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18. Diagnosis, prognosis & therapy of hepatocellular carcinoma
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Surveillance of patients at high risk and early
HCC diagnosis
Surveillance is cost efective if the expected HCC risk exceeds 1.5% per
year in hepatitis C and 0.2% per year in hepatitis B. Simple clinical scores
have been developed in hepatitis B (e.g., the REACH-B score) and hepatitis
C (e.g., the HALT-C score) to assess when HCC surveillance becomes costefective (Chen 2013, Yuen 2009, Lok 2009). Surveillance has to be based
on ultrasound examination at 6-month intervals. When 3- versus 6-month
surveillance intervals were compared in a randomised study involving
1200 patients, there was no evidence that the shorter interval improved
rates of early diagnosis and therapeutic outcomes. However, if patients with
cirrhosis harbor nodular lesions, the 3-mont hly cont rol interval is preferred
due to the high potential of malignancy and growth characteristics of such
lesions (Yao 2006). Thus, nodules <1 cm, which usually are not HCC, should
be monitored in 3-4 month intervals until they are proven to be stable or
disappear (for up to 24 months). Nodules >1 cm should be evaluated with
either 4-phase computed tomography (CT) or dynamic contrast-enhanced
magnetic resonance imaging (MRI) as outlined in the section on diagnosis.
Alpha-fetoprotein (AFP) has insuicient sensitivity and speciicity, and
thus is no longer recommended for HCC surveillance. Des-gammacarboxy prothrombin (DCP), glycosylated AFP (AFP-L3), and glypican-3
are being evaluated with respect to HCC surveillance, and integrated as
components of the GALAD score have outperformed ultrasound in a recent
study suggesting that their combination with ultrasound might result in
improved HCC surveillance of high risk patients (Yang 2019). The consistent
use of ultrasound in patients with high risk for HCC enables us to diagnose
carcinoma early in 30% of patients who then have a reasonable chance of
curative therapy. On the other hand, Caucasian patients with low or no
HBV activity are at low-risk for HCC, and surveillance is generally not
recommended in such patients.
Diagnosis
Patients who develop HCC usually have no symptoms other than
those related to the underlying chronic liver disease. However, in
patients with sudden hepatic decompensation such as ascites, jaundice,
hepatic encephalopathy or variceal bleeding oten caused by portal vein
thrombosis there is an increased likelihood of HCC. Occasionally patients
develop paraneoplastic syndromes (hypoglycaemia, erythrocytosis,
hypercalcaemia, severe watery diarrhoea, dermatomyositis and various
types of skin lesions), which apart from erythrocytosis herald a poor
prognosis (Luo 2002). Plasma micro-RNAs are currently under evaluation as
biomarkers for the non-invasive diagnosis of HCC at any stage (Borel 2012).
The diagnosis of HCC is made by detecting malignantly transformed
hepatocytes in a liver biopsy or by dynamic contrast-enhanced radiological
imaging techniques demonstrating intense arterial uptake followed by
wash-out of contrast in the delayed venous phases relecting arterialised
perfusion of the tumour. Contrast-enhanced ultrasound may falsely
suggest HCC in some patients with cholangiocarcinoma, and it should not
be used as the only diagnostic tool for HCC (Vilana 2010). Nevertheless,
novel diagnostic algorithms enable the diagnosis of HCC in a cirrhotic liver
without histopathology or reference to elevated tumour markers.
The revised WHO classiication distinguishes new speciic subtypes of
hepatocellular carcinoma (steatohepatitic, clear cell type, macrotrabecular
massive, chromophobe ibrolamellar, sc irrou s, neutrophil-rich, lymphocyterich (WHO 2019). In particular the distinction between a dysplastic nodule
and early HCC poses a particular challenge for the pathologist. Staining for
glypican-3, heat shock protein 70, and glutamine synthetase is advised in
this situation, and positivity for any two of these three markers conirms
the presence of HCC (International Working Party 2009). Diferentiation of
HCC from cholangiocarcinoma may also require cell-type speciic markers
such as keratin-7, keratin-19, or CA 19-9.
Radiological diagnosis of HCC uses detection of hyper-vascularised
nodular lesions. Contrast-enhanced computed tomography (CT) or nuclear
magnetic spin resonance tomography (MRI) are considered to be equivalent
diagnostic tools, and international consensus guidelines accept a diagnosis
of HCC without histopathology, if the patient with a nodular lesion in a
cirrhotic liver exhibits the following sequence of events: in the arterial
phase, HCC enhances more intensely than the surrounding liver, because
arterial blood in the liver is diluted by venous blood from the portal venous
circulation, whereas HCC contains only arterial blood. In the venous phase,
HCC enhances less than the liver, relecting the fact that HCC does not have
a portal venous blood supply and that the arterial blood lowing into the
lesion no longer contains contrast. This phenomenon is termed “washout”.
In the delayed phase “washout” persists, and occasionally HCC can only be
detected in this phase of a dynamic study. Thus, a four-phase dynamic study
is needed to reliably make a diagnosis of HCC (unenhanced, arterial, venous
and delayed venous phases). Contrast enhancement in the early arterial
phase, which disappears in the late venous phase, is highly speciic for HCC.
Difusion-weighted imaging (DWI) in MRI relects water mobility
in tissues, which is impeded in HCC tissue. Thus HCC results in signal
hyperintensity within the tumour relative to the liver parenchyma. A
recent meta-analysis provided evidence that DWI combined with dynamic
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contrast-enhanced MRI performed signiicantly better than any of the two
imaging techniques alone (Wu 2013). Hepatocyte-speciic contrast agents
such as gadoxate disodium and gadobenate dimeglumine are taken up by
normal hepatocytes. Since most HCCs do not contain funct ional hepatocytes,
signal hypointensity relative to the surrounding liver is observed in the
hepatobiliary phase. As a consequence, hepatobiliary phase images are
highly sensitive for HCC. However, this technique has only poor speciicity
(Bartollozzi 2013). Nodules with a hypointense signal in the hepatobiliary
phase but without diagnostic features of HCC in the other phases may
represent highly dysplastic nodules or early HCC and carry a high risk of
progressing to conventional hypervascular HCC.
The current recommendations for diagnosis of HCC are summarised
in Figure 1. For lesions smaller than 1 cm, detailed investigation is not
recommended because most lesions will represent regenerative nodules
rather than HCC. However, close follow-up in 3-month intervals should be
ofered using the same imaging technique that detected the lesion in the
irst place.
can be performed. If radiological indings are characteristic for HCC as
described above, a irm diagnosis of HCC can be made and no further steps
are necessary.
Contrast-enhanced CT and MRI exhibit excellent diagnostic sensitivity
and speciicity if the rules regarding early hypervascularity and washout
are strictly applied. The presence of arterial hypervascularisation alone
is not suicient for a diagnosis of HCC, which requires the presence of
venous washout as an essential second diagnostic component. In equivocal
situations the diagnosis must be clariied by biopsies, which may have to be
repeated within a short period of time.
Radiological assessment of treatment responses should not be based
on tumour size alone but apply modiied Response Evaluation Criteria in
Solid Tumours (mRECIST) (Lencioni 2010). High quality arterial-phase
imaging is required for this purpose. In general, MRI is preferred over CT
owing to its superior tissue contrast resolution and sensitivity to detect
both the tumour and post-treatment changes. Using contrast-enhanced
techniques, absence of uptake within the tumour is considered to relect
necrosis, while persisting uptake indicates vital tumourous tissue. Rim
contrast enhancement ater ablative loco-regional therapy is not indicative
of viable tumour, unless contrast enhancement also reveals nodular or
thick uptake along the tumour margins or a clear wash-out (Chung 2012,
Riaz 2009). Tumour recurrence is signaled by the re-appearance of vascular
enhancement.
Figure 1. Diagnostic algorithm for the diagnosis of hepatocellular carcinoma depending on
tumour size
For lesions larger than 1 cm, a guided biopsy of the lesion should be
performed because diagnostic accuracy of radiological procedures declines
with smaller liver tumours, while high (>90%) diagnostic sensitivity and
speciicity is maintained by histological analysis of biopsy specimens
(Serste 2012). Alternatively, either dynamic MRI or multidetector CT scans
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Stage-adapted therapy for liver cancer
The two key factors that are most important in determining a patient’s
prognosis and potential treatment options are the tumour mass and hepatic
functional reserve. Patients with early HCC have excellent chances for
curative cancer treatment. They can achieve 5-year survival rates of 50-70%
by surgical resection, liver transplantation or percutaneous ablative
procedures. With more advanced HCC, local transarterial embolisation
and multikinase inhibitor therapy can still prolong life. Figure 2 gives a
summary and concise overview of stage-adapted therapy for hepatocellular
carcinoma.
