Advances in Surgery 48 (2014) 97114

ADVANCES IN SURGERY

Current Treatment for Small

(<5 cm) Hepatocellular
Carcinoma
Evolving Roles for Ablation and Resection

Amudhan Pugalenthi, MD, C. Suzanne Cutter, MD,

Yuman Fong, MD*
Department of Surgery, City of Hope Medical Center, Duarte, CA 91010, USA

Keywords

Hepatocellular carcinoma
Liver cancer
Tumor ablation

Minimally invasive therapies
Radiofrequency ablation
Liver surgery
Key points

Tumor ablation is a safe and easily performed treatment for hepatocellular
carcinoma (HCC).

Randomized trials have shown tumor ablation to be durable and potentially
curative therapy for small HCC.

Tumor ablation and minimally invasive therapies are changing the treatment
paradigms for HCC.

These minimally invasive therapies are good bridge therapies to transplant for
patients with advanced cirrhosis.

INTRODUCTION
Liver cancer is the fifth most common cancer in men (523,000 cases, 7.9% in
total) and seventh most common cancer in women (226,000 cases, 6.5% in to-
tal). Eighty-five percent of the cases occur in developing countries. There were
an estimated 694,000 deaths from liver cancer in 2008. It is a highly fatal dis-
ease with an overall ratio of mortality to incidence of 0.93. As a result, liver
cancer is the third most common cause of death from cancer worldwide [1].
Defining treatment pathways for hepatocellular carcinoma (HCC) has great
public health implications. Until recently, liver resection was the only poten-
tially curative option for the treatment of HCC.

*Corresponding author. E-mail address: YFONG@COH.org

0065-3411/14/$ see front matter

http://dx.doi.org/10.1016/j.yasu.2014.05.012 2014 Published by Elsevier Inc.
98 PUGALENTHI, CUTTER, & FONG

HCC is the most common form of primary liver cancer, accounting for 80%
of cases. Most cases of HCC are associated with hepatitis B and hepatitis C vi-
rus infection [2], and associated chronic inflammation [3] or cirrhosis [4]. The
underlying parenchymal dysfunction makes surgical resection potentially more
dangerous than in patients with normal parenchyma. Thus, finding a less
morbid alternative to resection could potentially benefit a large number of pa-
tients (Box 1).
Over the last decades, the safety of surgical resections has greatly improved
because of advances in radiologic assessment, patient selection, and improve-
ments in perioperative principles. The operative mortality for hepatectomy
has decreased from the 10% to 20% range seen in the 1980s to less than 5% today

Box 1: Treatment options for HCC

Surgical
Liver transplantation
Resection

Needle-based treatments
Chemical ablations
Ethanol injection, acetic acid injection
Thermal ablation techniques
RFA, microwave therapy, cryotherapy, irreversible electroporation

Catheter-based treatments
Bland embolization
Chemo-embolization
Radio-embolization/internal radiotherapy
I-131, Yttrium-90

Systemic therapies
Chemotherapy (systemic)
Biologic therapies
Sorafenib, Avastin
Hormonal therapies
Anti-estrogens (eg, Tamoxifen), anti-androgen (eg, Seocalcitol)
Immunotherapy

Radiotherapies
Stereotactic Body Radiation Therapy (SBRT), Intensity-Modulated Radiation
Therapy (IMRT)
SMALL HEPATOCELLULAR CARCINOMA 99

[57]. However, many patients with poor liver function or other medical comor-
bidities are not candidates for hepatectomy. Technical developments in the last
decades have also produced widely available thermal ablation devices that offer
less invasive but effective treatments for HCC. In this article, resection and ab-
lations for liver tumor are reviewed. Then the outcomes of clinical experiences
of surgical resection or radiofrequency ablation (RFA) are compared, as well as
comparative studies of these treatments [810]. The article concludes by summa-
rizing the optimal treatment of HCC based on current evidence and by high-
lighting the use of resection and ablation as curative treatments.

