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Chapter10:Assessment and triageofHCC
http://internalmedicinebook.com
Conclusion
Several questions remain as we attempt to improve treatment
outcome in HCC patients. e pathophysiologic complexity
of HCC, balanced with a goal of providing eective tumor
therapy with preservation of organ function, makes optimal
treatment choice a clinical challenge. In addition, despite the
recent advances and renements in therapeutic strategies,
tumor recurrence remains a major issue in patients with HCC.
Several clinical trials investigating dierent combinations of
locoregional and systemic treatments for preventing early
recurrence and improving long-term outcomes are ongoing.
Encouraging safety and ecacy signals were captured by the
phase II studies completed so far.
42,43
However, an understanding of exactly which features of HCC and patient health may
predict the clinical outcome of combination regimens is essential for prescribing individualized, evidence-based therapeutic
strategies.
13. Chapiro J, Geschwind JF. Hepatocellular carcinoma:have we
nally found the ultimate staging system for HCC? Nat Rev
Gastroenterol Hepatol 2014; 11:334–336.
14. Mazzaferro V, Lencioni R, Majno P. Early hepatocellular
carcinoma on the procrustean bed of ablation, resection, and
transplantation. Semin Liver Dis 2014; 34:415–426.
15. Gervais DA, Goldberg SN, Brown DB, Soulen MC, Millward
SF, Rajan DK. Society of Interventional Radiology position
statement on percutaneous radiofrequency ablation for the
treatment of liver tumors. J Vasc Interv Radiol 2009; 20 (7
Suppl):S342–S347.
16. Crocetti L, de Baere T, Lencioni R. Quality improvement
guidelines for radiofrequency ablation of liver tumours.
Cardiovasc Intervent Radiol 2010; 33:11–17.
17. Lubner MG, Brace CL, Ziemlewicz TJ, Hinshaw JL, Lee FT Jr.
Microwave ablation of hepatic malignancy. Semin Intervent
Radiol 2013; 30:56–66.
18. Groeschl RT1, Pilgrim CH, Hanna EM, etal. Microwave
ablation for hepatic malignancies:a multiinstitutional analysis.
References
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United Kingdom:projections to the year 2025. Br J Cancer 2008;
99:1549–1554.
3. Davis GL, Alter MJ, El-Serag H, etal. Aging of the hepatitis C
virus (HCV)-infected persons in the United States:amultiple
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Gastroenterology 2010; 138:513–521.
4. Fong ZV, Tanabe KK. e clinical management of
hepatocellular carcinoma in the United States, Europe, and
Asia:acomprehensive and evidence-based comparison and
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6. European Association for the Study of the Liver; European
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7. Verslype C, Rosmorduc O, Rougier P; ESMO Guidelines
Working Group. Hepatocellular carcinoma:ESMO–ESDO
Clinical Practice Guidelines for diagnosis, treatment and
follow-up. Ann Oncol 2012; 23 Suppl 7:vii41–48.
8. Lencioni R. Evolving strategies in the diagnosis of hepatocellular
carcinoma. J Hepatol 2011; 54:184–186.
9. Kojiro M, Roskams T. Early hepatocellular carcinoma and
dysplastic nodules. Semin Liver Dis 2005; 25:133–142.
10. Lencioni R, Crocetti L. Loco-regional treatment of
hepatocellular carcinoma. Radiology 2012; 262:43–58.
11. Yau T, Tang VY, Yao TJ, Fan ST, Lo CM, Poon RT. Development
of Hong Kong Liver cancer staging system with treatment
stratication for patients with hepatocellular carcinoma.
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12. Sherman M. Staging for hepatocellular carcinoma:complex and
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Ann Surg 2014; 259:1195–1200.
19. Cannon R, Ellis S, Hayes D, Narayanan G, Martin RC 2nd.
Safety and early ecacy of irreversible electroporation for
hepatic tumors in proximity to vital structures. J Surg Oncol
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20. Lu DS, Kee ST, Lee EW. Irreversible electroporation:ready for
prime time? Tech Vasc Interv Radiol 2013; 16:277–286.