Potentially curative therapy in BCLC stages 0-A
Surgical resection constitutes the backbone of curative treatment in
patients with early HCC. It is the treatment of choice in patients with localised
tumour spread and small-sized cancers and tumours in a non-cirrhotic liver
18. Diagnosis, prognosis & therapy of hepatocellular carcinoma
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(evidence grade IIIA). Prognosis ater surgical resection is excellent, if the
tumour is not larger than 2 cm in diameter (5-year survival rates 70-90%
with rates of tumour recurrence below 10%). Excluding patients with poor
liver function keeps perioperative mortality below 5%. Favourable criteria
for surgical resection comprise single nodules less than 5 cm in size or a
maximum of 3 nodules in a single liver lobe. Patients should be carefully
selected to diminish the risk of postoperative liver failure. Patients should
have only moderately impaired liver function (Child’s stage A cirrhosis),
should not have portal hypertension (hepatic-portal-vein pressure gradient
>10 mm Hg, presence of oesophageal varices or splenomegaly together with
reduced platelet counts <100,000/l) and should have a serum bilirubin in
the normal range. Patients with tumour invasion of a major portal or hepatic
vein, direct invasion of neighboring organs other than the gallbladder,
peritoneal disease, and nodal or distant secondaries are not candidates for
su rger y.
Potentially curative partial hepatectomy is the optimal treatment for
HCC in patients with adequate hepatic functional reserve. Right hemihepatectomy in cirrhotic patients has a higher risk of inducing hepatic
decompensation than let hemi-hepatectomy. Non-anatomic resection
may be necessary to minimise loss of functional liver parenchyma.
Operative mortality for HCC is related to the severity of liver disease,
and patients with complications of cirrhosis such as marked portal
hypertension, ascites or bleeding have insuicient hepatic reserve to
withstand resection. Most deaths are due to postoperative liver failure and
< 10% are related to complications of bleeding. Ninety-day mortality rates
appear a more reliable indicator of outcomes than 30-day perioperative
mortality, especially in patients with extended resections and resections
of cirrhotic livers, since progressive jaundice, ascites and eventually death
develop slowly and well ater 30 days in patients with marginal residual
liver function. Of note, common prognostic tools, e.g. the Child-Pugh
Classiication or the Model for End-stage Liver Disease (MELD) score, are
not adaequate to identify patients with insuicient hepatic functional
reserve ater resection. Volume and function of the residual liver remnant
can be determined by hepatic volumetry which is best performed before and
ater portal vein embolisation. Also CLIP and ALBI scores help to assess the
hepatic functional reserve and risk of surgical resection. Because hepatic
regeneration is impaired in cirrhosis, resection in general should not
exceed 25% of the liver parenchyma. Preoperative portal vein embolisation
can be used in selected patients to increase the volume of the liver remnant
prior to major liver resections, particularly for right-sided tumours,
because it initiates hypertrophy and allows for more extensive resections
(Abulkhir 2008, Leung 2014). Selective arterial chemoembolisation (TACE)
has been recommended as a complementary procedure prior to portal vein
embolisation because it reduces arterial blood supply to the tumour and
also embolises potential arterioportal shunts (Yoo 2011).
Liver transplantation is an alternative therapeutic option, if the
liver cancer cannot be cured by local resection due to anatomical reasons,
if residual liver function ater resection is anticipated to be poor, or if
there is multi-nodular tumour spread into both liver lobes (grade IIIA
evidence). Virtually all patients considered for liver transplantation are
unresectable due to the degree of liver dysfunction rather than tumour
extent. Commonly, patients with HCC are selected for liver transplantation
according to the so-called Milan criteria, i.e., the patient has a single nodule
of less than 5 cm in diameter or at most 3 nodules, none of which exceeds
3 cm in diameter (Mazzaferro 1996). Patients who meet the Milan criteria
usually achieve survival rates of 80% and 70% one and ive years ater
liver transplantation. However, it has been demonstrated that selected
patients with more extensive stages of liver cancer can be transplanted with
reasonable long-term outcomes (Yao 2001). Selection of patients according
to the San Francisco criteria comprises solitary large nodules up to 6.5 cm
as well as multi-nodular HCC with a maximum of 3 nodules, each of which
must be smaller than 4.5 cm with a total sum of all nodule diameters less
than 8 cm. Patients who remain within these extended selection criteria
can still reach 70-80% ive-year survival rates ater liver transplantation.
However, there is very limited data to support extending selection criteria
for liver transplantation any further (Pomfret 2010).
A central issue in liver transplantation is the process of fair organ
allocation. Shortage of donor organs is particularly critical in patients
with liver cancer, because the tumour will continue to expand while the
patient is on the waiting list, and can ultimately reach a stage that makes
liver transplantation a futile option. It has been estimated that ater one
year on the waiting list, approximately 40% of patients can no longer be
cured by liver transplantation (Poon 2007). In the Eurotransplant registry
donor livers are allocated to patients according to their MELD scores. To
circumvent the problem that patients with early HCC who are eligible for
liver transplantation have rather low MELD scores, Eurotransplant accepts
the diagnosis of HCC within the Milan criteria as so-called standard
exemption, allocating additional points on top of the patient’s lab MELD
score in an incremental time-dependent fashion.
EASL/EOTC guidelines recommend to treat liver cancers locally when
the expected time on the waiting list exceeds 6 months (EASL/EOTC
2012). Bridging therapy can be done by transarterial chemoembolisation,
radiofrequency ablation or partial resection. This strategy probably also
facilitates patient selection for liver transplantation, because those with
stable disease ater chemoembolisation achieve a greater than 90% iveyear survival rate ater liver transplantation, while only 35% of patients in
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the group with progressive tumour expansion survive ive years post-liver
transplantation (Otto 2006).
Sirolimus, an inhibitor of mammalian target of rapamycin (mTor
inhibitor) seems to be a promissing immunosuppressive agent in liver
transplantation of HCC, because it has antiproliferative activity against
HCC in vitro and in vivo and can interfere with vascular endothelial growth
factor (VEGF). Several early reports suggested a lower risk of posttransplant
HCC recurrence with the use of sirolimus, and a registry-based comparison
of 2491 adult patients with liver cancer, who underwent transplantation,
versus 12,167 liver transplantations for other diagnoses suggested a
postransplant survival beneit for the use of sirolimus, that was speciic to
patients transplanted for HCC (Toso 2010). In support, a recent meta-analysis
suggested that sirolimus-based regimens signiicantly decreased overall
tumour recurrence rates and recurrence-associated mortality (Menon
2013). Although these data are encouraging, the International Consensus
Conference on Liver Transplantation for HCC does not yet generally
recommend sirolimus for transplantation in HCC, since available data are
entirely derived from retrospective studies (Clavien 2012). Everolimus,
a semisynthetic form of sirolimus may have similar efects as sirolimus
but has not been studied adaequately in patients with HCC. Side efects
of sirolimus comprise thrombosis of the hepatic artery, delayed wound
healing, incisional hernias, hyperlipidaemia, bone marrow suppression,
mouth ulcers, skin rashes, albuminuria, and pneumonitis. Because of their
side efect proile, in particular hepatic artery thrombosis, mTor inhibitors
should not be used in the irst three months ater liver transplantation.
Non-surgical local procedures: Image-guided ablation is
recommended for patients with early HCC when surgical options are
precluded.
Radiofrequency ablation (RFA) is currently considered the standard
technique, because most clinical data are available for RFA: A cohort study
on percutaneous radiofrequency ablation demonstrated that complete
ablation of lesions smaller than 2 cm is possible in more than 90% of
patients with local recurrence in less than 1% (Livraghi 2008). In larger
tumours, ive-year survival rates are somewhat lower, at 70-80% for
nodules less than 3 cm in diameter, and 50% for tumours between 3 and 5
cm (Lopez 2006). A cumulative meta-analysis has suggested that survival
is better ater radio frequency ablation than ater ethanol injection (Cho
2009). In up to a third of patients a self-limited postablation syndrome has
been reported ater RFA which was associated with fever, malaise, chills,
right upper quadrant pain, nausea and elevated liver enzymes (Dodd 2005).