Outcomes after resection

The goal of treatment of HCC is eradication of the disease, leaving behind a func-
tional liver. Total hepatectomy and liver transplantation offer a solution for the
disease as well as for the underlying liver cirrhosis. However, shortage of donors,
high cost, graft-failure complications, long waiting list, and need for chronic immu-
nosuppression are additional obstacles. In addition, clinical data have proven that
only patients with early-stage cancer benefit from transplantation for HCC [11].
These reasons are why criteria for early cancer, such as the Milan criteria (solitary
tumor 5 cm in size or 3 tumors each 3 cm in size with no evidence of gross
vascular invasion), are used clinically for the selection of patients. Consequently,
liver transplantation is offered for a minority of patients suffering from HCC.
Surgical resection (partial hepatectomy) is considered the gold standard
curative therapy for HCC. Until the early 1980s, operative mortality was
high. Recent years have seen a drop in mortality to less than 5% at most major
centers [57]. The improving safety is partly due to improvements in patient
selection according to extent of resection [12] and baseline liver function [13
18]. Outcomes have also improved because of preoperative preparatory tech-
niques such as portal vein embolization [1921]. Patient selection is also
improved by the recent advances in imaging that allows assessment of vascular
invasion and satellite metastases [2224].
The safety of hepatic resections in the last decade has been well documented.
As reported by Fan and colleagues [25], there was 0% mortality in 110 consec-
utive hepatic resections. Other investigators such as Grazi and colleagues [26]
reported a drop in mortality of 9.3% to 1.3% for cases done before 1991 and
after 1991, respectively. Operative improvements are partly based on mature
understanding of liver physiology and anatomy [27]. Much of the improve-
ment in safety is also due to willingness to accept lesser margins to avoid
loss of functional parenchyma [2832]. Such parenchymal-sparing segmental
resections seem to offer the same benefit as classic lobar resection with lesser
risk than removal of a large volume of liver tissue [25,33]. The morbidity of
liver resections has also been improving, particularly with the development
and popularization of minimally invasive approaches, such as laparoscopic re-
sections [34], single port [35], and robotic approaches.
The long-term outcomes of patients with HCC after resection are also well
documented. The results of selected large series of hepatic resections reported
100 PUGALENTHI, CUTTER, & FONG

after the year 2000 in different centers are summarized in Table 1. A 5-year rate
of survival of 40% has been reported in a collected series of 1500 patients from
various centers in Europe. These results are particularly impressive considering
that most of the patients were beyond the Milan transplantation criteria: tumor
size was more than 5 cm, with multifocal disease, or major vascular invasion in
40% [36]. For small HCC, which is the population of tumors also under consid-
eration for ablation or transplantation, favorable results after resection are also
well documented. Five-year survival after resection is greater than 70% as re-
ported by Yamashita in 2007 [37]. Similarly, Poon and colleagues reported a
5-year survival of 70% for patients fulfilling Milan criteria [77].
Thermal ablation
Only 10% to 20% of patients with HCC are candidates for surgery. Surgery is
precluded in most HCC patients because of anatomic location, size, or number
of tumors or because of poor hepatic reserve and performance status. Hence,
various types of nonresectional, locoregional treatments have been developed
as an alternate to hepatectomy in patients with HCC.
Treatments of small tumors by direct injection of chemicals, such as ethanol
or acetic acid, have been used for decades (see Box 1). Engineering has resulted
in tumor ablation instruments that are available, accessible, and reliable in
killing cancer by modifying the temperature within the tumor, including instru-
ments that deliver radiofrequency (Fig. 1), microwave, cryoablation, laser, and
focused ultrasound. In particular, the tremendous improvements in power sup-
plies for microwave ablation, with a shift from 975-MHz wavelengths to
2.45 GHz now allow reliable killing of tumors as large as 7 cm rapidly and
durably (Fig. 2).
In this article, comments are restricted to RFA, because this is the hyperther-
mal ablation technique with the longest history and most data. There are now
large studies with long follow-up showing the safety and efficacy of RFA for
HCC. In fact, there are now randomized control trial data supporting the asser-
tion that RFA may be curative and equally effective to hepatectomy.
RFA
RFA is a treatment method causing coagulation necrosis of liver tumors by
dielectric heating with radio waves (460  5 Hz) around an electrode inserted
into a lesion. The electrodes can be introduced into tumors percutaneously, via
laparoscopic surgery, or during open surgery. Generally, placement of the elec-
trode probes is performed under image-guidance by sonography or computed
tomography. Widespread clinical use of RFA for human HCC began in the
1990s [38,39]. The results of randomized controlled trials have confirmed
RFA to be more effective than injection of tumors with caustic chemical,
such as percutaneous ethanol injection [40,41] or percutaneous acetic acid injec-
tion [42,43].
Patients selected for RFA generally are those with small tumors and few tu-
mors [44]. Contraindications include tumor adherence to stomach and intes-
tine, gall bladder, bile duct, and the heart, due to the risk of injuring these
SMALL HEPATOCELLULAR CARCINOMA 101