21. Silk MT, Wimmer T, Lee KS, etal. Percutaneous ablation of
peribiliary tumors with irreversible electroporation. J Vasc
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22. Dunne RM, Shyn PB, Sung JC, etal. Percutaneous treatment
of hepatocellular carcinoma in patients with cirrhosis:a
comparison of the safety of cryoablation and radiofrequency
ablation. Eur J Radiol 2014; 83:632–638.
23. Li GZ, Speicher PJ, Lidsky ME, etal. Hepatic resection for
hepatocellular carcinoma:do contemporary morbidity and
mortality rates demand a transition to ablation as rst-line
treatment? J Am Coll Surg 2014; 218:827–834.
24. Chen MS, Li JQ, Zheng Y, etal. A prospective randomized trial
comparing percutaneous local ablative therapy and partial
hepatectomy for small hepatocellular carcinoma. Ann Surg 2006;
243:321–328.
25. Huang J, Yan L, Cheng Z, etal. A randomized trial
comparing radiofrequency ablation and surgical resection
for HCC conforming to the Milan criteria. Ann Surg 2010;
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26. Feng K, Yan J, Li X, etal. A randomized controlled trial
of radiofrequency ablation and surgical resection in the
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27. Wang Y, Luo Q, Li Y, Deng S, Wei S, Li X. Radiofrequency
ablation versus hepatic resection for small hepatocellular
carcinomas:a meta-analysis of randomized and nonrandomized
controlled trials. PLoS ONE 2014; 9:e84484.
28. Lencioni R, Kudo M, Ye SL, etal. GIDEON (Global
Investigation of therapeutic DEcisions in hepatocellular
carcinoma and Of its treatment with sorafeNib):second interim
analysis. Int J Clin Pract 2014; 68:609–617.
29. Lencioni R. Chemoembolization for hepatocellular carcinoma.
Semin Oncol 2012; 39:503–509.
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30. Lammer J, Malagari K, Vogl T, etal. Prospective randomized
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treatment of hepatocellular carcinoma:results of the
PRECISION V study. Cardiovasc Intervent Radiol 2010;
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31. Oliveri RS, Wetterslev J, Gluud C. Transarterial (chemo)
embolisation for unresectable hepatocellular carcinoma.
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32. Ray CE, Haskal ZJ, Geschwind JFH, Funaki BS. e use
of transarterial chemoembolization in the treatment of
unresectable hepatocellular carcinoma:aresponse to the
Cochrane Collaboration Review of 2011. J Vasc Interv Radiol
2011; 22:1693–1696.
33. Forner A, Llovet JM, Bruix J. Chemoembolization for
intermediate HCC:is there proof of survival benet? J Hepatol
2012; 56:984–986.
34. Kulik LM, Carr BI, Mulcahy MF, Lewandowski RJ, Atassi
B, Ryu RK, etal. Safety and ecacy of 90Y radiotherapy
for hepatocellular carcinoma with and without portal vein
thrombosis. Hepatology 2008; 47:71–81.
35. Riaz A, Kulik L, Lewandowski RJ, Ryu RK, Giakoumis Spear
G, etal. Radiologic-pathologic correlation of hepatocellular
carcinoma treated with internal radiation using yttrium-90
microspheres. Hepatology 2009; 49:1185–1193.
36. Salem R, Lewandowski RJ, Mulcahy MF, Riaz A, Ryu RK,
Ibrahim S, etal. Radioembolization for hepatocellular
carcinoma using Yttrium-90 microspheres:a comprehensive
report of long-term outcomes. Gastroenterology 2010;
138:52–64.
37. Salem R, Lewandowski RJ, Kulik L, etal. Radioembolization
results in longer time-to-progression and reduced toxicity
compared with chemoembolization in patients with
hepatocellular carcinoma. Gastroenterology 2011; 140:497–507.
38. Salem R, Mazzaferro V, Sangro B. Yttrium 90 radioembolization
for the treatment of hepatocellular carcinoma:biological
lessons, current challenges, and clinical perspectives. Hepatology
2013; 58:2188–2197.
39. Llovet JM, Ricci S, Mazzaferro V, etal. Sorafenib in advanced
hepatocellular carcinoma. N Engl J Med 2008; 359:378–390.