RFA is avoided for lesions in the hepatic dome or along the inferior liver
edge to avoid diaphragmatic injury or intestinal perforation. In addition to
size the local eicacy is also afected by the proximity of a lesion to large
blood vessels (Lu 2005), probably because the blood low carries away
heat from the lesions (the “heat sink” phenomenon). Following RFA gas
bubbles may form in the liver as a result of treatment and should not be
mistaken for infection or infarction (Park 2008). Although RFA is relatively
well tolerated, severe and potentially fatal complications can occur, e.g.
liver abscess, pleural efusion, pneumothorax and skin burns, subcapsular
hepatic hematoma and needle tract seeding of tumour cells (Takaki, 2013).
Outcomes of RFA are superior to percutaneous ethanol injection and may
be equivalent to surgery in small tumours.
Some alternative treatment modalities have recently attracted attention
because they may overcome some of the limitations associated with RFA.
Microwave ablation (MWA) can generate very high temperatures in
the tumour tissue in a very short time. This can potentially lead to enhanced
treatment eicacy and larger ablation zones and can reduce susceptibility
to heat dispersion by blood low in major vessels (Boutros 2010).
Cryoablation refers to methods, which destroy tissue by local
freezing or alternating freezing and thawing. Rapid tissue freezing and
thawing produce a cytotoxic efect by disrupting cellular membranes and
inducing cell death. The cryolesion is hypechogenic and can be visualised
and monitored by intraoperative ultrasound. Cryoablation can lead to
equivalent treatment outcomes as RFA (Wang 2015). However, meanwhile
most centres have abandoned cryoablation, because other techniques, e.g.
RFA are technically easier to do, may potentially be associated with less
local recurrence and lower complication rates.
Irreversible electroporation (IRE) induces cell death by repeated
application of short-duration high-voltage electrical pulses, which
irreversibly injure cellular membranes. Although hyperthermic efects
may occur with high power applications, cell death associated with IRE
is induced non-thermally. Hence, cooling owing to high perfusion is not a
problem with this technique (Schefer 2014). However, general anesthesia
with neuromuscular blockade and cardiac gating to prevent arrhythmias
are required. Other energy-based ablation treatment approaches comprise
laser induced thermal therapy (LITT) and high-intensity focused
ultrasound (HIFU). Eicacy and safety of HIFU for primary or recurrent
HCC has been predominantly studied in Hong Kong and appeared similar to
outcomes with RFA. However, clinical experience outside of China is rather
limited, since only a few centres worldwide have adopted these techniques.
Thus, the place of HIFU is currently undeined.
Adjuvant therapy, in the context of resection, liver transplantation
or local-ablative procedures, does seem to ofer additional beneits. Thus
far, antiviral treatment of hepatitis B with nucleos(t)ide analogs remains
the single approved treatment ater removal or local destruction of HCC.
Interestingly, one study (Su 2014) reported that recurrence-free survival
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and overall survival were signiicantly better in 9,461 Taiwanese patients
who had liver resections for HBV-associated HCC between 1997 and 2011,
when they were on anti-platelet therapy.
A randomised phase 3 trial involving 1,114 HCC patients ater liver
resection or local ablation, who were randomised to receive either sorafenib
or placebo for 4 years or until tumour recurrence (STORM trial), did not
meet its primary and secondary endpoints of recurrence-free survival, time
to recurrence or overall survival (Bruix 2015). Positive reports are available
from phase 2 trials with transarterial radioactive 131-iodine, capecitabine,
heparanase and thalidomide. However, conirmatory phase 3 data are not
yet available for any of these agents.
Tumour recurrence is frequent ater putatively curative treatment of
HCC. Although there is no generally accepted consensus on posttreatment
surveillance, most centres apply CT or MRI imaging every 3 to 6 months for
irst two years ater therapy, then annually, and if initially elevated, also
recommend monitoring serum AFP every 3 months for irst two years, then
every 6 months (Clavien 2012). Most HCC recurrences are intrahepatic and
relect local recurrence or a new second primary lesion (Hatzaras 2014). The
best predictors of HCC recurrence are high serum alpha-fetoprotein levels
(AFP >500 ng/mL), microvascular invasion and/or additional tumour sites
besides the primary lesion. Solitary nodules might be amenable to repeat
resection, but HCC recurrence is f requently multifocal owing to intrahepatic
dissemination of the tumour. Some patients with HCC recurrence ater
primary resection might beneit from salvage transplantation. The role of
HBV infection for HCC recurrence ater resection is under debate (Sun 2007,
Cescon 2009, Char 2014), and early HCC recurrence has been reported to
be even greater in hepatitis C infected patients than HBV infected patients
(Utsunomiya 2015). Therapy with antiviral drugs seems to reduce late (≥ 2
years) HCC recurrence in chronic hepatitis B and C but does not seem to
have much efect on early HCC recurrences (Yin 2013, Huang 2015). The
efects of direct antiviral therapy in patients with HCV-related HCC is not
yet clear, since rapid recurrence and expansion of HCCs have been reported
to occur shortly ater DAA therapy, even when the primary HCC had been
“cured” quite some time before (Conti 2016, Kozbial 2016, Reig 2016).
Palliative therapy in BCLC stages B and C
non-surgical HCC who are also not suited for percutaneous ablation and do
not have extrahepatic tumour spread. HCC exhibits intense neoangiogenic
activity, so that even well-diferentiated HCCs become highly dependent
on arterial blood supply. Thus, hepatic arterial obstruction is performed
either by angiographic transarterial embolisation or transarterial
chemoembolisation. Usually lipiodol combined with an embolising agent
such as gelatin or microspheres is mixed with cytostatic drugs and applied
to the liver via an intra-arterial catheter. Suitable cytotoxic agents are
doxorubicin, mitomycin and cis-platinum, but the optimal combination
of drugs and treatment schedules has not been established. In randomised
studies demonstrating a beneit of chemoembolisation, doxorubicin or
cis-platinum was administered in 3-4 angiographic sessions per year.
Chemoembolisation carries the risk of ischemic damage to the liver,
potentially leading to fulminant liver failure. To minimise this risk
chemoembolisation should be ofered only to patients with good residual
hepatic function, who have asymptomatic multi-nodular liver cancer
without vascular invasion or extrahepatic tumour spread. Vice versa
patients with decompensated liver disease (liver cirrhosis, Child’s B or C) or
imminent hepatic failure should not undergo chemoembolisation. Table 2
lists absolute and relative contraindications for chemoembolisation.
Table 2. Contraindications for transarterial chemotherapy for HCC
Absolute contraindications:
Macrovascluar invasion of the portal vein with thrombus in the main portal vein and/or
portal vein obstruction
Hepatic encephalopathy
Biliary obstruction
Liver cirrhosis stage Child-Pugh C
Relative contraindications:
Serum bilirubin > 2 mg/dL
Lactate dehydrogenase > 425 U/L
Aspar tate aminotransferase > 100 U/L
Tumour mass > 50% of the liver
Cardiac or renal insufficiency
Severe thrombocytopenia
Transjugular intrahepatic portosystemic shunt TIPS
Complications of portal hypertensison such as ascites or gastrointestinal bleeding
Palliative treatment remains the only therapeutic option for patients
with advanced stages of liver cancer that cannot be controlled by local
therapy.
Arterial chemoembolisation is the most frequent palliative
intervention ofered to patients with HCC and is considered for patients with
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The side efects of interarterial chemoembolisation are the same as for
systemic chemotherapy and consist of nausea, vomiting, bone marrow
depression, alopecia and renal damage. TACE is a risk factor for hepatitis
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B virus reactivation and antiviral prophylaxis is recommended in HBsAg
positive patients. Common ischemic complications comprise a hepatic
abscess, acute cholecystitis and damage to biliary tracts. Interstitial
pneumonitis and gastrointestinal ulcerations due to abnormal shunting
may occur owing to radiation injury. Pulmonary or cerebral lipiodol
embolisations are rare but potentially fatal complications. Overall,
treatment-related mortality rates are about 2%. As a frequent complication
of hepatic ischaemia, more than 50% of patients also develop a so-called
post-embolisation syndrome with fever, abdominal pain and a moderate
degree of ileus. Fasting and luid replacement is mandatory, but the
post-embolisation syndrome is usually self-limited and patients can be
discharged safely ater 2 days.
