, unresectable hepatocellular carcinoma. J Clin Oncol 2008;26(18):2992–8.

162 Kaseb AO, Garrett Mayer E, Morris JS, et al. Efficacy of bevacizumab and erlotinib for advanced hepatocellular carcinoma and predictors of outcome: final results of a phase II trial. Oncology 2012;82(2):67–74.

163 Zhu AX, Park JO, Ryoo BY, et al. Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomized, double-blind, multicenter, phase 3 trial. Lancet Oncol 2015;16(7):859–70.

164 Johnson PJ, Qin S, Park J-W, et al. Brivanib vs. sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized phase III BRISK-FL study. J Clin Oncol 2013;31(28):2517–24.

165 Llovet J, Decaens T, Raoul J, et al. Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed: results from the randomized phase III BRISK-PS study. J Clin Oncol 2013;31(28):3509–16.

166 Cainap C, Qin S, Huang W-T, et al. Phase III trial of linifanib versus sorafenib in patients with advanced hepatocellular carcinoma (HCC). J Clin Oncol 30:2012(suppl 34; abstr 249).

167 Zhu AX, Sahani DV, Duda DG, et al. Efficacy, safety, and potential biomarkers of sunitinib monotherapy in advanced hepatocellular carcinoma: a phase II study. J Clin Oncol 2009;27(18):3027–35.

168 Faivre S, Raymond E, Boucher E, et al. Safety and efficacy of sunitinib in patients with advanced hepatocellular carcinoma: an open-label, multicentre phase II study. Lancet Oncol 2009;10(8):794–800.

169 Koeberle D, Montemurro M, Samaras P, et al. Continuous sunitinib treatment in patients with advanced hepatocellular carcinoma: a Swiss Group for Clinical Cancer Research (SAKK) and Swiss Association for the Study of the Liver (SASL) multicenter phase II trial (SAKK 77/06). Oncologist 2010;15(3):285–92.

170 Cheng AL, Kang Y, Lin D, et al. Phase III study of sunitinib versus sorafenib in advanced hepatocellular carcinoma. J Clin Oncol 2011;29(suppl; abstr 4000).

171 El-Khoueiry AB, Melero I, Crocenzi TS, et al. Phase I/II safety and antitumor activity of nivolumab in patients with advanced hepatocellular carcinoma (HCC): CA209-040. J Clin Oncol 2015;33(suppl;abstr LBA101).

172 El-Khoueiry AB, Sangro B, Yau TC, et al. Phase I/II safety and antitumor activity of nivolumab in pateints with advanced hepatocellular carcinoma: interim analysis of the CheckMate-040 dose escalation study. J Clin Oncol 2016;34(suppl; abstr 4012).

173 Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guidelines (version 1.1) Eur J Cancer 2009;45(2):228–47.

174 Abou-Alfa GK, Zhao B, Capanu M, et al. Tumor Necrosis as a Correlate for Response in Subgroup of Patients with Advanced Hepatocellular Carcinoma (HCC) Treated with Sorafenib. ESMO 2008, Stockholm, Sweden, abstract 547P.

175 Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis 2010;30(1):52–60.