40. Cheng AL, Kang YK, Chen Z, etal. Ecacy and safety
of sorafenib in patients in the Asia-Pacic region with
advanced hepatocellular carcinoma:a phase III randomised,
double-blind, placebo-controlled trial. Lancet Oncol 2009;
10:25–34.
41. Llovet JM, Hernandez-Gea V. Hepatocellular
carcinoma:reasons for phase III failure and novel perspectives
on trial design. Clin Cancer Res 2014; 20:2072–2079.
42. Pawlik TM, Reyes DK, Cosgrove D, Kamel IR, Bhagat N,
Geschwind J. Phase II trial of sorafenib combined with
concurrent transarterial chemoembolization with drug-eluting
beads for hepatocellular carcinoma. J Clin Oncol 2012;
29:3960–3967.
43. Lencioni R, Llovet JM, Han G, etal. Sorafenib or placebo
in combination with transarterial chemoembolization
(TACE) with doxorubicin-eluting beads (DEBDOX) for
intermediate-stage hepatocellular carcinoma (HCC):phase II,
randomized, double-blind SPACE trial. J Clin Oncol 2012; 30
(suppl 4; abstr LBA154).
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Chapter
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Image-guided ablation of hepatocellular carcinoma
11
Laura Crocetti, Maria Clotilde Della Pina, Dania Cioni, and Riccardo Lencioni
Introduction
Hepatocellular carcinoma (HCC) is the sixth most common
cancer and the third leading cause of cancer-related death.1
Early diagnosis of HCC can be achieved by surveillance of
at-risk populations.
assessment of tumor characteristics, liver function, and physical status is required for proper therapeutic management even
in patients with early-stage tumors.5 When surgical options
are precluded, image-guided tumor ablation is recommended
as the most appropriate therapeutic choice, and is considered a potentially curative treatment in properly selected
candidates.
5
Several classication systems are available for HCC. e
Barcelona Clinic Liver Cancer (BCLC) classication has
emerged during recent years as the standard classication
that is used for the clinical management of patients with HCC
(Tables11.1 and 11.2).
cation with a recommended treatment strategy and denes
standard of care for each tumor stage. It has been endorsed by
a European Association for the Study of the Liver (EASL) panel
of experts and the American Association for the Study of Liver
Diseases (AASLD) guidelines.
somewhat dierent and the Asian Pacic Association for the
Study of Liver recommendations and the recently published
Hong Kong Liver Cancer (HKLC) staging system mirror current clinical practice in Asian countries.
According to the BCLC staging system,6 image-guided
tumor ablation is recommended in patients with early-stage
HCC. Radiofrequency ablation (RFA) has shown superior ecacy and greater survival benet with respect to
the seminal percutaneous technique, ethanol injection, in
meta-analyses of randomized controlled trials (RCTs), and is
currently established as the standard method for local tumor
treatment.
10–14
In this chapter, image-guided ablation in very early and
early-stage HCC is discussed, underlining the advantages and
limitations of current locoregional treatments with respect to
surgical approaches. Evolving methods, such as microwave
ablation (MWA) and irreversible electroporation (IRE), will be
described.
2–4
However, a careful multidisciplinary
6,7
is classication links stage strati-
2,5
Practices on HCC in Asia are
8,9
Very-early-stage hepatocellular carcinoma
In very-early-stage HCC the presence of a solitary small nodule,
less than <2cm in diameter, in Child–Pugh Apatients, and the
absence of microvascular invasion and dissemination oers the
highest likelihood of cure. According to the BCLC staging system– endorsed by the EASL and the AASLD
can be oered surgical resection if they are non-cirrhotic or
if they have cirrhosis but still have well-preserved liver function, normal bilirubin, and in the absence of clinically signicant portal hypertension. Such patients will not decompensate
aer resection and may achieve a 5-year survival of better than
15,16
75%.
Anatomical resection, dened as the en-bloc removal
of a portion of liver supplied by a major branch of the portal
vein and the hepatic artery, is considered the preferred surgical
technique, as it theoretically allows the eradication of intrahepatic metastases of HCC, resulting in a better outcome when
compared to non-anatomical resection.
