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Review Article · Übersichtsarbeit

Onkologie 2004;27:294–303
DOI: 10.1159/000077982

Multimodal Treatment of Hepatocellular Carcinoma (HCC)


J.W. Sturm M. Keese
Chirurgische Universitätsklinik, Universitätsklinikum Mannheim, Klinische Fakultät der Universität Heidelberg, Mannheim, Germany

Key Words Schlüsselwörter


Hepatocellular carcinoma · Liver resection · Liver Hepatozelluläres Karzinom · Leberresektion ·
transplantation · Radiofrequency ablation · Transarterial Lebertransplantation · Radiofrequenzablation ·
chemoembolisation Transarterielle Chemoembolisation

Summary Zusammenfassung
Screening of patients at risk for hepatocellular carcino- Regelmäßige Vorsorgeuntersuchungen bei Risikogrup-
mas (HCC) and preventive virustatic therapy are the first pen und preventive virustatische Therapie sind die ers-
steps in a multimodal treatment concept, because de- ten Stufen im multimodalen Konzept der Behandlung
layed detection leads to a poor prognosis with median des hepatozellulären Karzinoms (HCC), da eine verzöger-
survival of <10 months. Surgical resection of HCC is still te Diagnosstellung zu einer drastisch schlechteren Pro-
the treatment of choice in patients with good residual gnose mit einer medianen Überlebenszeit von <10 Mo-
liver function, however, recurrence-free 5-year survival naten führt. Therapie der Wahl bei HCC-Patienten mit
after curative resection is low (33%). In patients with cir- Zirrhose aber guter Leberfunktion ist noch immer die Re-
rhosis, only 25% of HCC are resectable, limited by low sektion, jedoch mit niedriger rezidivfreier 5-Jahres-Über-
hepatic functional reserve. HCC in patients with non-cir- lebensrate (33%). Zudem ist eine kurative Resektion
rhotic livers are the domain of extended resections. In durch die zirrhosebedingt eingeschränkte funktionelle
newer reports, transplantation in patients with cirrhosis Reserve der Leber nur in 25% der Fälle möglich. HCC bei
is rated more positively when restricted to patients with Patienten mit nicht zirrhotischer Leber sind die Domäne
solitary nodules <5 cm or up to 3 tumors <3 cm. A new auch ausgedehnter Resektionen. Die Erfolgsaussichten
option in HCC therapy are the local methods for tumor nach Transplantation beim HCC werden in neueren Stu-
ablation, preferably radiofrequency ablation (RFA), espe- dien mit strikten Selektionskriterien, die bei Patienten mit
cially in patients with limited liver function, non-re- Zirrhose nur solitäre HCC (<5 cm) oder bis zu 3 Tumoren
sectable or multifocal tumors. A new horizon is opened <3 cm zur Transplantation zulassen, deutlich positiver
combining these options and multimodal approaches eingeschätzt. Eine neue Möglichkeit der HCC-Therapie
with transarterial chemoembolisation (TACE). This trend sind die lokal ablativen Methoden, insbesondere die Ra-
to multimodal approaches promises a yet unknown im- diofrequenzablation (RFA), vor allem für Patienten mit
provement in the prognosis of patients with HCC. Con- eingeschränkter Leberfunktion, nicht resektablen oder
trolled randomized studies comparing and validating the multifokalen Tumoren. Eine neue Perspektive hat sich
different methods and defining combined treatments ac- durch den multimodalen Ansatz mit Kombination der
cording to liver function and tumor stage are eagerly verschiedenen Verfahren und mit transarterieller Che-
awaited. moembolisation (TACE) ergeben. Mit dem Trend zu mul-
timodalen Therapieansätzen ist eine hoffnungsvolle, jetzt
noch nicht abzusehende Verbesserung der Prognose und
ein Wandel der therapeutischen Strategien beim HCC
eingeleitet. Kontrollierte randomisierte Studien, die ein
abgestuftes Therapiekonzept, ausgerichtet auf Leber-
funktion und Tumorstadium definieren, sind dringend
vonnöten.
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© 2004 S. Karger GmbH, Freiburg Dr. Jörg W. Sturm


Chirurgische Klinik, Universitätsklinikum Mannheim GmbH
Fax +49 761 4 52 07 14 Accessible online at: Thodor Kutzer Ufer, D-68167 Mannheim
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E-mail Information@Karger.de www.karger.com/onk Tel. +49 621 383-2357, Fax -2166


www.karger.com E-mail joerg.sturm@chir.ma.uni-heidelberg.de
Introduction Table 1. Treatment options for HCC