Objective response rates vary between 16% and 60%, but less than 2%
of patients achieve complete remission. Residual tumour cells recover their
blood supply and the tumours continue to grow. Thus, repeated therapy
may be needed. However, multiple courses can increase death from liver
failure despite good tumour reduction; thus, counterbalancing the potential
survival beneits from repeated treatment. TACE should be limited to the
minimum number of interventions needed to control tumour growth.
Chemoembolisation is currently considered to signiicantly improve
survival in suitable palliative patients (Llovet 2002). Beyond that,
combination therapy with TACE and RFA appears to be the most eicient
treatment of early HCC (Lan 2016) and is used as bridging therapy for HCC
patients on the waiting list for liver transplantation. However, its use in
patients allocated to curative resection it is not recommended, because
surgical complication rates are increased thereater.
DEB TACE (transarterial chemoembolisation using drug eluting beads)
constitutes a modiication of chemoembolisation, where embolising
particles act as carriers and are loaded in vitro with cytotoxic agents
such as doxorubicin. In addition to their ischemic efects, drug-eluting
beads release the drug into the tumour microenvironment in a slow and
controlled fashion, thus potentially enhancing their antitumoural activity.
While the clinical response to DEB chemoembolisation is rather similar to
conventional chemoembolisation, systemic exposure to chemotherapy is
apparently reduced; in particular, biliary side efects are less frequent and
let ventricular funct ion better preserved (Vogl 2011). Conversely, treatmentassociated gastrointestinal adverse efects appear to be more frequent in
DEB-TACE than in conventional chemoembolisation. Meanwhile, also
irinotecan-eluting beads are being studied.
Radiotherapy with Yttrium-90 microspheres has been developed as
a novel alternative palliative treatment of liver cancer with unexpectedly
impressive anti-tumoural activity in selected indiv idual cases (Sangro 2006,
Jacobs 2007, Salem 2006, Liu 2004). Very small particles (25 – 45 m) made
of glass (TheraSpheres®) or resin (SI-Spheres®) serve as sealed sources of
the radio-emitting isotope 90-yttrium (90Y). Microspheres are injected
during hepatic angiography and ultimately lodge in the abnormal tumour
vessels. To avoid misplacement of microspheres into extrahepatic territories
a thorough angiographic evaluation comprising injection of 99Tc macroaggregated albumin is necessary prior to treatment in order to detect and
eventually occlude aberrant vessels, and to also assess hepatopulmonary
shunting. Of note, unlike chemoembolisation, small microspheres do not
occlude the blood vessels and can also be applied in the presence of portal
vein thrombosis. Radioembolisation potently induces tumour necrosis.
However, the therapeutic response to 90Y-radiotherapy is delayed; the
median time to develop necrosis (reduced contrast enhancement) and
tumour shrinkage are approximately 30 and 120 days, respectively (Keppke
2007). Furthermore, heterogenous contrast enhancement in a perivascular
distribution of a 90Y-treated liver segment or lobe relects radiation
injury and should not be interpreted as tumour progression (Riaz 2009).
In a randomised controlled, prospective phase 2 study on 45 HCC patients
in BCLC stages A and B, 90Y radioembolisation resulted in signiicantly
longer times to progression than chemoembolisation (>26 months versus
6.8 months, Salem 2016).
Randomised controlled trials comparing radioembolisation to other
treatment strategies are not yet available. However there is accumulating
good evidence from several well-characterised large cohort studies
(Hilgard 2010, Salem 2010, Sangro 2011, Mazzaferro 2013). Taking into
account tumour stage, intermediate tumour stage patients treated by
radioembolisation achieve 16 to 18 months of median survival time (Salem
2010, Sangr o 2011, Mazzaferro 2013). Adverse events, response rates and time
to progression appeared improved while overall survival was equivalent
when radioembolisation was compared to chemoembolisation (Salem 2011).
When downstaging to transplantation is allowed by local regulations,
radioembolisation outperforms chemoembolisation (Lewandowski 2009).
Finally, a randomised controlled phase 3 trial in 467 patients comparing
radioembolisation to sorafenib chemotherapy did not reveal any signiicant
survival diference between the two treatment arms (SIT: 8.0 months
versus sorafenib 9.9 months; p=0.18) (Villain 2017).
Systemic chemotherapy with conventional anti-cancer drugs does
not seem to ofer survival beneits, whether given as a single agent or as
part of combination chemotherapy (Llovet 2003). Likewise, anti-hormonal
therapy with tamoxifen or octreotide has not provided improved patient
survival when studied under controlled conditions (Gallo 2006, Yuen 2002).
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Systemic palliative HCC therapies
Molecular-targeted therapeutic strategies ofer new hope for
efective palliative therapy in liver cancer. Sorafenib (Nexavar®) is an
orally available multi-kinase inhibitor acting on several distinct tyrosine
kinases (VEGFR2, PDGFR, c-kit receptor) as well as on serine/threonine
kinases (b-Raf and p38). Thus, by inhibiting angiogenesis and cellular
proliferation, sorafenib can block two of the major signalling pathways of
HCC expansion. In a phase 3 study (the SHARP trial) involving 602 patients,
sorafenib 400 mg BID was moderately well-tolerated and associated with
improved survival in 44% of patients resulting in 3 months extended
survival in treated patients (10.7 months in the sorafenib arm versus 7.9
months in the control arm). The eicacy of sorafenib has been conirmed
in a second randomised placebo-controlled trial, mostly involving patients
with HBV-associated HCC (Cheng 2009) and in 1586 patients of the GIDEON
(Global Investigation of Therapeutic Decisions in Hepatocellular Carcinoma
and of its Treatment with Sorafenib) prospective database (Lencioni
2012). Sorafenib has established itself as the irst option in patients with
HCC who can no longer be treated with local therapies. The SHARP trial
largely included patients with preserved liver function. Although the
pharmacologic proile is favourable, data in Child-Pugh class B patients are
scarce (Abou Alfa 2011). Patients with liver cirrhosis Child class C, however,
do not achieve a survival beneit from sorafenib and should only receive
best supportive care. Diarrhea, weight loss, hand-foot syndrome and rash,
hypertension, renal toxicity with hypophosphataemia, thromboembolism,
bleeding, cardiotoxicity, thyroid dysfunction, pruritus, alopecia, impaired
wound healing and hepatotoxicity are important side efects of sorafenib.
Sorafenib has also been associated with fulminant hepatic toxicity,
which is characterised by elevated aminotransferases, coagulopathy and
hyperbilirubinaemia. Sorafenib is apparently particularly efective in HCC
related to chronic hepatitis C. However, its role for treatment of recurrent
HCC ater liver transplantation currently remains still undeined. Sorafenib
can be safely combined with chemoembolisation therapy (Pawlik 2011) but
this combination apparently does not provide any clinical beneit. Likewise,
in the SORAMIC study the combination of sorafenib with 90 Yttrium
radiotherapy (SIT) did not result in better survival than sorafenib alone.
However, certain patient subgroups, e.g. young patients, non-cirrhotic
patients or those with a non-alcoholic aetiology, may still beneit from a
SIT/sorafenib combination treatment.
Lenvatinib (Lenvima®), is an inhibitor of VEGF receptors 1-3,
FGF receptors 1-4, PDGF receptor a, RET and KIT and shows activity
in hepatocellular carcinoma. The phase III REFLECT study comparing
lenvatinib (8-12mg/d) to sorafenib (400 mg twice daily) in untreated
patients with advanced hepatocellular carcinoma revealed that lenvatinib
was not inferior to sorafenib and improved survival to 13.6 (12.1-14.9)
months (sorafenib 12.3 (10.4-13.99 months n.s.) (Kudo 2017). Quality of life
scores deteriorated in both treatment groups ater treatment with rather
similar toxicity proiles: However, patients, who received lenvatinib,
experienced fewer instances of palmar-plantar erythrodysaesthesia,
diarrhoea and alopecia but more instances of arterial hypertension,
proteinuria, dysphonia, and hypothyroidism. In summary, lenvatinib has
been approved in Japan, Europe and the US as a second, irst-line treatment
option in patients with advanced hepatocellular carcinoma. The safety
of lenvatinib and its use in combination regimens is further evaluated in
multiple ongoing studies.
Other antagonists targeting VEGFR, EGFR, ERBB2, Akt-mTor or Wnt/
β-catenin signal transmission pathways have been evaluated in HCC.
However, sunitinib, brivanib, linifanib, tivantinib, or the combination of
erlotinib with sorafenib, everolimus and ramucirumab, all have failed to
demonstrate relevant survival beneits.