Despite the recent renements in surgical techniques that
result in a reduction of treatment-related mortality to 1–3%,
most groups restrict the indication for anatomical resection to
patients with very early HCCs that are in a suitable location
for resection, to maximally preserve non-cancerous functional
liver parenchyma.17 In fact, depending on the volume of the
liver segments that need to be resected, signicant impairment
of liver function, and possibly liver failure, could follow surgical intervention.17 Nodules <2cm, that are not subcapsular or
perivascular, are the ideal target for percutaneous RFA, which
is considered the standard technique for liver tumor ablation
at most institutions.
5,10,18,19
In patients with very early HCC
the complete response rate approaches 97%, with 5-year survival rates of 68%.20 In these small, centrally located tumors,
therefore, RF ablation seems to challenge the role of surgical
resection, allowing a long-term survival rate similar to those of
resection, with the preservation of liver parenchyma.
Recently, conrmatory information about the respective role
of resection and RFA in the clinical management of very early
HCC has been provided by a decision analysis study. Cho etal.
concluded that RFA and hepatic resection are to be considered
equally eective for the treatment of very early HCC.21 From a
cost-eectiveness perspective, RFA has been proved superior to
2,5
– these patients
17
Interventional Oncology, Second Edition, ed. Jean-François H. Geschwind and Michael C. Soulen. Published by Cambridge University Press.
©Cambridge University Press2016
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Table 11.1 Barcelona Clinic Liver Cancer classification in patients
diagnosed with hepatocellular carcinoma (HCC)
6
Stage Classication
Very early stage PS 0, Child–Pugh A, single HCC < 2 cm
Early stage PS 0, Child–Pugh A–B, single HCC or three
nodules < 3 cm
Intermediate stage PS 0, Child–Pugh A–B, multinodular HCC
Advanced stage PS 1–2, Child–Pugh A–B, portal neoplastic
invasion, nodal metastases, distant metastases
Terminal stage PS > 2, Child–Pugh C
PS = performance status.
Table 11.2 Child–Pugh classification
a
Points scored for observed ndings
1 2 3
Encephalopathy
grade
Ascites Absent Mild–moderate Severe–refractory
Serum bilirubin
(mg/dL)
Serum albumin
(g/dL)
INR < 1.7 1.71–2.20 > 2.20
a
Child–Pugh class is assessed according to the following criteria of
Child–Pugh classification7:
Child–Pugh A: 5– 6 points
Child–Pugh B: 7–9 points
Child–Pugh C: 10–15 points
If there are several test results for one test item, the lower point result will
be used to determine the Child–Pugh classification.
INR = international normalized ratio.
None Mild Severe
< 2 2–3 > 3
> 3.5 2.8–3.5 < 2.8
individual variables, including tumor location, would make
RFA not feasible or notsafe.
Early-stage hepatocellular carcinoma
Early-stage disease includes patients with preserved liver function (Child–Pugh Aand B) with solitary HCC or up to three
nodules <3cm in size. ese patients can be eectively treated
by resection, liver transplantation, or percutaneous ablation
with the possibility of long-term cure, with 5-year survival
estimates ranging from 50% to 75%. Among dierent ablative
techniques, RFA is currently considered the best treatment
option in patients with early stage HCC.
compared RFA versus percutaneous ethanol injection (PEI) for
the treatment of early-stage HCC. ese investigations consistently showed that RFA is more eective than PEI, leading to a
better local control of the disease
29–33
e assessment of the impact of RFA on survival has been
more controversial. While a survival benet was identied in
the three RCTs performed in Asia, the two European RCTs
failed to show statistically signicant dierences in overall
survival between patients who received RFA and those treated
with PEI, despite the trend favoring RFA. Nevertheless, three
independent meta-analyses, including all RCTs, have conrmed that treatment with RFA oers a survival benet as
compared with PEI, particularly for tumors larger than 2cm,
thus establishing RFA as the standard percutaneous technique
in these patients
11–13
(Figure11.1). Recent reports on long-term
outcomes of RFA-treated patients have shown that, in patients
with Child–Pugh class Aand early-stage HCC, 5-year survival
rates are as high as 51–64%, and may reach 76% in patients who
meet the BCLC criteria for surgical resection
erefore, an open question is whether RFA can compete with
surgical resection as rst-line treatment not only for patients
5,10,18
Five RCTs have
(Table11.3).