Best supportive care


Hepatocellular carcinoma (HCC) is the most common prima-
Chemo-/ immunotherapy
ry liver tumor with an incidence of 1 million new manifesta- Embolization
tions per year. Cirrhosis is the main risk factor to develop TACE, TAE, portal vein
HCC (relative risk: 5% /year), with close correlation to dura- Ablative therapies
tion and cause of cirrhosis (HCC incidence: chronic hepatitis PEI, RFA, LIT, cryoablation
Resection
B (HepB): 3.9% /year, hepatitis C (HepC): 10.4% /year) [1].
Atypical (wedge), anatomic (segment orientated), hemihepatectomy
In patients with both hepatitis B and C the risk to develop an Transplantation
HCC is twice as high [2]. A sequence from regenerating nod- Combined therapies
ules to hyperplasia to hepatocellular carcinoma could be de- TACE + chemotherapy, ablation, resection, or transplantation
tected in specimens after resection [3]. The lack of controlled Ablation + resection or transplantation
Adjuvant therapies
studies comparing the efficacy of the available surgical or
Virustatic drugs, chemo- /immunotherapy, TACE
loco-regional ablative treatments renders selection of thera-
peutic options difficult. Resulting from specific difficulties due LIT: laser induced thermo-ablation, PEI: percutaneous ethanol instillati-
to the predisposing liver disease and cirrhotic alteration thera- on, RFA: Radiofrequency ablation, TAE: trans arterial embolization,
peutic strategy of HCC is exemplary for the need of close in- TACE: transarterial chemoembolization.
terdisciplinary cooperation and modulated therapy concepts.
Multimodal treatments of HCC offer the most promising ther-
apeutic option to achieve complete tumor control (table 1). Table 2. Survey of prognostically relevant factors of HCC