organs [45]. Relative contraindications for RFA include jaundice or refractory

ascites. Results are also suboptimal when lesions are close to major vasculature
because of the heat sink effect that dissipates heat by convection. Patients
with pacemakers are also contraindicated for RFA.
Effectiveness of RFA is clearly related to size and location of tumors. In a
review by Mulier and colleagues [46] of more than 5000 patients who under-
went RFA, the local recurrence rates increased from 14% for tumor size less
than or equal to 3 cm to 25% for tumors between 3 and 5 cm and to 58%
for tumors greater than 5 cm in size, which has been confirmed by other series
showing the greatest durable responses to RFA to occur in tumors that are less
than 2.5 cm in size [47]. This finding is due to the fact that the ablation zone by
the currently available RFA technology is limited up to 4 to 5 cm in maximum
diameter. Thus, unless multiple, overlapping ablation zones are used, a single
probe is only capable of ablating a tumor with a 3-cm diameter if 1-cm margins
are sought.
Table 2 summarizes the most recent nonrandomized clinical series [4857]
using RFA as sole modality. Outcome relates directly to tumor size selection
criteria. Five-year survival ranges from 40% [54] for tumors fulfilling the Milan
criteria to as high as 88% for patients with 2 cm or less or those belonging to
Barcelona clinic liver cancer (BCLC) very early stage [57]. These results are
similar to outcomes based on size as reported earlier [46]. A cohort study of
RFA showed that complete ablation of lesions smaller than 2 cm is possible
in more than 90% of cases, with a local recurrence rate of 1% [52]. Hasegawa
and colleagues [58] reported that although the recurrence rate was higher in
RFA-treated cases, there was no difference in overall 5-year survival.
As per the American Association for the Study of Liver Diseases guidelines
2005, ablation is recommended for very early stage and early stage HCC
(BCLC) patients, who cannot undergo resection/transplantation because of
increased portal pressure or who cannot tolerate surgery because of associated
diseases, respectively [59].

Resection versus RFA

Encouraged by initial results obtained by RFA, many investigators have
compared RFA with resection for early HCC. Table 3 includes 13 case-
controlled reports published in the past decade [58,6068].
There have been 7 comparative studies examining outcome of patients
within the Milan criteria [58,6368]. The results confirm the safety of RFA.
In addition, for the series with small tumors, long-term outcome after RFA
was similar to resection. Five-year survival was generally more than 50%
[64,65,68].
There have been 4 randomized controlled trials comparing resection, and
ablation reports are from China (Table 4). Two of them, Chen and colleagues
[8] and Huang and colleagues [9], compared tumors fulfilling the Milan tumor
criteria for transplantation. Chen and colleagues [8] compared resection to RFA
for tumors less than 5 cm in size. The 1-year, 3-year, and 4-year survivals were
 102
Table 1
Results of resection for HCC reported after 2000
Survival (%)
Author, year Mortality
country N Period Cirrhosis (%) (30 d) 1y 3y 5y Remarks
Zhou et al [75], 2001 1366 (19671988) 3.7% 76 48 37 Tumor size >5 cm
China 1000 (19671988) 89 1.5% 91 77 65 Tumor size 5 cm
Grazi et al [26], 2001 107 (19831991) 100 9.3%a 53 32
Italy 157 (19921998) 1.3%a 72 50
Nagasue et al [76], 2001 56 (19861999) 0 3.0% 97 76 50