34–37
(Table11.4).
with very early HCC but also for patients with small, solitary
HCC >2cm. Published results on this topic remain contro-
resection in the case of patients with a single HCC <2cm. In
such patients Cucchetti etal. demonstrated that RFA provided
better life expectancy and quality-adjusted life expectancy at
a lower cost in comparison to resection. It should be noted,
however, that the dierences observed between life expectancy
and quality-adjusted life expectancy of the two treatments
were marginal. RFA costs were, however, signicantly lower
than those of hepatic resection and, from a cost-eectiveness
perspective, RFA dominated hepatic resection.22 It has also
been pointed out that individual characteristics of each patient
(e.g., whether the tumor is central or peripheral, close or distant from bile ducts, occurring in a patient who is lean or overweight, who presents with or without portal hypertension)
inuence the results of each treatment, making it better or
worse than average.
21,23
Since clinical experience suggests that
treatment by RFA of HCC tumors in a subcapsular location
or adjacent to the gallbladder is associated with an increased
risk of major complications and incomplete ablation,
24–28
such
tumor locations are considered favorable for hepatic resection.
erefore, in patients with very early HCC, RFA can be oered
as a rst-line treatment, considering a surgical approach when
versial. An RCT comparing resection vs. ablation in Child
Apatients with single HCC 5cm or less in diameter has failed
to show statistically signicant dierences in overall survival
and disease-free survival between the two treatment arms.38
Conversely, a recent RCT comparing RFA and resection in
patients conforming to Milan criteria suggested that surgical
resection may provide better survival and lower recurrence
rates than RFA.39 e two RCTs both have important limitations. In the rst the minimal sample size was not calculated on
the basis of the expected overall survival, while in the latter the
loss to follow-up rate was signicantly higher in the resected
patients group (15.6% vs. 6.1% in the RFA-treated group).
38,39
e most recent RCT was conducted in Beijing by Feng
et al. in 2012.40 ey compared the outcomes of resection
(n=84) and RFA (n=84) in patients with ≤2 lesions that were
≤4cm in diameter each, in whom the liver function was classied as Child–Pugh class Aor B.e 3-year overall survival rate
(the primary endpoint) was 74.8% in the resection group and
67.2% in the RFA group, with no signicant dierence between
the two groups. ese inconclusive results, mainly due to major
aws in study design, prevent us from drawing a denitive
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Table 11.3 Randomized controlled trials comparing radiofrequency ablation (RFA) versus percutaneous ethanol injection (PEI) for the treatment of
early-stage hepatocellular carcinoma
Overall survival (%)
Author and year Initial CR Treatment failure
Lencioni et al., 2003
29
RFA (n = 52) 91% 8% 88 81 NS
PEI (n = 50) 82% 34% 96 73
Lin et al., 2004
30
RFA (n = 52) 96% 17% 82 74 0.014
PEI (n =52) 88% 45% 61 50
Shiina et al., 2005
31
RFA (n = 118) 100% 2% 90 80 0.02
PEI (n = 114) 100% 11% 82 63
Lin et al., 2005
32
RFA (n = 62) 97% 16% 88 74 0.031
PEI (n = 62) 89% 42% 96 51
Brunello et al., 2008
33
RFA (n = 70) 96% 34% 88 59 NS
PEI (n = 69) 66% 64% 96 57
CR = complete response; NS = not significant.
a
Includes initial treatment failure (incomplete response) and late treatment failure (local recurrence).
a
1-year 3-year P
Table 11.4 Studies reporting 5-year survival of patients with early-stage hepatocellular carcinoma who received radiofrequency ablation as the sole first-line
non-surgical treatment
Overall survival (%)
Lencioni et al., 2005
Child–Pugh A 144 100 76 51
Child–Pugh B 43 89 46 31
Tateishi et al., 2005
Child–Pugh A 221 96 83 63
Child–Pugh B–C
Choi et al., 2007
Child–Pugh A 359 NA 78 64
Child–Pugh B 160 NA 49 38
N'Kontchou et al., 2009
BCLC resectable
BCLC unresectable 168 NA 49 27
NA = not available ; BCLC = Barcelona Clinic for Liver Cancer.
a
Only 4 of 98 patients had Child–Pugh C cirrhosis.
b
BCLC criteria for resection include single tumor, normal bilirubin level (< 1.5 mg/dL), and absence of significant portal hypertension.