Prognostic factor References


Tumor-Related Prognostic Factors
Tumor-related prognostic factors of HCC are tumor size and Tumor stage 4, 15, 41, 45, 49, 55, 56
number of nodules, vascular infiltration and positive lymph Early detection 5, 11, 16–18, 21, 26
nodes. HCC is classified according to UICC classification, his- Degree of cirrhosis 12, 15, 22–25, 27, 42, 46, 50
tological typing, grading according to Edmondson-Steiner, and liver function
Strategy and therapy selection 21, 22, 25, 26, 29, 30, 35, 41–43, 60, 61,
metastatic spread, and Okuda classification (table 2–5). Multi-
63, 69, 73, 76, 75
locular lesions are present in two thirds of HCC patients with Type of treatment 4, 22, 26, 31, 35–37, 41–43, 45, 54, 57, 63,
a tumor size between 3 and 5 cm, and in 50% vascular infiltra- 64, 66, 67, 69, 72, 73, 76, 70, 81, 85
tion is already microscopically detectable. In one third of Treatment-related 21, 26, 31–35, 47, 48, 63, 65, 74, 82
HCC <2 cm an extracapsular tumor growth, portal branch in- complications
Recurrence and therapy of 38, 39, 43–45, 49, 52
vasion, and satellite nodules are detectable [4]. Typical routes
recurrent disease
of metastatic dissemination of HCC are: 1. hematogenous dis-
semination with early invasion of portal and hepatic veins, 2.
lymphatic spread in direction to the liver hilus, hepato-duode-
nal ligament and celiac trunk and 3. continuous infiltration was seen in HepB virus carriers [8]. Virustatic therapy is dis-
into the diaphragm, gallbladder, duodenum and rarely in large cussed after resection or ablative methods to reduce viral ac-
hepatic ducts (but often compression and encasing growth of tivity in responders. Reduction of virus load or elimination of
extrahepatic bile ducts can be observed). the virus could reduce the development of hepatitis-associated
HCC [4]. Hence this approach might be adequate in adjuvant
settings, with tumor recurrence after curative resection as well
Prevention as hepatitis and HCC recurrence in the transplanted liver as
targets e.g. with nucleoside analogues [9]. First experimental
Prophylactic therapy is a promising future concept to prevent studies for gene therapy for HCC are initiated but preliminary
or delay the development of HCC by identification of patients results are disappointing [10].
at risk [5]. In a routine vaccination program in Taiwan, includ-
ing newborns of pregnant women positive for HepB surface
antigen, the incidence of HCC (0.7/100,000) in children could Screening and Diagnosis
be reduced by half [6]. A multivariate retrospective analysis of
738 patients with chronic HepC showed that interferon thera- Early Detection
py decreased the risk of developing an HCC by 48% in all pa- A significant beneficial effect on long-term prognosis of HCC
tients with a significant effect in interferon-responders (nor- by early detection could be demonstrated in a large prospec-
malized transaminases) (risk responder vs. non-responder: tive randomized study on 18,000 patients at risk comparing
0.16 vs. 0.74) [7]. Whereas only a moderate interferon effect low-cost screening (alpha fetoprotein (AFP) monitoring and
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Carcinoma (HCC)
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Table 3. Union Internationale Contre le Cancer (UICC) classification of vival of 12.8% [13]. However, these results are biased again by
HCC liver function, as shown by Barbara et al. [14], observing the
natural course of untreated hepatocellular carcinoma in cir-
UICC stage TNM stage Tumor characteristics
rhosis patients with a median tumor doubling time of 172
I T1 ≤2 cm solitary days. In multivariate analyses of 39 patients with solitary
II T2 >2 cm solitary asymptomatic HCC, Child stage was a significant prognostic
≤2 cm multiple, unilobar factor for survival (Child A vs. Child B/C: 2-year survival 82
≤2 cm + little vascular infiltration
vs. 35.6% and 3-year survival 62 vs. 0%). It is noteworthy that
IIIa T3 >2 cm + little vascular infiltration
≤2 cm multiple + little vascular infiltration resected solitary minute HCC (<1 cm) had no better differen-
IIIb N1 regional lymph node metastases tiation grade than larger tumors (<3 cm), with corresponding
IVa T4 multiple + bilobar prognosis [15]. In a prospective screening study in 285 patients
infiltration hepatic vein or portal vein branch with advanced cirrhosis, HCC was detected in 16.2%. During
N1 regional lymph node metastases
a 4-year observation period CT (computed tomography)
IVb M1 distant metastases
achieved the best screening sensitivity (88%) compared to
AFP serum monitoring (62%) and ultrasound (59%) [16].
Table 4. Grading according to Edmondson and Steiner, classification
Clinical symptoms such as pain, fever, jaundice, hepatomegaly,
based on cellular grading and differentiation and ascites are signs of an incurable advanced tumor stage
with poor prognosis. It is obvious that screening should be
Grade I trabecular, only minor cellular atypical signs, bile production, routine in patients at risk and can increase early detection
difficult to differentiate from normal parenchyma or
with a chance for curative resection and a better long-term
adenoma
Grade II tubular, pseudoglandular or acinous, modest cellular atypical
prognosis [17].
signs, often bile production
Grade III in majority solid with loss of organized structure, modest to Diagnostic Steps Influencing Therapeutic Decision
high cellular atypical signs, rarely bile production, often AFP serum levels correlate with tumor size: only in one third
vascular infiltration
of asymptomatic patients AFP is >200 IU/ml, whereas in 70%
Grade VI solid with complete loss of organized structure, highly dyspla-
stic cellular signs, mismatch of nuclear/plasma relation, very
of patients with symptomatic tumors AFP is >500 IU/ml. Al-
rarely bile production, HCC are heterogeneous tumors with though AFP mRNA serum levels are no specific indicator for
different grades of differentiation in one tumor. Malignancy hematogenous dissemination and tumor cell shedding of HCC
increases with dedifferentiation [18]. A competitive RT-PCR assay for AFP-mRNA showed
positive results in 26% of HCC patients, in 17% of patients
with tumors of different typesand in 8% of healthy controls
Table 5. Okuda Classification of HCC stage [19]. The cell proliferation marker tissue polypeptide specific
antigen (TPS) may be more predicative: with preoperatively
Symptom Value Points Value Points
elevated TPS serum levels >150 U/l the probability of recur-
Tissue replacement ≤50% 0 >50% 1
rence after curative resection was higher (2-year recurrence
Ascites no 0 yes 1 rate 53.3 vs. 20.8%), whereas no correlation was observed for
Bilirubin ≤3 mg/dl 0 >3 mg/dl 1 AFP [20]. An HCC detection rate of 92% was reported for ul-
Albumine >3 g/dl 0 <3 g/dl 1 trafast contrast enhanced CT. Magnetic resonance imaging
(MRI) with MR angiogram (MRA) and liver-specific contrast
Stage I = 0 points, stage II = 1–2 points, stage III = 3–4 points.
media can provide further information, whereas differentia-
tion of regeneration nodules and HCC can be difficult with
routine ultrasound. Lipiodol embolisation is very sensitive be-
ultrasound every 6 months) and no screening (resection rate cause of the mainly arterially supplied tumor vasculature and
70 vs. 0% and 2-year survival 77.6 vs. 0%) [11]. Excellent re- can be used as first selective step. Gold standard for intraoper-
sults are reported after curative resection of early carcinoma ative detection and resection planning is intraoperative ultra-
(5-year survival 93%). In these studies long-term prognosis sound. For further staging thorax CT and bone scintigraphy
was mainly influenced by the underlying disease and not by are useful. The identification of focal hypervascular lesions,
HCC [4]. Data on the spontaneous course of the underlying verified by 2 coincident imaging techniques, is considered suf-
disease and of HCC are helpful for the decision on the appro- ficient evidence to confirm the diagnosis of HCC [21]. Tumor
priate treatment option. 5 years after diagnosis of cirrhosis the biopsy is not required, because test results can be misleading
probability to develop a decompensated cirrhosis is 35% with and are falsely negative in at least 10% of cases, moreover, a
a survival of 70% [12]. In 22 patients with small (<3 cm) soli- tumor dissemination by biopsy is discussed. Preoperative di-
tary HCC in cirrhotic livers conservative observation resulted agnostic imaging still fails to reliably predict the most impor-
in 1-year survival of 90.7, 2-year survival of 50, and 3-year sur- tant prognostic factor, vascular infiltration [22].
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Table 6. Child-Pugh criteria for estimation of liver function in cirrhosis Table 7. Prognostic factors for long-term survival of HCC patients

Points After resectiona


 Tumor-related symptoms
1 2 3
Tumor size
Number of tumors
Bilirubin, mg/dl <2 2–3 >3
Vascular infiltration
Albumine, g/dl >3.5 3–3.5 <3
Lymph node positivity
Ascites – + ++
Preoperative indocyanine green test
Encephalopathy – + ++
Intraoperative blood loss
International normalized ratio (INR) <1.7 1.7–2.3 >2.3
Curative resection (R0)
Cirrhosis-related liver function
Child A: <8, Child B: 8–10, Child C: >10 points