PUGALENTHI, CUTTER, & FONG

Japan
Poon et al [77], 2002b 135 (19891999) 3.7% 90 76 70 Milan criteria
China
Wayne et al [78], 2002 249 (19801999) 100 41 <5 cm tumor
USA
Belghiti et al [79], 2002 300 (19901999) 50 6.4%a 81 57 37
France
Grazi et al [80], 2003 102 (19811991) 100 4.9%a 86 64 42
Italy
Ercolani et al [81], 2003 224 (19831999) 100 83 63 43 n 181 (5 cm),
Italy 43 (>5 cm)
 SMALL HEPATOCELLULAR CARCINOMA
Pawlik et al [82], 2005 300 (19841999) 100 6% 45 17 10
USA
Wu et al [83], 2005 161 (19911996) 100 3.7% 28.2 (199196) outside Milan
Taiwan 265 (19972002) 0.4% 34 (19972002) Milan criteria
Taura et al [84], 2007b 166 (19902003) 57 4% 89 78 61 Milan criteria
Japan
Yamashita et al [37], 2007 201 (19852004) 100 76 Anatomic resection
Japan 120 74 Limited resectionMilan
Cherqui et al [85], 2009b 67 (19902007) 100 4.5% 72 Milan criteria
France
Lee et al [86], 2010 130 (19972007) 100 0.8% 80 65 52 Outside Milan
Korea
Shrager et al [87], 2012 206 (19872009) 0 2.9%c 79 60 46 Outside Milan
USA
Kishi et al [88], 2012 63 (19942009) 97 91 73 3 cm, 3 tumors
Japan 147 89 69 55 Advanced
a
Hospital mortality.
b
Milan criteria.
c
90-day mortality.

103
104 PUGALENTHI, CUTTER, & FONG

Fig. 1. (A) Cirrhotic patient with a 4-cm HCC (arrow) treated by RFA. (B) Ablation scar
(arrow) 5 years later.

Fig. 2. (A) Cirrhotic patient with HCC immediately on the right portal pedicle ablated by
2.45-GHz microwave ablation. Tumor before ablation is shown by arrow. (B) Avascular abla-
tion defect (arrow) 4 years later.
 SMALL HEPATOCELLULAR CARCINOMA
Table 2
Selected series of RFA for HCC reported after 2000
Survival (%) Recurrence (%)
Author, year Cirrhosis
country N Period childs criteria Clinical characteristics 1y 3y 5y 1y 3y 5y
Lencioni et al [48], 2005 206 19962003 A/B Size 5 cm or 3 nodules 3 cm 97 71 48 14 49 81
Italy
Tateishi et al [49], 2005 319 19992003 A/B/C 2 cm-87 patients 95 78 54
Japan 25 cm-215 patients
5 cm, 17 patients
Yan et al [50], 2008 266 19992006 A/B/C Nodule size-(1.26.7 cm) 83 58 43
China
Choi et al [51], 2007 570 19992005 A/B Size 5 cm or 3 nodules 3 cm 95 70 58
Korea
Livraghi et al [52], 2008 218 19952006 A 2 cm 76 55
Italy
Ng et al [53], 2008 209 20012005 A/B/C >5 cm, 11 patients 88 60 42
China 5 cm, 198 patients
NKontchou et al [54], 2009 235 20012007 A/B 5 cm 60 40
France 3 nodules
Peng et al [55], 2010 224 19992007 A Solitary 5 cm 60
China
Hung et al [56], 2011 190 20022007 A/B Size 5 cm or number 3 97 77 67 37 71 80
Taiwan
Kao et al [57], 2012 109 20022008 A/B Age 65, size 2 cm 100 88 88
Taiwan Age >65, size 2 cm 95 84 65 27 60 76
149 A/B Age 65, size >2 cm 98 86 72 39 78 87
Age >65, size >2 cm 95 72 65