34
35
a
36
37
b
98 90 65 31
67 NA 82 76
evidence-based conclusion and, on the other hand, properly
designed RCTs to compare RFA versus resection would require
a very large sample size to demonstrate even a slight survival
benet of a treatment on theother.
Large-scale nationwide surveys can provide evidence
regarding the respective role of resection versus percutaneous
Author and year Number of patients
ablation in clinical practice. In Japan, a prospective cohort analysis was conducted by Hasegawa etal.41 ey compared the
1-year 3-year 5-year
outcome of liver resection (n=5,361), RFA (n= 5,548), and
ethanol injection (n=2,059) in HCC patients in Child–Pugh
class Aor B and up to three lesions with a maximum diameter
of no more than 3cm. e 3-year and 5-year recurrence rates
were 43.3% and 63.8%, respectively, in the liver resection group
vs. 57.2% and 71.7%, respectively, in the RFA group, indicating signicantly lower recurrence rates aer treatment by liver
resection. e 3-year and 5-year survival rates were 85.3% and
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A
RFA for death was 0.84 (95% condence interval, 0.74–0.95;
P=0.006).
41
e results of studies based on such large numbers of cases
are of signicance, but because there were also signicant differences in the background factors among the treatment groups,
the conclusions cannot be described as denitive. Arestrospective comparison of resection and RFA in the treatment of a large,
selected group of patients, i.e., single HCC smaller than 3cm in
Child–Pugh class Acirrhosis, was recently published.42 Hepatic
resection and RFA ablation were oered to patients in 15 Italian
centers, following clinical practice protocols. Four-year overall
B
survival rates were 74.4% in the resection group and 66.2% in
the RFA group (P=0.353). Four-year cumulative HCC recurrence rates were 56% in the resection group and 57.1% in the
RFA group (P=0.765). Aer propensity score matching, both
survival and tumor recurrence were still not signicantly dierent, although a trend towards lower recurrence was observed in
resected patients. e results of this study seem to conrm that,
when ablation is performed in the appropriate patients, with
compensated liver cirrhosis and small HCCs, this approach can
be oered as a rst-line treatment option.
An important factor aecting the success of RFA is the
CD
ability to ablate all viable tumor tissue and create an adequate
tumor-free margin. e target tumor should not exceed 3cm
at its longest axis to achieve best rates of complete ablation
using most of the currently available devices.10 Moreover,
even in small tumors, the ability of RFA to achieve complete
tumor eradication appears to be dependent on tumor location.
Histological studies performed in liver specimens of patients
who underwent RFA as bridge treatment to transplantation
showed that the presence of large (3mm or more) abutting
vessels result in about 50% drop in the rate of complete tumor
EF
necrosis because of the heat loss due to perfusion-mediated tissue cooling within the area to be ablated.43 erefore, in patients
with solitary HCC >3cm and <5cm in size, the success rate of
RFA alone is decreased; combination with intra-arterial treatment could be considered.
44–48
A combination of transarterial chemoembolization (TACE)
followed by RFA has been used to minimize heat loss due to
perfusion-mediated tissue cooling and increase the therapeutic
eect of RFA.
44–47
Recently, the results of an RCT aimed at evaluating the therapeutic ecacy of combining RFA with TACE for
treating intermediate-sized (3.1–5cm) HCCs have been pub-
Figure 11.1 Radiofrequency ablation of early-stage hepatocellular carcinoma
in a 78-year-old male patient with hepatitis C virus-related liver cirrhosis.
