Рак печени

Заболеваемость и смертность

Liver cancer is the sixth most common cancer and the second leading cause of cancer mortality worldwide [1]. Incidence rates are highest in east and south-east Asia and in northern and western Africa. Worldwide, hepatocellular carcinoma (HCC) represents 70–90% of liver cancers [1]. Statistical data are compiled by the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program for the category of “liver and intrahepatic bile duct cancer” [2].

According to the American Cancer Society, approximately 40,710 new cases of liver and intrahepatic bile duct cancers (29,200 men and 11,510 women) are diagnosed and approximately 28,920 deaths (19,610 men and 9,310 women) from these cancers occur annually in the United States [3]. The incidence rate of cancers of the liver and intrahepatic bile ducts, overall, based on cases diagnosed between 2009 and 2013, was approximately 8.4 per 100,000 persons per year. During the same time period, the age-adjusted death rate was 6.1 per 100,000 persons per year. The lifetime risk of developing cancer of the liver and intrahepatic bile ducts is approximately 0.95%. These overall statistics largely reflect those of HCC, which in the United States accounts for 73.8% of cancers of the liver and intrahepatic bile duct [2].

Этиология и факторы риска

Вирусный гепатит

Infection with viral hepatitis B (HBV) and C (HCV) are collectively responsible for 74.3% of HCC cases worldwide [4]. A member of the Hepadnaviridae family of DNA viruses, HBV integrates itself into the host genome and initiates viral replication through reverse transcription. Hepatocarcinogenesis occurs as a result of genomic instability caused by insertional mutagenesis, viral protein oncogenesis, and by inflammation and fibrosis elicited by the host immune response [5]. The degree of HBV replicative activity has been shown to correlate with increased HCC risk [6]. HCV is an RNA Flavivirus that induces chronic liver inflammation, oxidative stress, and cycles of regeneration, proliferation, and fibrosis. These events cause genomic, proteomic, and transcriptomic aberrations that ultimately lead to HCC. Unlike HBV, HCC that arises in the context of HCV infection is virtually always preceded by cirrhosis [7]. Treatment of viral hepatitis has been shown to reduce, but not eliminate, the risk of 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.

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