105
 106
Table 3
Case-controlled studies of hepatic resection versus RF ablations for HCC reported after 2000
Tumor characteristics DFS (%) OS (%)
Author/year
country Rx N Age (y) Number Diameter (cm) 1y 3y 5y 1y 3y 5y
Vivarelli et al [60], 2004 RES 79 65  8 1 (83%); >1 (17%) 3 cm (27%); >3 cm (73%) 79 50 83 65
Italy RFA 79 68  9 1 (58%); >1 (42%) 3 cm (28%); >3 cm (72%) 60 20 78 33
Hong et al [63], 2005 RES 93 49  10 1 2.5  0.8 76 55 98 84
Korea RFA 55 59  10 1 2.4  0.6 74 40 100 73
Ogihara et al [61], 2005 RES 47 60  12 1 7.4  5.2 75 65 31
USA RFA 40 69  10 1 4.6  2.9 78 58 39
Guglielmi et al [62], 2008 RES 91 1 (76%); >1 (24%) <3 cm (34%); 36 cm (66%) 83 56 27 84 64 48
Italy RFA 109 1 (60%); >1 (40%) <3 cm (30%); 36 cm (70%) 60 22 22 83 42 20
Abu-Hilal et al [64], 2008 RES 34 67 1 15 cm 77 28 91 56
UK RFA 34 65 1 15 cm 42 21 83 57
Hasegawa et al [58], 2008 RES 2857 67 (4877) 1 (84%); 23 (16%) 2.2 (1.03.0) 98
Japan RFA 3022 69 (5280) 1 (72%); 23 (28%) 2.0 (1.03.0) 99

PUGALENTHI, CUTTER, & FONG

Ueno et al [65], 2009 RES 123 67 (2885) 1 (89%); >1 (11%) 2.7  0.1 80 47 38 99 92 80
Japan RFA 155 66 (4079) 1 (65%); >1 (35%) 2.7  0.1 78 36 20 98 92 63
Santambrogio et al [66], 2009 RES 78 68 8 1 2.9  1.2 53
Italy RFA 74 68 7 1 2.7  1.1 41
Takayama et al [67], 2010 RES 1235 1 2 cm 91 98
Japan RFA 1315 1 2 cm 84 99
Peng et al [68], 2012 RES 74 51 (2475) 1 2 cm 75 56 51 91 71 62
China RFA 71 53 (2874) 1 2 cm 76 65 60 99 88 72
Abbreviations: DFS, disease-free survival; OS, overall survival.
 SMALL HEPATOCELLULAR CARCINOMA
Table 4
Randomized controlled trials of hepatic resection versus RF ablations for HCC reported after 2000
Tumor characteristics DFS (%) OS (%)
Author/year Rx N Age Number Diameter 1y 3y 4y 5y 1y 3y 4y 5y P
Chen et al [8], 2006 RES 90 49  11 1 5 cm 87 69 46 93 73 64 NS
RFA 71 52  11 1 5 cm 86 64 52 96 71 68
Liang et al [69], 2008a RES 44 49  12 3 5 cm 79 45 31 28 .8
RFA 66 55  11 3 5 cm 77 49 40 40
Huang et al [9], 2010 RES 115 56  13 3 5 cm (77%) 85 61 51 98 92 76 NS
RFA 115 57  14 3 5 cm (73%) 82 46 29 87 70 55
Feng et al [10], 2012 RES 84 47 (1876) 2 4 cm 91 61 96 75 .3
RFA 84 51 (2483) 2 4 cm 86 50 93 67
Abbreviations: DFS, disease-free survival; NS, not significant; OS, overall survival; Rx, treatment.
a
Treatments for recurrent disease.