Regorafenib (Stivarga®) is a small molecule multikinase inhibitor with
structural analogy to sorafenib. Regorafenib targets VEGF receptors 1-3,
TIE2, PDGFR, FGFR, RET, KIT, RAF kinase and MAPK thus intensively
inhibits several pathways involved in angiogenesis, oncogenesis, metastasis
and tumor immunity. In the RESOCE phase 3 trial regorainib met its
primary study endpoints and revealed prolonged survival (10.6 versus 7.8
months) and better disease control than placebo in patients who had failed
on sorafenib (Bruix 2016). Thus, regorafenib has recently been licensed
for HCC patients progressing on irst-line drug treatment. The most
common adverse efects of regorainib were rash and hand-foot syndrome,
hypertension, increased AST, and hyperbilirubinemia. Similar to sorafenib
skin toxicity with regorainib was a ssociated with improved overall surv ival
(Bruix 2018). Of note, re-analysis of the data from the REFLECT study,
where 75% of patients subsequently were treated with sorafenib, suggests
that sorafenib may ofer an alternative second-line treatment strategy for
patients with HCC who had received lenvatinib as a irst-line drug.
The multikinase inhibitor cabozantinib (Cabometyx®) is active
against VEGFR2, c-MET, and AXL, as well as RET, Kit and FLT3. Beyond
angiogenesis and oncogenesis inhibited kinases are implicated also
in pathways of resistance to VEGF inhibitors such as sorafenib.
Consequentially cabozantinib was tested as a second-line treatment versus
placebo in 707 patients with advanced HCC who received up to 2 prior system
treatment regimens (including sorafenib) and who had disease progression
(CELESTIAL trial) (Abou-Alfa GKI 2018). In this study Cabozantinib
substantially improved overall survival versus placebo (median 10.2 versus
8 months) and the beneit was more pronounced when patients had received
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18. Diagnosis, prognosis & therapy of hepatocellular carcinoma
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sorafenib as the only prior therapy (11.3 versus 7.2 months). Cabozantinib
also achieved greater progression-free survival (5.2 versus 1.9 months), and
thus has become licensed as a second-line treatment option for patients
failing on or intolerant to sorafenib. Dose reductions were frequent in the
treatment arm (63%), oten caused by side efects (16%) such as hand-foot
skin reaction, hypertension, elevated liver enzymes, fatigue, diarrhoea,
asthenia and decreased appetite. Thus, poor tolerability of cabozantinib
may limit its use in clinical practice.
Ramucirumab (Cyramca®) is a humanized monoclonal antibody which
selectively inhibits VEGFR2 and showed activity against HCC in early
trials. Of note, the REACH trial of ramucirumab against placebo indicated a
survival beneit particularly for the subgroup of HCC patients with elevated
AFP levels (Zhu 2015). This observation formed the basis for the biomarkerdriven REACH-2 trial, which evaluated ramacirumab versus placebo in
advanced HCC patients with failure of or intolerance to sorafenib and high
AFP (≥400 ng/ml) (Zhu 2019). REACH-2 met its primary study endpoint
and conirmed that ramucirumab improved overall survival (8.5 versus
7.3 months, p=0.02) and progression free survival (2.8 versus 1.5 months,
p<0.0001). A pooled safety and eicacy analysis of the REACH-2 trial with
the patients who had AFP levels ≥400 ng/ml in the REACH study conirmed
these indings (Zhou 2018), so that ramacirumab has been licensed as a
biomarker-controlled second-line treatment for the subgroup of HCC
patients with high AFP. Ramucirumab has a manageable safety proile with
hypertension and hyponatriemia as the most common side efects, and on
the other hand revealed declines in disease-releated symptoms, making it a
second-line drug demonstrating both improved survival and quality of life.
Immune-based therapy. Currently cancer immunotherapy has
become encouraging because monoclonal antibodies (mAbs), which block
molecules that negatively regulate T-cell responses, can reverse T-cell
exhaustion and reconstitute anti-tumour immunity (Prieto 2015). Immune
checkpoint inhibitors, such as ipilimumab (anti-CTLA-4), nivolumab (antiPDL-1) and pembrolizumab (anti-PD-1) have already received approval from
regulatory agencies for therapy of malignant melanoma, lung and renal
cancer. Checkpoint inhibitors reactivate the exhausted antitumour response
and can result in an objective and maintained immune control of tumour
growth. Initial data from the CheckMate 040 study, an open-label phase 1/2
dose escalation and expansion trial with intravenous bi-weekly application
of the PD-L1 antagonist nivolumab, reported 20% objective response rates
across all underlying etiologies of liver cancer (El-Khoueiry 2017). However,
the results of a randomised controlled phase 3 trial, CheckMate 459, did
not reach its primary study endpoint. The PD-1 inhibitor pembrolizumab
induced complete remission, in 1% and partial remission in 16.3% of 104
patients with advanced liver cancer, who had disease progression on
sorafenib in the KEYNOTE-224 phase 2 study but likewise failed to reach
its primary study endpoint in the KEYNOTE-240 trial. Based on their
phase II data both nivolumab (Opdivo®) and pembrolizumab (Keytruda®)
were licensed for patients with advanced HCC in the US but not in Europe.
However, both antibodies are further evaluated as components in various
combination rescue studies for patients with progressive HCC.
The spectrum of adverse efects associated with nivolumab and
pembrolizumab comprises a variety of autoimmune and grat-versushost-disease like reactions such as skin disease, diarrhoea, thyroiditis
and autoimmune-like hepatitis but overall side efects appear still to be
acceptable.
Recently, a phase III study comparing the combination of monoclonal
antibodies atezolizumab and bevacizumab versus sorafenib (IMbrave150
study; Cheng AL et al. ESMO Asia 2019) has created new hope, because the
combination resulted in substantially improved survival, delay of disease
progression and quality of life across almost all groups of patients at
acceptable adverse efects. However, patients with liver cancer of non-viral
etiology appeared to have less beneit from this novel systemic treatment
option.
Figure 2. Overview of stage-adapted therapy of liver cancer relative to the BLCL criteria.
*Systemic therapy comprises Sorafenib and Lenvatinib as first line options, Regorafinib,
Cabozantinib , and Ramucirumab as further options after failure or intolerance of first line
drug therapies.
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Prophylaxis of liver cancer
Despite conspicuous progress in the diagnosis and therapy of HCC, the
prognosis of HCC has not improved very much over t ime. Thus, prophylactic
measures are of pivotal importance. HBV vaccination, now recommended
by many national vaccination councils, has been proven in Taiwan to
markedly reduce HBV infection rates along with the incidence of HCC as a
complication of chronic hepatitis B in later life (Lok 2004).
Patients with chronic HBV and patients with chronic hepatitis C should
be ofered antiviral therapy as efective secondary prophylaxis of HCC.
Although HBe antigen positive (van Zonneveld 2004) and HBe antigen
negative patients with chronic hepatitis B showed reduced incidence rates
of HCC when successfully treated with interferon (Papatheoridis 2001,
Brunetto 2002, Lampertico 2003), antiviral therapy with nucleos(t)ide
analogs seems to reduce the risk of HCC less convincingly (Papatheoridis
2010, Papatheoridis 2011). Newer, more potent nucleos(t)ide analogs such
as entecavir seem to reduce the risk of HBV-associated liver cancer more
potently, particularly in high risk patient groups (Hosaka 2012). Systematic
analysis of the available data suggests that HBV-treatment can reduce
the relative HCC risk by about 60%. Also, several meta-analyses suggest
that successful interferon therapy will reduce the risk of HCC in chronic
hepatitis C (Camma 2001, Paptheoridis 2001a, Veldt 2004). Despite some
initial confusion on the role of the newly available directly acting antiviral
drugs in hepatitis C concering HCC prevention it has meanwhile become
clear that rates of HCC development are substantially diminished ater
DAA therapy (Carrat 2019) . Nevertheless, patients who have cirrhosis and/
or long disease duration prior to antiviral therapy should be be followed in
HCC surveillance programs, since their risk of liver cancer remains still
high even ater achieving a sustained virological response (Yu 2006, Van
der Meer 2012, Aleman 2013).