After transplantationb
Tumor-related symptoms
Tumor size (3/5 cm)
Number of tumors
Degree of Cirrhosis and Liver Function Vascular infiltration
Of outstanding importance for therapeutic strategy as well as Grading
for prognosis of HCC is the extent of underlying cirrhosis and Lymph node positivity
Cirrhosis
liver function. In cirrhosis ischemic tolerance as well as regen-
erative capacity are impaired, with altered lymphatic drainage a Ref: 17, 22, 23, 26–28, 32, 35, 36–39, 41, 42, 58, 59, 61.
and portal blood flow. In consequence nutrition and synthetic b Ref: 22, 35, 42, 58–60, 63.
capacity are reduced [23]. Impeded liver mobilization by cir-
rhosis results in severely reduced tolerance to surgical trau-
ma. Clamping of the hepatoduodenal ligament (Pringle’s ma-
neuver) for 30 min during resection was tolerated in Child A achieved [29, 30]. As a rule of thumb, exclusion criteria for la-
cirrhosis but in Child B cirrhotic livers lethality increased to parotomy and resection are bilirubin >3 mg/dl combined with
29%, compared to 8% without Pringle’s maneuver. In normal ascites (despite diuretics).
livers considerable reduction of parenchyma does not result in
increased portal pressure, because of increased splanchnic
drainage, but in cirrhosis this compensative way is exhausted Therapeutic Options
and portal pressure increases [24]. Today no reliable test is
available to determine the exact remaining functional capacity It is difficult to define an objective therapy decision protocol
after cytoreductive maneuvers. Liver size, tumor replacement, because appropriate selection is a crucial factor and prospec-
signs of cirrhosis and degree of portal hypertension can be de- tive studies with matched survival rates for the different treat-
tected in ultrasonography and CT scans. Routine determina- ment options and at least the most promising combined treat-
tion of blood parameters such as vitamin-K-dependent coagu- ment regimens are lacking.
lation factors, fibrinogen, bleeding time, bilirubin, transami-
nases, cholinesterase, alkaline phosphatase, blood glucose, Resection
HepB,C screening, and liver function tests such as ICG (indo- Resection of HCC as potentially curative treatment, is limited
cyanine green test) or MEGX-test (lidocain metabolization) by the fact that many HCC develop multifocally in cirrhosis.
combined with Child-Pugh criteria (table 6) and the tumor DNA ploidity and microsatelite instability could give further
marker AFP give a rough estimate to decide on the therapeu- prognostic hints for patient selection for transplantation and
tic strategy. In cirrhotic patients Miyagawa et al. [25] used a multimodal treatment [22]. Bismuth advocated the Child cri-
bilirubin cut-off level of <1.5 mg/dl for anatomic resections. teria as landmarks for the safe extent of resection possible in
With the selection criteria ICG retention <10%/15 min, nor- cirrhotic livers: Child A: 50% parenchyma, Child B: 25%
mal bilirubin in serum and absent ascites operative mortality parenchyma, Child C: no resection (enucleation) [26]. Con-
could be reduced to 1%. Routine determination of liver para- traindications for resective therapy of HCC are: too small and
meters, Child stage, and liver function are used to stratify for insufficient rest livers, Child C cirrhosis, bilobar, multifocal,
resection in Child A and ‘good’ Child B or liver transplanta- and metastatic HCC or extrahepatic tumor manifestation
tion in Child C patients with HCC [26]. In multivariate analy- (stage IVa, b). Curative resection is less expensive than liver
sis the ICG retention rate was an independent prognostic fac- transplantation and there is no need for life-long immunosup-
tor after curative resection [27]. ICG retention <14% is used pression. In addition, the limited donor supply has to be kept
as cut-off level for extended resections [28]. By selecting pa- in mind. With intensified screening and improved imaging
tients with normal bilirubin and no portal hypertension very techniques the proportion of patients with HCC eligible for
low perioperative morbidtiy after HCC resection can be resection is around 40%.
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Perioperative Management patients without underlying liver disease (126 pat.) with a 2-
Perioperative low central venous pressure reduces blood loss year recurrence rate of 75% and a 5-year survival of 39.4% for
because of the direct correlation between portal pressure and fibrolamellar and 11.2% for non-fibrolamellar HCC [44]. The
both central venous and arterial pressure. Selective portal fibrolamellar subtype (2% of HCC) has a better long-term
clamping and/or intermittent clamping of the hepatic pedicle prognosis and is mostly detected in younger patients with non-
during hepatectomy reduces operative bleeding and morbidity cirrhotic livers without a history of hepatitis [45]. Neuhaus et
[31]. Today’s standard after resection of HCC are 5-year sur- al. state that ‘it is still unknown whether hepatocellular carci-
vival rates of 50±14%, with recurrence-free 5-year survival of nomas in cirrhosis and in non-cirrhotics are identical or di-
14–28%. The mainly cirrhosis-related perioperative morbidity verse malignant diseases’ [22]. In addition, HCC with negative
is 20–40% with a reported hospital mortality of 0.8–6% after virus markers are diagnosed in advanced stages and are gener-
resection [27, 32–35]. ally less differentiated with more invasive growth. Therefore,
Prognostic Factors After Resection life expectancy of these patients is comparable to that of HCC
Curative resection of HCC with good residual liver function patients with positive virus markers, although cirrhosis was
gives the best long-term prognosis (table 7). In an analysis of manifest only in 16.7% [46].
822 patients with HCC, median survival for conservatively Complications After Resection
treated patients was 10 weeks, for palliative resection 40 Postoperative liver insufficiency is directly correlated to the