(A) Pretreatment computed tomography (CT) shows the tumor as a 25-mm
hypervascular nodule (arrow) in the arterial phase, in subcapsular location.
(B) Under ultrasound guidance a radiofrequency multitined expandable
electrode is placed and deployed within the nodule (arrow). On CT images
obtained in the arterial (C) and the portal venous phase (D) 1 month after
treatment, the tumor is replaced by a non-enhancing ablation zone (arrow)
slightly exceeding in size the diameter of the naïve tumor. Complete response
is confirmed at 6-month CT examination (arrows, E, F).
lished. Local tumor progression rates were signicantly lower in
the TACE-RFA-treated group compared to the RF-only group
(6% vs. 39%, P=0.012).49 TACE with drug-eluting beads has
also been performed aer an RFA procedure to increase tumor
necrosis by exposing to high drug concentration the peripheral part of the tumor, where only sublethal temperatures may
be achieved in a standard RFA treatment.48 Further research to
determine optimal methods of combining chemotherapeutic
regimens (both agent and route of administration) with RFA is
needed. In particular, a phase III, randomized, double-blinded,
placebo-controlled study investigating the ecacy and safety of
71.7%, respectively, in the liver resection group vs. 81.0% and
61.1%, respectively, in the RFA group. According to the results
of a multivariate analysis, the hazard ratio of liver resection to
thermally sensitive liposomal doxorubicin in combination with
RFA compared to RFA-alone in the treatment of non-resectable
HCC has been recently completed.
50
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Patients with solitary large tumors (exceeding 5 cm in
size) deserve a special mention. Even if these patients cannot
be considered in an early stage because they do not qualify for
transplantation, no upper limit of size for surgical resection
appears in the BCLC owchart, and these patients should not
escape surgical referral because their tumors are too large.23
Dierent ablative modalities are not currently providing sufcient volume of ablation to successfully treat these tumors
and the results of transarterial therapies as stand-alone treatment are highly variable in this clinical scenario.
5,10
Moreover,
when tumor size is above 5cm, the advantages of combination
therapies seem negligible.
46,51
On the other hand, it has been
suggested that patients with large solitary tumors may benet
from surgery because surgical mortality has decreased and
because patients with operable solitary large tumors may be a
self-selected group with low tendency for multifocal disease.
When RFA is not feasible and/or safe – for example, in
the 10–25% of tumors arising in unfavorable tumor loca-
34,52
tion
– TACE with drug-eluting beads can represent a valuable treatment option. In a recent series of patients submitted
to drug-eluting beads TACE before liver transplantation, histologic evaluation of the explanted livers demonstrated complete
necrosis in 77% of treated tumors.
53
MWA with respect to those treated with RFA. It is therefore
essential to perform multicenter clinical trials and to standardize as much as possible treatment protocols, considering the
dierences among dierent MW devices.
A new, non-chemical non-thermal image-guided ablation
technique that is currently undergoing clinical investigation
in early-stage HCC is IRE60 (Figure11.2). IRE is a method of
inducing irreversible disruption of cell membrane integrity, by
changing the transmembrane potential, resulting in cell death
without the need for additional pharmacological injury.61 IRE
creates a sharp boundary between the treated and untreated
area in vivo. is would suggest that IRE has the ability to
sharply delineate the treatment area from the non-treated, and
that treatment planning can be precisely performed according to mathematical predictions. Moreover, because IRE is a
23
non-thermal technique, there appears to be complete ablation to the margin of blood vessels without compromising the
functionality of the blood vessels. erefore, issues associated
with perfusion-mediated tissue cooling or heating (a signicant challenge with thermal methods) are not relevant. In a
recent report the safety and short ecacy of IRE in tumors
near hepatic veins and/or portal pedicles were examined.62
e authors concluded that IRE performed in such tumors
was a safe technique. None of the hepatic veins within 1cm
Image-guided ablation:Evolving methods
and techniques
MWA is emerging as a valuable alternative to RFA for thermal
ablation of HCC. Electromagnetic microwaves heat matter by
agitating water molecules in the necrosis.54 e main features of
MW technology, when compared with existing thermoablative
technologies, include consistently higher intratumoral temperatures, larger tumor ablation volumes, faster ablation times,
and an improved convection prole. As a result, the advantage
of MWA over RFA is that treatment outcome is less aected
by vessels located in the proximity of the tumor.55 In addition,
because MW ablation does not rely on an electrical circuit as
does RF ablation, multiple applicators can be applied simultaneously. Two large cohort trials investigated the safety of MW
ablation in the treatment of liver tumors.