Improving additional risk factors such as obesity and poorly controlled
diabetes mellitus may further reduce the risk of HCC development: weight
reduction and exercise improve the prognosis of steatohepatitis, and
metformin and thiazolidinedione should be favoured over sulfonylurea
drugs in the treatment of diabetes (Greten 2013). The use of aspirin but not
other nonsteroidal antiinlam matory drugs was a ssociated with a decreased
risk of HCC in a US Diet and Health study (Sahasrabuddhe 2012), and several
studies suggest that use of statins leads to a lower risk of HCC (Singh 2013,
Shi 2014, Hsiang 2015). Finally, daily consumption of two or more cups of
cofee reduces the risk of HCC by 40-50% in patients with chronic viral
hepatitis (Gelatti 2005, Bravi 2007, Larsson 2007, Wakai 2007).
References
Abou-Alfa GK, Mey er T, Cheng AL, El Khoueir y AB, et al. Cabozantin ib in patients with advanced an d progressing hepatoc ellular carcinoma.
N Engl J Med 2018; 379: 54- 63.
Abulkhir A., Limongelli P, Healey, et al. Preoperative portal vein embolization for major liver resection: a meta-analysis. Ann Surg 2008;
247:49- 57.
Aleman S, Rahb in N, Weiland O, et al . The risk for hepatocel lular carcinoma persists l ong-term ater sustained viro logical respons e in patients
with hepatitis C-a ssociated liver cirrhosi s. Clin Infect Dis 2013;57:230 -236.
Anonymus. Prospective validation of the CLIP score: a new prognostic system for patie nts with cirrhosis and hepatocellular carcinoma. The
Cancer of the Liver Itali an Program (CLIP) Investigators Hepatology. 2000 ;31:840-5.
Bartolozzi C, Battaglia V, Bargellini I, et al. Contrast-enhanced magnetic resonance imaging of 102 nodules in cirrhosis: correlation with
histologica l indings on explanted live rs. Abdom Imaging 2013;38: 290-296.
Borel F1, Konstantinova P, Jan sen PL. Diagnosti c and therapeutic potential of m iRNA signatures in p atients with hepatocellular carc inoma.
J Hepatol. 2 012;56:1371-83.
Boutros C, Somasundar P, Garrean S, Saied A, Espat NJ. Microwave coagulation therapy for hepatic tumours: review of the literature and
critical analysis . Surg Oncol 2010;19: e22-e32
Bralet MP, Regimbeau J M, Pineau P, et al. Hep atocellular carcinoma o ccurring in nonibroti c liver: epidemiologi c and histopathologic a nalysis
of 80 French case s. Hepatology 2000;3 2:200-204.
Bravi F, Bosetti C , Tavani A, et al. Cofee drinking a nd hepatocellular carci noma risk: a meta-analysis. H epatology 2007;46:430-435.
Bruix J, Takayama T, Mazzaferro V, et al. Adjuvant sorafenib for hepatocellular carcinoma ater resection or ablation (STORM): a phase 3 ,
randomised, d ouble-blind, pla cebo-controlled tri al. Lancet Oncol 2 015;16:1344-1354.
Bruix J, Qin S , Merle P, Granito A, Huang YH, et al . ; RESOCE Investigators. Regorafe nib for patients with hepatocell ular carcinoma who
progressed on s orafenib treatment (RESOCE): a rand omised, double-bl ind, placebo- controlled, phase 3 tri al. Lancet. 2017; 389:56 -66
Bruix J, Merle P, Granito A, Huang YH, et al. RESOCE investigators. Hand-foot skin reaction (HFS) and overall survival (OS) in the
phase 3 RESOCE t rial of regorafenib for treatment of hepatocellular carc inoma (HCC) progressing on sorafenib. J Clin Oncol 2018;
36 suppl: 412.
Brunetto MR, O liveri F, Coco B, Leandro G, Col ombatto P, Gorin JM, Bonino F. O utcome of anti-HBe positive chroni c hepatitis B in alpha-
interferon treated and unt reated patients: a long term co hort study. J Hepatol 2002;36: 263-270.
Camma C, Giunta M, Andreone P, Craxi A. Interferon and prevention of hepatocellular carcinoma in viral cirrhosis: an evidence-based
approach. J H epatol 2001;34:593-602.
Carrat F, Fontaine H, Dorival C, et al. Clinical outcomes in patients with chronic hepatitis C ater direct-acting antiviral reatment: a
prospective co hort study. Lancet 2019; 393: 1453-1464.
Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied coho rt of
U.S . adults. N Engl J Med 2003 ;348:1625-38.
Cescon M , Cuchetti A, Grazi GL , et al. Role of hepatitis B virus infecti on in the prognosis ater hepatecto my for hepatocellu lar carcinoma in
patients with cirrhos is: a Western dual-center expe rience. Arch Surg 2009 ;144:906- 913.
Chau GJ. Resection of hepatitis B virus-related hepatocellular carcinoma: Evolving strategies and emerging therapies to improve outcome.
World J Gast rolenterol 2014; 20: 12473-12484.
Chen CJ, Yang HI, Su J , et al. REVEAL-HBV Study Group. Risk of hepatocellu lar carcinoma across a biolo gical gradient of serum hep atitis B
virus DNA level. JAMA 200 6;295:65-73.
Chen TM, Chang CC, Huang PT, Wen CF, Lin CC. Performance of risk estimation for hepatocellular carcinoma in chronic hepatitis B
(REACH-B) score in classifyin g treatment eligibilit y under 2012 Asian Paciic Asso ciation for the Study of the Liver (APASL) guideline
for chronic hepati tis B patients. Aliment Pharm acol Ther 2013; 39:243-251.
Cheng AL, Kang YK, Chen Z, et al. Eicacy and safety of sorafenib in patients in the Asia-Paciic region with advanced hepatocellular
carcinoma: a ph ase III randomised, double- blind, placebo -controlled trial. L ancet Oncol 2009; 10:25-34.
Cho YK, Kim JK, Kim MY, Rhim H, Ha n JK. Systematic review of randomiz ed trials for hepatocellular carc inoma treated with percutaneous
ablation therap ies. Hepatology. 2009 ;49:453-459.
Chung WS, Lee KH, Park MS, Lee YJ, Kwon J, Baek SE , Kim MJ. Enhancement patterns of hepatocellular carcinoma ater transarterial
chemoembolization using drug-eluting beads on arterial phase CT images: a pilot retrospective study. AJ Am J Roentgenol.
2012;199 :349-59.
Clavien PA, Lesurtel M, Bossuyt PM, et al. Recommendations for liver transplantation for hepatocellular carcinoma: an international
consensus co nference report. Lancet O ncology 2012;13:e11-e22 .
Davila JA, Morgan O, Shaib Y, McG lynn KA, El-S erag HB. Diabetes increas es the risk of hepatocellular carcinoma in the United S tates: a
population b ased case control study. Gut 2 005;54:533-539.
Dodd GD 3rd, N apier D, Schoolield JD, Hu bbard L. Percutaneous ra diofrequency ablation of hep atic tumours: postablation syndro me. AJ
Am J Roentgenol 2005; 185 : 51-57.
Donato F, Tagger A, G elatti U, et al. Alcohol and hep atocellular carcinoma: the efect of lifetime intake and hepatitis virus infe ctions in men
and women. Am J Epi demiol 2002;155: 323-331.
EASL-EOTC Clincical Prac tice Guidelines: M anagament of hepatoce llular carcinoma. J Hep atol 2012; 56: 908-943.
El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, et al. Nivolumab in patients with advanced hepatocellular carcinoma
(CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet Lond Engl 2017;389:
:2492– 502
Falleti E, Fabris C, Cmet S, et al. PNPLA3 rs738409C/G polymorphism in cirrhosis: relationship with the aetiology of liver disease and
hepatocellul ar carcinoma occurrenc e. Liver Int 2011;31:1137-1143.
Gallo C, De Maio E, Di Maio M, et al, CLIP (Cancer of the Liver Italian Programme) Investigators. Tamoxifen is not efective in good
prognosis pat ients with hepatocellular c arcinoma. BMC Canc er 2006 24;6:196.
Gelatti U, Covo lo L, Talamini R, et al. N -Acetyltransferase-2 , glutathione S-transferase M1 an d T1 genetic polymorp hisms, cigarette smokin g
436 437
18. Diagnosis, prognosis & therapy of hepatocellular carcinoma
https://t.me/medicina_free
and hepatocel lular carcinoma: a case- control study. Int J Cancer 2005;115:301-30 6.
Gelatti U, Covolo L, Franceschini M, et al. Brescia HCC Study Group. Cofee consumption reduces the risk of hepatocellular carcinoma
independently of its a etiology: a case-con trol study. J Hepatol 2005;42:528- 534.