weeks and for curatively resected patients 100 weeks [36]. Fac- amount of resected functional parenchyma because of the re-
tors for higher risk of tumor recurrence after curative resec- duced regenerative and compensatory capacity of the cirrhot-
tion were: tumor size >3–5 cm, multiple tumor nodules, lack of ic liver. In cases with preoperatively diagnosed, although com-
or infiltrated tumor capsule, infiltration of the portal and/or pensated portal hypertension the risk of postoperative thera-
liver veins, and satellite nodules. After curative resection 70% py-refractory ascites is significantly increased [47]. Postopera-
5-year survival is reported [37–39]. The importance of techni- tive deaths are caused by therapy-refractory ascites, liver
cal expertise and the extent of resection in relation to liver failure, and infection. Intraoperative blood loss is an indepen-
function [27] is shown by the fact that in some studies blood dent prognostic factor for postoperative liver insufficiency and
loss is a relevant factor for long-term prognosis [32]. Stage 4 complications [32]. Frequent complications after resection of
tumors are not in principle excluded from resection, e.g. in HCC in patients with cirrhotic livers are liver failure (4%),
case of a tumor-related portal branch occlusion the non-af- prolonged jaundice, therapy-refractory ascites (up to 20%),
fected lobe can compensate for the major resection [40]. Re- pleural effusions (20%), delayed wound healing (14%) and in-
viewing 488 patients with resected HCC, including 120 with fection (7%) [48].
tumors >10 cm, Poon et al. [41] reported a hospital mortality Recurrent Tumors
of 5%, although significantly more major resections were per- Autopsy studies showed that extrahepatic disease correlates
formed in the group with larger tumors. Median overall sur- to tumor size, histological type, and number of HCC nodules
vival in patients with tumors >10 cm was 18.8 vs. 62.8 months (hematogenous spread: single tumor 14% vs. multinodular tu-
for patients with smaller tumors and disease-free survival was mors 82%) [49]. Tumor recurrence is common and more fre-
5.5 vs. 25.4 months (both p < 0.001). But the median survival quent (60–80% in the remaining liver and 10% lung metas-
period of curatively resected patients with large tumors and tases) after resection (up to 80% in 5 years), whereas after
no macroscopic evidence of venous invasion was 38 months liver transplantation for HCC (23% tumor recurrence)
(vs. 10.5 months). hematogenous spread prevails (lung metastases 56%) [45].
Is There a Difference in Prognosis of HCC Occurring Recurrence of HCC after resection is dependent on Child
in Non-Cirrhotic Liver? stage, cirrhosis and number of perioperative transfusions [50].
In the majority of patients with non-cirrhotic livers, HCC is di- Long-term prognosis is directly related to the recurrence-free
agnosed in an advanced stage with symptoms such as palpable interval; tumors developing 1 year after resection are classi-
mass, pain, or fever due to tumor necrosis or rarely rupture. fied as late recurrence [39]. Belghiti et al. [37] described a rate
Extended resections of HCC in non-cirrhotic patients prevail of 86% of recurrent hepatic tumors within 2 cm of the resec-
with 5-year survival rates of 40% because of advanced tumor tion margin – probably related to tumor growth stimulated by
size. Good functional capacity of the non-cirrhotic rest liver regenerative activity in the region near the resection plane.
explains the low postoperative mortality of 3% in non-cirrhot- However, newer studies proposed that recurrent tumors de-
ic patients compared to 10% in those with cirrhosis [22, 42]. velop by intrahepatic metastatic spread because of angioinva-
Microscopic dissemination of HCC in patients with a non-cir- sion. In this model, metastasis formation is not influenced by
rhotic liver is likely and in consequence they bear a higher risk the security distance of curative resection margins [36, 51],
of recurrence after transplantation with a reported 5-year sur- highlighting the difficulty to classify these tumors either as
vival after transplantation of only 38% compared to 82% after true recurrent tumors, overlooked small satellites, de novo tu-
curative resection [43]. This was confirmed by a systematic re- mors, time-shifted manifestation of multilocular disease, or
view of 16 publications about liver transplantation for HCC in metastases [38]. With the detection of different clones of pri-
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mary tumors and putative recurrent tumors the origin could Table 8. Intention-to-treat analysis of surgical treatment of early HCC
be further verified [88]. Undoubtedly, recurrent tumors again [63]. Long waiting lists and organ shortage are relevant factors in the de-
cision for the type of treatment for early HCC
should be treated by resection or ablative therapies (radiofre-
quency ablation, RFA; trans-arterial chemoembolisation, Good Bad p-Value
TACE; percutaneous ethanol instillation, PEI), this is also candidates candidates
true for recurrent tumors in transplanted livers. After curative
resections of recurrent tumors in transplanted livers a recur- Resection
Patients, n 35 25
rence-free survival of 3.1 years could be achieved [45]. Re-
Characteristics bilirubin < 1, no bilirubin > 1, high
peated curative resection improved the long-term prognosis (mild) portal portal pressure
of recurrent HCC (3-year survival: 85.1% vs. 59.5% with pal- hypertension
liative RFA, PEI and TACE vs. 0% with best supportive care) 5-Year survival 74% 25% <0.00001
[52]. Patient’s age is mentioned repeatedly as a prognostic fac- Transplantation
Patients, n 50 37
tor in studies analyzing tumor recurrence. However, the rele-
Waiting days 62 162
vant factor might be the longer duration of hepatitis/cirrhosis 5-Year survival 84% 54% <0.003
manifestations and not the numerical age of the patient [53].