107
108 PUGALENTHI, CUTTER, & FONG

93%, 73%, and 64% for resection and 96%, 71%, and 68% for RFA. The au-
thors concluded that RFA was as effective as surgical resection in treatment
of solitary HCC 5 cm or smaller in terms of overall and disease-free survival
after 4 years with no significant difference in outcome between the 2 groups
on follow-up. In this study, postrandomization exclusion from RFA occurred
in 19 of 90 patients (21%), when patients refused to undergo RFA and chose
resection instead.
Huang and colleagues [9] concluded that surgical resection to have better
outcomes than RFA. This conclusion was based on a recurrence rate at 5 years
of 63% in the RFA group and 41% in the resection group. However, it must be
pointed out that more patients in the resected group had tumors less than 3 cm
in size. In addition, the overall survival was not statistically different between
the 2 treatment groups.
Feng and colleagues [10] and Liang and colleagues [69] confirmed the similar
efficacy of RFA to resection in tumors less than 4 cm. Both groups found RFA
and resection to have similar overall survival in a follow-up period after 3 years.
They also mentioned that at certain sites percutaneous RFA may be inadequate
for complete treatment, and open or laparoscopic approaches may be the better
choice. In these studies, the independent predictors of recurrence were tumors
at multiple locations and preoperative indocyanine green (ICG) retention rates.
Results of the multicenter prospective randomized study of surgery versus
RFA for early HCC (SURF trial) are now underway in Japan, and the results
are eagerly awaited.

Resection and ablation

Resection and ablation are not mutually exclusive options in the treatment of
HCC. It is clear that each has an important role in treatment that may provide
long-term survival. Resection provides the greatest oncologic benefit when
treating larger tumors. Ablations including RFA provide benefit in treatment
of small HCC (23 cm), while minimizing morbidity of treatment. Beyond
this size, most patients will already have macroscopic vascular invasion or sat-
ellite nodules that will dictate high incidence of recurrence [70]. For tumors
smaller than 3 cm in size, RFA can achieve a 1-cm safety margin, which is
the standard for local excision [30]. Livraghi and colleagues [52] in 2008 re-
ported results of a prospective multicenter analysis of percutaneous RFA
with patients with solitary HCC 2 cm. The 5-year rate of survival was
68% in these patients, whose tumors were considered to be operable. An
increased risk of local recurrence was also reported by others to be associated
with large tumor size greater than 2 cm in the greatest dimension and a subcap-
sular location [71]. In the study by Zytoon and colleagues [72] in 2007, large
tumor size (larger than or equal to 2.3 cm) proved to be the highest risk ratio
for local recurrence (8.4036, P .0096). In the 2010 expert consensus state-
ment on HCC, Jarnagin and colleagues [73] concluded that the highest proba-
bility for complete local tumor control of HCC with RFA occurred in tumors
less than 2 cm in diameter. According to the Nationwide Follow-Up Survey of
SMALL HEPATOCELLULAR CARCINOMA 109

Fig. 3. Algorithm of care for small (<5 cm) HCC.

Primary Liver Cancer in Japan reported by the Liver Cancer Study Group of
Japan, there were no significant differences in the 5-year survival rate between
RFA and resected cases in all RFA-treated and hepatectomy-treated cases, with
(Child-Pugh A) patients with either single 2-cm or smaller HCC cases or single
2-cm to 5-cm HCC cases [74].
It is rational to conclude that RFA can be used as a first line of treatment in
operable patients for single HCC 2 cm or smaller (ie, very early stage HCC
according to BCLC criteria, stage 0) and can provide equivalent overall sur-
vival rate similar to resection. RFA at open surgery provides better tumor
killing and more durable effects. RFA by percutaneous method causes less post-
operative complications, less pain, and a shorter hospital stay and has the
added advantage of repeating ablation if residual tumor is suspected by imag-
ing on follow-up.
Algorithm for care
Fig. 3 shows a rational algorithm of care for small HCC. If the patient has poor
liver function (poor Childs B or Childs C) and cannot be medically optimized,
supportive care is the only reasonable option for treatment. Childs B patients
whose liver function improves with medical treatment can have tumors abla-
ted. For patients with good liver function, peripheral lesions tend to be re-
sected, because modest parenchyma will be lost and operations often can be
performed using minimally invasive techniques. Central lesions near large ves-
sels and bile ducts should also be resected because of the high likelihood of
treatment failure because of the heat sink effect and the morbidity of injuring
the central bile duct. Other deep small lesions should generally be treated by
tumor ablation, with resection reserved for localized tumor recurrences.
110 PUGALENTHI, CUTTER, & FONG

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