Greten T.F, Malek N P, Schmidt S, et al. Di agnosis of and therapy for hep atocellular carcinoma . Z Gastroenterol 2013;51:1269 -1326.
Hatzaras I, Bischof DA, Fahy B, et al. Treatment options and surveillance strategies ater therapy for hepatocellular carcinoma. Ann Surg
Oncol 2014; 21:758-766
Hilgard P, Hamami M, Fouly AE, et al. Radioembolisation with yttrium-90 glass microspheres in hepatocellular carcinoma: European
experience o n safety and long-term survival . Hepatology 2010; 52:1741-1749.
Hosaka T, Suzuki F, Kobaya shi M, et al. Long-term ente cavir treatment reduces hepato cellular carcinoma inci dence in patients with hepatit is
B virus infection . Hepatology 2013;58:98 -107.
Hsiang JC, Wong GL, Tse YK, et al . Statin and the risk of hepatocellular carcinoma and death in a hospital-based hepatitis B population: a
propensity s core landmark analysis. J Hep atol 2015; 63:1190-1197.
Huang G, Lau WY, Wang ZG, et al. Antiviral therapy improves postoperative survival in patients with hepatocellular carcinoma: a
randomized contro lled trial. Ann Surg 2015; 261: 56- 66.
Iloeje UH, Yang HI, Su J, Jen CL, You SL, Chen CJ, Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-In HBV
(the REVEAL-HBV) Study Group. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology
200 6;130: 678-68 6.
International Working Party. Pathologic diagnosis of early hepatocellular carcinoma: a report of the international consensus group for
hepatocellul ar neoplasia. Hep atology 2009;49:658- 664.
Jemal A, Bray F, Ce nter MM, Ferlay J, Ward D, Forman D . Global Cancer Stat istics. CA Cancer J Clin 2 011;61:69-90.
Johnson PJ, Berhane S, Kagebayashi C, Satomura S, Teng M, Reeves HL, O’Beirne J, Fox R, Skowronska A, Palmer D, Yeo W, Mo F, Lai
P, Iñarrairaegui M, Chan SL, Sangro B, Miksad R, Tada T, Kumada T, Toyoda H. Assessment of liver function in patients with
hepatocellul ar carcinoma: a new evidenc e-based approach-the ALBI grade . J Clin Oncol. 2015 Feb 20 ;33(6):550-8.
Kaseb AO, Hassan MM, Lin E, Xiao L , Kumar V, Pathak P, Lozano R, Rashid A, Abbruzzese JL, Morris JS. V-CLIP: Integrating plasma
vascular endothelial growth factor into a new scoring system to stratify patients with advanced hepatocellular carcinoma for clinical
trials. Cancer. 2011a;117:2478-88.
Kaseb AO, Abbruzzese JL , Vauthey JN, Aloia TA, Abdal la EK, Hassan MM , Lin E, Xiao L, El-D eeb AS, Rashid A , Morris JS. I- CLIP: improved
stratiication of a dvanced hepatocellular c arcinoma patients by integrat ing plasma IGF-1 into CLIP score . Oncology 2011b;80:373- 81.
Keppke AL, Sa lem R, Reddy D, Huang J, Jin J, La rson AC, Miller FH. Imaging of he patocellular carcinoma ater tr eatment with yttrium-90
microspheres . AJ Am J Roentgenol. 2007;188:768 -75.
Kudo M, Finn RS, Qin S, Han K-H, Ikeda K, Piscaglia F, Baron A , et al. Lenvatinib versus sorafenib in irst-line treatment of patients with
unresectable h epatocellular carcino ma: a randomised phase 3 no n-inferiority trial. Lanc et 218; 392: 1163-1173
Kumar V, Kato N, Urabe Y, et al. Gen ome-wide association study i dentiies a susceptibi lity locus for HCV-induced hepato cellular carcinoma.
Nature Geneti cs 2011; 43: 455-459.
Lai SW, Chen PC, Liao KF, Muo CH, Lin CC, Sung FC. Risk of hepatocellular carcinoma in diabetic patients and risk reduction associated
with anti-diabet ic therapy: a population-b ased cohort study. Am J Gastroente rol 2012;107:46-52
Lan T, Chang L, Rahmathullah MN, Wu L, Yuan YF. Comparative Eicacy of Interventional Therapies for Early-stage Hepatocellular
Carcinoma: A PRISM A-compliant Systematic Revi ew and Network Meta-analysis . Medicine (Baltimore). 2016; 95: e3185.
Lampertico P, Del Ninno E, Vigano M, et al. Long-term suppression of hepatitis B e antigen negative chronic hepatitis B by 24-month
interferon therapy. Hepatol ogy 2003;37:756-763.
Larsson SC , Wolk A. Cofee consumpt ion and risk of liver cancer: a meta- analysis. Gastroenterol ogy 2007;132:1740-1745.
Lencioni R , Llovet JM. Modiied RE CIST (mRECIST) assessment for hepatoce llular carcinoma. S em Liver Dis 2010;30:52- 60.
Lencioni R1, Kudo M, Ye SL, Bronowicki JP, Chen XP, Dagher L, Furuse J, Geschwind JF, Ladrón de Guevara L, Papandreou C, Sanyal AJ,
Takayama T, Yoon SK, Nakajima K, Cihon F, Heldner S, Marrero JA. First interim analysis of the GIDEON (Global Investigation of
therapeutic dec isions in hepatocellular c arcinoma and of its treatment with sorafen ib) non-intervention al study. Int J Clin Pract. 2012
Jul;66(7):675-83.
Leung U, Simps on AL, Araujo RL, et al . Remnant growth rate ater portal vein emb olization is a good e arly predictor of post-hepatecto my liver
failure. J Am Coll Su rg 2014; 219:620-630.
Lewandowski RJ, Kulik LM, Riaz, A, et al. A comparative analysis of transarterial downstaging for hepatocellular carcinoma :
chemoembo lization versus radi0em bolisation . Am J Transplant 2009 ;9:1920-1928.
Liaw YF. Prevention and sur veillance of hepatitis B vi rus-related hepatocellul ar carcinoma. Semin L iver Dis 2005;25 Suppl1:40 -47.
Livraghi T, Meloni F, Di Stasi M, Rolle E, Solbiati L, Tinelli C, Rossi S. Sustained complete response and complications rates ater
radiofrequency ablation of very early hepatocellular carcinoma in cirrhosis: Is resection still the treatment of choice? Hepatology
2008;47:82- 9.
Llovet JM, Brui x J. Systematic review of randomiz ed trials for unresectable he patocellular carcinoma : Chemoembolization im proves survival.
Hepatology 2003 ;37:429-442.
Llovet JM, Bustamante J, Castells A, et al. Natural history of untreated nonsurgical hepatocellular carcinoma: rationale for the design and
evaluation of therap eutic trials. Hepatolo gy 1999;29:62-67.
Llovet JM, Real MI, Montana X, et al . Barcelona Liver Cancer Group. Arterial embolisation or chemoembolisation versus symptomatic
treatment in pati ents with unresectable hepato cellular carcinoma: a rand omised controlled trial . Lancet 2002; 359:1734-1739.
Lok AS. Preventi on of hepatitis B virus-related h epatocellular carcino ma. Gastroenterolo gy. 2004;127(Suppl 1):S303-9 .
Lok AS, Seef LB, Morgan TR, et al. Incidence of hepatocellular carcinoma and associated risk factors in hepatitis C-related advanced liver
disease. G astroenterology 2009 ;136: 138-148.
Lopez P, Villanueva A, Llovet JM. Updated systematic review of randomized controlled trials in hepatocellular carcinoma. 2002-2005 .
Aliment Pharmaco l Ther 2006; 23:1535-1547.
Lu DS, Yu NC, Ra man SS, et al. Radi ofrequency ablation of hep atocellular carcinoma: t reatment success as dein ed by histologic examinat ion
of the explanted liver. Radio logy 2005;234:954-960.
Luo JC, Hwang SJ , Wu JC, et al. Clinica l characteristics and pro gnosis of hepatocel lular carcinoma in patie nts with paraneoplastic syn dromes.
Hepatogastroenterology 2002;49:1315-1319.
Mazzaferro V, Regalia E , Doci R, et al. Liver transp lantation for the treatment of small hep atocellular carcinomas in p atients with cirrhosis.