Transplantation
Transplantation is the only simultaneous treatment of primary
liver disease and HCC [22]. However, immunosuppression in- cause of small HCC and cirrhosis is still reduced compared to
creases the risk of intrahepatic recurrence and alters growth those transplanted because of cirrhosis without HCC (1-year
kinetics of disseminated tumor cells, resulting in a shorter survival 88 vs. 99% and 5-year survival 71 vs. 84%). Again,
tumor doubling time after transplantation than after resection relevant prognostic factors for small HCC are: solitary, unilo-
[54]. Therefore, only patients who may profit from transplan- bar tumors without vascular infiltration (5-year survival: stage
tation are now selected for this treatment option. I–III: 71, VIa: 17%) [56]. Selection has to exclude patients
Selection of Patients with HCC for Transplantation with extrahepatic spread and, most difficult, HCC with vascu-
The results of studies on transplantation should be judged lar infiltration [35, 42, 60] (table 7). In some centers, a further
based on whether deteriorating cirrhosis or the diagnosis of exclusion criterium is an AFP serum level >400 ng/dl [61, 62].
HCC initially led to the decision for transplantation: in about If strict selection criteria are applied, a comparable long-term
25% of transplantations because of cirrhosis an incident HCC survival can be achieved after transplantation for HCC in cir-
is detected. Depending on the degree of cirrhosis leading to rhotic livers (UICC stages I–III) and for benign indications
transplantation, the prognosis of patients with multifocal [22]. But long waiting lists and organ shortage have to be
HCC detected in the specimen are better [55] or worse [56]. taken into account as relevant factors in the decision for the
Reviewing the results of patients transplanted for HCC, in- type of treatment for early HCC, as was shown in an inten-
cluding those with large tumors, Pichlmayr and coworkers tion-to-treat reanalysis by Llovet et al. [63]. Patients with
stated that hepatic resection is the treatment of choice only compensated liver function and mild portal hypertension had
for patients with well-preserved liver function [43, 57]. In a a better long-term prognosis after resection than patients who
comparative retrospective study of two high-volume centers were candidates for transplantation but had to deal with long
(Tokio, Pittsburgh) analyzing the results after resection versus waiting lists (table 8).
transplantation for HCC the authors came to the same con-
clusion, because long-term results were comparable (5-year Non-Resective Ablation
survival: resection 47.1, transplantation 54.5%), perioperative Compared to the standard procedures resection and trans-
risk was lower, and lethal complications were fewer after cu- plantation, ablative therapies are less burdening for the pa-
rative resection [35]. They advised transplantation only for a tient as they bear lower collateral risks, preserve more func-
selected group of patients with cirrhotic livers and small tioning liver parenchyma, and can be repeated several times.
(<5 cm), solitary tumors without vascular infiltration and With percutaneous ethanol instillation (PEI) a tumor necrosis
without distant spread, because transplantations for advanced rate of 80% can be achieved in tumors <5 cm (4.8 injections/
HCC achieved a worse long-term survival compared to resec- tumor). In small tumors (<3 cm) good results with PEI and
tions [57, 58]. Early experiences with liver transplantation complete tumor necrosis are reported, with long-term results
[59] led to reduced indication for transplantation for HCC comparable to resection (5-year survival 48% in 628 treated
today, favoring small HCC with less than 3 nodules in cirrhot- patients) [64]. In tumors >3 cm ethanol distributes inhomoge-
ic livers without vascular infiltration. Then 5-year survival nously followed by incomplete necrosis, also after repeated in-
rates of 70%, with a 60% rate of 5-year disease-free survival jections [29]. For radio frequency ablation (RFA) alternating
vs. only 14% in patients undergoing resection can be achieved high-frequency voltage (460–480 kHz) causes friction and
[22, 42]. However, life expectancy of patients transplanted be- heating, protein-denaturation and coagulation necrosis. The
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extension of the thermic lesion after RFA depends on the en- couraging results were confirmed in a multicenter randomized
ergy, the type of the probe, heat extension (in tissue) and per- controlled trial: chemoembolization could significantly im-
fusion-related cooling (convection). The impedance of the prove 2-year survival in patients with unresectable, locally ad-
tumor tissue is different from the surrounding cirrhotic liver vanced HCC (63 vs. 27%) [73]. Median recurrence-free sur-
tissue allowing a calculated application confined to the tumor vival after resection was significantly improved by adjuvant
[65]. Success and extension of RFA or PEI can be easily mon- transarterial embolisation (TAE) with lipiodol and yttrium
itored during application with ultrasound or contrast-en- microspheres (14.3 vs. 7 months). TACE is contraindicated in
hanced CT or MRI. The long-term effect of RFA is superior patients with known contrast reactions, severe coagulation dis-
to PEI [66]. HCC in cirrhotic tissue seems to respond better to orders, severe COPD and Child C and Okuda III cirrhosis and