tion rate was in the range of 2.6–2.9%,
56,57
Major complica-
56,57
while minor complications were reported to be 7.3%.57 e authors concluded that,
probably even owing to previous experience with RFA, MWA
ablation had to be considered a safe technique. So far, only
one RCT has compared the eectiveness of MWA with that
of RFA.58 Although no statistically signicant dierences were
observed with respect to the ecacy of the two procedures, a
trend favoring RFA was recognized in that study with respect
to local recurrences and complication rates. It has to be pointed
out, however, that MWA technology has evolved signicantly
since the publication of this trial. Recent advances in MW engineering have allowed the design of new MW systems with the
potential for larger, more controlled ablation zones.59 Despite
MW ablation has entered in clinical practice, results of RCTs or
large cohort studies are still missing. Very large patient populations would be needed to demonstrate signicant advantages
in survival in patients with very early or early HCC treated with
of treated tumors was occluded on postprocedure imaging.
ere were similar ndings with ablations performed within
1cm of portal in-ow structures, except for 1 patient with a
segmental pedicular injury; it is unclear if this thrombosis was
caused by electrical eects of IRE or the thermal eect was created in the tissue immediately adjacent to the IRE electrode.62
Anothor critical tumor location for thermal treatments, it is
represented by tumors adjacent to major bile ducts, due to the
risk of producing severe stenosis of biliary structures. Clinical
experience regarding this matter has been published and the
results suggested that IRE may be a treatment option for centrally located liver tumors with margins adjacent to major bile
ducts where thermal ablation techniques are contraindicated.63
So far, however, the published data of IRE technique concern
studies conducted in preclinical models and small case series
and the results of the ongoing prospective clinical trials are
strongly demanded.
60,61
Conclusion
Image-guided ablation plays a major role in the current therapeutic management of HCC. It is established as the best therapeutic choice for patients with early-stage HCC when surgical
resection or liver transplantation is precluded. However, some
issues regarding the role of ablative therapies need to be investigated. Compared with other prevalent cancers, only a few
suitably powered RCTs have been conducted to evaluate potential therapeutic interventions in patients with HCC who are
unsuitable for or have failed curative therapy and guidelines
concerning the optimum treatment algorithm for patients with
unresectable HCC as their disease recurs aer initial curative
therapy are still missing. In fact, reallocating patients to treatment as naïve patients following the BCLC treatment strategy
would not be possible in all cases. When a new HCC occurs in
95
ABC
http://internalmedicinebook.com
D
E
FGH
IJ
Figure 11.2 Irreversible electroporation of early-stage hepatocellular carcinoma in a 70-year-old female with hepatitis C virus-related liver cirrhosis. Pretreatment
magnetic resonance imaging (MRI) shows the tumor as a 22-mm nodule in S7, hyperintense in T2w images (arrow, A), hyperintense (arrow, B) in T1w images
acquired during the arterial phase and hypointense in the portal-venous phase (arrow, C). The procedure was performed under ultrasound guidance, with three
monopolar electrodes (D). On MRI obtained 2 months after treatment, a central hypointense area surrounded by a hyperintense rim is depicted in the site of
the tumor on T2w images (arrow, E). A hypointense area is demonstrated on T1w images in the arterial and portal venous phases (arrow, F, G). Follow-up MRI
12 months after treatment confirms complete response, demonstrating the reduction in size of the ablation zone at T2w images (H) and on T1w images in the
arterial and portal venous phases (I, J).
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a previously resected cirrhotic patient, re-resection would be
dicult to perform, even in a patient with preserved liver function and in the absence of portal hypertension.64 Image-guided
ablation is by denition a repeatable technique and, as long
as the tumor characteristics allow a local ablative approach,
patients can be referred forit.
65
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