N Engl J Med 1996;334:693- 9.
Mazzaferro V, Sposito C , Bhoori S, et al. Yttrium- 90 radioemboliz ation for intermediate-advan ced hepatocellular c arcinoma: a phase 2 study.
Hepatology 2013; 57:1826 -1837.
Menon KV, Hakeem AR, Heaton ND. Meta-analysis: recurrence and survival following the use of sirolimus in liver transplantation for
hepatocellul ar carcinoma. Aliment Ph armaol Ther 2013; 37:411-419.
Nischalke HD, B erger C, Luda C, et a l. The PNPLA3 rs738409 148M/M Genotype Is a Risk Factor fo r Liver Cancer in Alcoholic C irrhosis but
Shows No or Weak Asso ciation in Hepatitis C Cirrho sis. PLoS One 2011;6: e27087.
Otto G, Herber S , Heise M, et al. Response to transarterial chemoembolization as a biological selection criterion for liver transplantation in
hepatocellul ar carcinoma. Liver Transpl 200 6;12:1260-1267.
Papatheodoridis GV, Manesis E, Hadziyannis SJ. The long-term outcome of interferon-alpha treated and untreated patients with HBeAg
negative chronic h epatitis B. J Hepatol 20 01;34:306-313.
Papatheodorid is GV, Pa padimitropoulos VC, Had ziyannis SJ. Efect of interferon th erapy on the development of hepato cellular carcinoma in
patients with hepa titis C virus-related cirrhosis : a meta-analysis. Aliment Pharm acol Ther 2001;15:689 -698.
Papatheodorid is GV, M anolakopoulos S, Touloumi G , et al.; HEPNET. Greece Coho rt Study Group. Virological supp ression does not prevent
the development of hepatocellular carcinoma in HBeAg negative chronic hepatitis B patients with cirrhosis receiving oral antiviral(s)
starting with lamivudin e monotherapy: results of the nationwi de HEPNET. Greece cohort study. Gut 2011; 60:1109-1116.
Papatheodorid is GV, Lampertico P, Manol akopoulos S, Lok A . Incidence of hepatoc ellular carcinoma in chroni c hepatitis B patients receivi ng
nucleos(t)ide therapy: a systemat ic review. J Hepatol 2010;53:348-356 .
Park 2008, Rhim H, Kim YS, Choi D, Lim HK, Lee WJ. Spectrum of CT indings ater radiofrequency ablation of hepatic tumours.
Radiographics. 2008;28:379-90;
Pawlik TM, Reyes DK, Cosgrove D, Kamel IR , Bhagat N, Geschwind JF. Phase II trial of sorafenib combined with concurrent transarterial
chemoembo lization with drug-elutin g beads for hepatocellul ar carcinoma. J Clin On col 2011;29:3960-39 67.
Pomfret EA, Washbu rn K, Wald C, et al. Report of a nat ional conference on liver allocati on inpatients with hepatocellul ar carcinoma in the
United States. Live r Transpl. 2010;16:262-278 .
Poon T, Fan ST, Lo CM, Liu CL , Wong J. Diference in tum our invasiveness in cirrhotic pat ients with hepatocellular ca rcinoma fulilling the
Milan criteria treat ed by resection and transpl antation: impact on long-te rm survival. Ann Surg 2007;245:51-58 .
Prieto J, Melero I, Sangro B. Immunological landscape and immunotherapy of hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol
2015;12: 681–700.
Riaz A, Kulik L , Lewandowski RJ, yu RK, Giakoumis S pear G, Mulcahy MF, Abecassi s M, Baker T, Gates V, Nayar R, Miller F H, Sato KT,
Omary RA, S alem R. Radiologic-p athologic correlation of hep atocellular carcinoma treate d with internal radiation using yttrium- 90
microspheres . Hepatology. 2009r;49:1185-93 .
Salem R, Lewandowski RJ, Mulcahy MF, et al. Radioembolization for hepatocellular carcinoma using yttrium-90-microspheres: a
comprehensive rep ort of long-term outcomes . Gastroneterology 2010; 138: 52 -64.
Salem R, Lewandowski RJ, Kulik L ., et al. Radioembolization results in longer time-progression and reduced toxicity compared with
chemoembo lisation in patients with he patocellular carcinom a. Gastroenterology 2 011;140:497-507.
Salem R, G ordon AC, Mouli S, Hick ey R, Kallini J, Ahmed Ga br A, Mulcahy MF, Baker T, Abeca ssis M, Miller FH, Yaghma i V, Sato K, Des ai
K, Thornb urg B,1 Benson AB, Radem aker A, Ganger D, Kulik L , Lewandowski RJ. Y90 Radioemb olization signiicantly prol ongs time
to progression c ompared with chemoembo lization in patients with hep atocellular carcinoma . Gastroenterology 2016; 151:!!%%-!!&§
Sangro B, Carpanese L, Cianni R, et al. European Network on Radioembolisation with Yttrium-90-Resin Microspheres (ENY). Survival
ater yttrium-90 resin microsphere radioembolisation of hepatocellular carcinoma across Barcelona clinic liver cancer stages: a
European evaluat ion. Hepatology 2011;54:868 -878.
Sahasrabuddhe VV, Gunja MZ, Graubard BI, et al. Nonsteroidal anti-inlammatory drug use, chronic liver disease, and hepatocellular
carcinoma. J N atl Cancer Inst 2012;104:1808 -1814.
Schefer HJ, Nielsen K, de Jong MC, et al. Irreversible electroporation for nonthermaltumour ablation in the clinical setting: a systematic
review of safety and e icacy. J Vasc Interv Radiol 2014; 25:997-1011.
Shi M, Zhen g H, Nie B, et al. Stat in use and risk of liver cancer: an up date meta-analysis. BMJ op en 2014;4:e005399.
Serste T, Barrau V, Ozenne V, et al. Accu racy and disagreement of c omputed tomography and magne tic resonance imagin g for the diagnosis of
small hepatoc ellular carcinoma and dyspl astic nodules: role of bio psy. Hepatology 2012;55:800 -806.
Singh S, S ingh PP, Singh AG, et al. Statin s are associated with a reduced ri sk of hepatocellular canc er: a systematic review and meta-analysis .
Gastroenterol ogy 2013, 144: 323-332.
Spira D, Fench el M, Lauer UM, Clauss en CD, Gregor M, Bitzer M , Horger M. Comparison of diferent tumour respon se criteria in patients
with hepatocellu lar carcinoma ater systemic th erapy with the multikinase inhi bitor sorafenib. Acad Radio l. 2011 Jan;18(1):89-96 .
Starley BQ, Calcagno CJ, Harrison SA. Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection. Hepatology
2010;51:1820-1832 .
Su, C. , et al., Antiplatelet therapy is ass ociated with better prognos is in patients with hepatitis B virus-re lated hepatocellular carci noma ater
resection surg ery. Hepatology 2014; 60 (Suppleme nt 1): 198A.
Sun HC, Zhan g W, Qin LX, et al. Positive serum hep atitis B e antigen is associa ted with higher risk of early recurrence an d poorer survival in
patients ater curat ive resection of hepatitis B -related hepatocellu lar carcinoma. J Hepatol 2 007;47:684-690.
Takaki H, Yamakado K, Nakatsuka A, Yamada T, Shiraki K, Takei Y, Takeda K. Frequency of and risk factors for complications ater
liver radiofrequency ablation under CT luoroscopic guidance in 1500 sessions: single-center experience. AJ Am J Roentgenol.
2013;200:658-64
Toso C, Merani S , Bigam DL, et al. Siro limus-based immunosupp ression is associated with in creased survival ater liver transpla ntation for
hepatocellul ar carcinoma. Hepatol ogy 2010;51:1237-1243.
Trepo E, Nahon P, Bonte mpi G, et al. Associ ation between the PNPLA3 (rs738409 C>G) variant and hepatocellul ar carcinoma: evidence f rom
a meta-analysis of ind ividual participant data . Hepatology 2014; 59(6):2170-7.
TsengTC, Liu HC, Yang HC, et al. Serum hepatitis B surface antigen levels help predict disease progression in patients with low hepatitis B
virus loads. Hep atology 2013;57:441-450.
Utsunomiya T, Shimada M, Kudo M, et al. A comparison of the surgical outcomes among patients with HBV positive, HCV positive, and
non-B non-C hep atocellular carcinoma : a nationwide study of 11,950 patients. Ann S urg 2015; 261: 513-520.
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