RFA than nodules in healthy livers. Contraindications for the patients with bilirubin >5 mg/dl, GOT >200U/l, and ascites
percutaneous approach are: nodules located near the liver [74].
capsule, the venous confluence and diaphragm or in contact to TACE-Related Complications
the bowel. They should be treated with RFA under laparo- TACE-related lethality rate leaps to 40% in patients with
scopic control or with open access. In follow-up rest- and re- Child C cirrhosis compared to below 10% in Child A or B pa-
perfusion (contrast MRI, CT, or contrast-enhanced color tients. In 14% of patients an angiographically visible vasculitis
Doppler ultrasound) of the ablated area are indicators for per- as contraindication for further embolization is detected. Liver
sistent viable tumor and repeated application is necessary [67, insufficiency with ascites (14%) and jaundice (12%), renal in-
68]. RFA of recurrent tumors and in the palliative setting is a sufficiency (13%), cholecystitis (10%), superinfection of the
very promising option also in case of deteriorating liver func- embolized area with consecutive sepsis, abscesses, pancreatitis,
tion after primary therapy [69]. and splenic infarction because of reflux of embolisation mate-
Combination of Resection or Laparotomy and Ablative rial were observed [26]. Less severe but common reactions in
Therapies the first week after TACE are slight fever (<38.5 °C) and
Heat loss because of convection in tumors near larger vessels nausea [65].
leads to insecure extension radii of RFA. The coagulation ra- TACE Combined with Ablative Treatment
dius can be enlarged if inflow-occlusion is applied leading to To combine treatment options is to use synergistic effects and
more homogenous and larger necrosis zones [68, 70, 71]. to reduce side effects, because often a dose reduction is possi-
Tumor nodules near the diaphragm, bowel or the liver capsule ble. Convincing and very promising setups combining TACE
are easy to treat with RFA ablation if detection and targeting with interventional methods, such as RFA or PEI, lead to bet-
is improved by intraoperative ultrasound, and the liver is mo- ter recurrence-free survival and excellent long-term results:
bilized, positioned and exposed with gauze pads. A combined with TACE + PEI a 50% 3-year recurrence-free survival was
regimen with resection of a large tumor mass and RFA of ad- achieved compared to 50% tumor recurrence in the first year
ditional tumor nodules in the other lobe can reduce parenchy- with TACE alone. In well vascularized tumors a ‘wash-out
mal loss. Thus, even otherwise irresectable tumors can be phenomenon’ of the injected ethanol can be observed, there-
completely eliminated [67]. Explorative laparotomy leading to fore embolization as first step makes sense. After TACE
the decision for transplantation can ideally be combined with tumor consistency softens and ethanol is more homogenously
an ablative treatment to reduce the risk of further tumor distributed. In addition, a fibrous wall in the periphery of the
growth during the waiting period. tumor forms, permitting a larger amount of ethanol per injec-
tion (30–40 ml/session). Complete tumor necrosis could be
Chemoembolization achieved with TACE + PEI for 80% of patients with solitary
Modern concepts favor multimodal treatment regimes as the tumors in compensated cirrhosis [75]. TACE combined with
most promising option of complete tumor control in HCC. intraoperative cryotherapy was effective in large unresectable
Emulsions with chemotherapeutic drugs and the iodinated oil tumors with a 2-year survival of 63% [26]. The most promising
lipiodol (TACE) have a prolonged effect compared to applica- combination, TACE + RFA, enhanced tumor necrosis and is
tion of the chemotherapeutic alone. Lipiodol and the drug are superior to TACE + PEI in tumor control [29, 76, 70]. PEI or
deposited in tumor tissue at a ratio of 4:1. The injected emul- RFA can be applied very effectively under intraoperative ul-
sion delays arterial perfusion. Based on presinusuidal arterio- trasound control or guided by laparoscopy and also in combi-
portal anastomoses, part of the effect is due to the portal sys- nation with resection of other foci [67, 70].
tem. Gelfoam is used for closing embolization to ease re-em- TACE as Pretreatment before Resection
bolisation via the same access after recanalization (3–4 weeks) Theoretical advantage of TACE in neoadjuvant concepts is
to treat newly formed tumor collaterals. Yttrium 90, in con- preoperative tumor control by embolization of the arterialized
trast to lipiodol 131, is suitable for larger HCC nodules. In one vasculature of the tumor periphery and pseudo capsule, the
third of 82 patients with unresectable HCC, AFP levels could resection plane is sealed off and cell shedding is blocked [76].
be reduced and median survival was prolonged to 21 months This should be beneficial especially for HCC in non-cirrhotic
versus 4.5 months in non-responders [72]. Recently, these en- livers because they lack a fibrotic tumor wall and have better
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flow capacity. Another positive factor is improved detection of ized controlled studies interferon alpha failed to influence
previously not mapped tumor nodules to prove solitary dis- tumor growth or survival rates [30, 84]. Octreotide, a potent
ease. Bismuth and Fecteau [26] used TACE as neoadjuvant inhibitor of vascular endothelial growth factor (VEGF), the
tool: in 62% TACE-induced down-staging or total tumor major angiogenetic factor in tumors, may have an effect in
necrosis associated with improved recurrence-free survival HCC. At least 50% of HCC tumors express somatostatin re-
after resection as well as after transplantation was achieved. A ceptors, providing an additional rationale for inclusion of so-
higher response to TACE was seen in the group of larger tu- matostatin analogues in the treatment regimen. A significant
mors (>5 cm). In addition, TACE improved resectability of uptake of radio-labeled octreotide in HCC nodules can be
previously unresectable tumors. For tumor mass reduction re- demonstrated and patients with somatostatin-receptor-ex-
peated TACE sessions (every 6 weeks) were scheduled. pressing tumors can be identified. Two randomized trials con-
Preoperative Portal Embolization cerning octreotide treatment achieved different results: in
To stimulate the compensatory response of the remaining liver Child B/C patients with advanced HCC Kourolamis et al. [85]
parenchyma and to reduce perioperative blood loss, a preop- observed a significant survival advantage in the treatment
erative portal embolization of liver lobes bearing larger tu- group (octreotide subcutaneously 500 µg/d) 1 and 2 years after
mors as preparation for resection is discussed, also in case of initiation of treatment, whereas long-acting octreotide (30 mg
reduced liver function [77]. 1× per month) showed no effect [86]. Different patient selec-
TACE Prior to Transplantation tion might have biased these results.
Even if a patient fulfills the strict criteria for transplantation,
he has to wait at least a year before a suitable organ is avail- External Radiation
able. For bridging this gap, TACE and RFA are advocated, External beam radiation is of limited value since HCC is rela-
otherwise tumor progression, vascular infiltration and/or tively radio-resistant in contrast to the radiosensitive normal
metastases can be expected [26, 63]. In a retrospective study liver parenchyma. Treatment is therefore associated with the
Majno et al. [76] observed a significant survival benefit after risk of radiation hepatitis. One of the rare positive reports in-
transplantation for TACE responders. Therefore response to cluded radiation in a combined treatment plan of irresectable
TACE might serve as selection criterion for transplantation. large HCC: after induction chemotherapy and external beam
This was confirmed by Bismuth et al. [42] who found a signifi- radiation (21 Gy) in the treatment arm with intraartial cis-
cantly better survival after down-staging with TACE prior to platin and 131I polyclonal antiferritin, 1-year and 2-year sur-
transplantation (5-year survival 79 vs. 29%). vival were 37 and 9%, respecively versus 17 and 4% in the
doxorubicin control group [87].
Chemotherapy
The HCC response rate to systemic chemotherapy is below
20% [71] and neither single-agent nor combination chemo- Conclusion
therapy have demonstrated a reproducible survival benefit for
patients with HCC [21, 78]. Intraarterial application showed Close follow-up and screening for patients at risk of develop-
no improvement of long-term prognosis, but the incidence of ing an HCC can improve the prognosis after therapy. Im-
severe complications was increased. Reported positive effects proved diagnostics and imaging enable to stratify for best
are mainly due to concomitant micro embolizations [79]. A therapeutic options, based on liver function and tumor stage.
comparative study with doxorubicin pre-, intra-, and postoper- Although not yet based on hard evidence, we see a trend to
atively implied a significant increase of survival compared to multi-modal treatment of HCC. The decision tree for treat-
historic controls. However, tumor stages were not well strati- ment of HCC is as follows: liver transplantation is confined to
fied and 3-year survival rates did not compare to other series the group with small solitary tumors (<5 cm) or up to 3 small
without adjuvant therapy [80]. As adjuvant treatment, nodules (largest <3 cm) in patients with cirrhosis and ad-
chemotherapy showed no effect or even worsened prognosis vanced liver dysfunction. Resection is advocated for HCC pa-
after resection [81, 82]. Nevertheless, doxorubicin or a combi- tients with cirrhosis and good liver function and also for those
nation of doxorubicin, 5-fluorouracil, and cisplatin is adminis- with large tumors and no cirrhosis. The most promising devel-
tered routinely in some centers after transplantation [26, 42]. opment may be the ablative methods (RFA prior to PEI) in
In a pilot study, cisplatin, used as radio sensitizer, could in- combination with transarterial chemoembolisation (TACE).
crease the response rate (stable disease, responder) after em- This combined treatment achieved excellent results and is in-
bolization with 131I-lipiodol TACE to 90% compared to only dicated for patients with multilocular tumors or those with
40% after TACE alone [83]. small tumors and cirrhosis and as best palliative treatment.
Hormone Therapy Virustatic protocols have to be evaluated after resection or
In theory, HCC should be influenced by tamoxifen, an estro- transplantation to reduce the risk of de novo carcinoma devel-
gen receptor antagonist, but several studies failed to show a opment. Recurrent HCC should be resected or ablated by
survival benefit after anti-androgenic therapy [84]. In random- RFA combined with TACE if liver function is adequate.
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