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11 Clinical Management of Pyogenic Liver Abscesses
139© Springer International Publishing Switzerland 2016
J.M. Millis, J.B. Matthews (eds.), Diffi cult Decisions in Hepatobiliary
and Pancreatic Surgery, Diffi cult Decisions in Surgery: An Evidence-Based
Approach, DOI 10.1007/978-3-319-27365-5_12
Chapter 12
Which Is Better Local Therapy for HCC,
RFA or TACE?
Thuong G. Van Ha
Abstract Loco-regional therapies such as radiofrequency ablation and transarterial
chemoembolization have been used in the treatment of hepatocellular carcinoma
not suitable for resection and have proven to increase survival. To improve outcomes, it is important to identify patient populations who can be appropriately
treated with these modalities.
Keywords Hepatocellular carcinoma (HCC) • Radiofrequency ablation (RFA) •
Transarterial chemoembolization (TACE)
Introduction
Worldwide, hepatocellular carcinoma (HCC) is the sixth most common cancer and
third leading cause of cancer-related deaths [ 1 ]. Historically, the rates of HCC have
been lower in the United States compared to other countries. However, the incidence in the US tripled between 1975 and 2005 [ 2 ]. Given current screening proto-
cols of patients with known cirrhosis , HCC is now increasingly recognized at an
early stage [ 3 ]. Still, most patients are diagnosed in late stages so that less than
one-third of the patients are candidates for surgical treatments such as resection or
liver transplantation [ 4 – 6 ]. For patients who do not qualify for resection or liver
transplantation, loco-regional therapies such as transcatheter arterial chemoembolization (TACE) and thermal ablation are accepted treatments that prolong survival
by eradicating or controlling tumor while preserving liver function [ 7 ]. Both tech-
niques have limitations in treating HCC, with incomplete necrosis of tumor and
subsequent tumor recurrence using TACE, and inadequate control of medium to
large size HCC for both TACE and ablative therapy.
T . G . Va n H a ( *)
Section of Cardiovascular Interventional Radiology, Department of Radiology ,
University of Chicago , MC 2026 5841 South Maryland Ave , Chicago , IL 60615 , USA
e-mail:
tgvanha@radiology.bsd.uchicago.edu
140
The Barcelona-Clinic Liver Cancer classifi cation groups patients into fi ve stages
and allocates treatment according to their status [ 8 – 10 ]. Briefl y, very early stage
refers to HCC with tumor <2 cm in diameter, and early stage refers to with single
tumor =/>2 cm or up to three satellite nodules, each </= to 3 cm. Intermediate HCC
refers to multinodular asymptomatic patients and advanced HCC with symptomatic
tumor, macrovascular tumoral involvement, or extrahepatic disease. Advanced
stage and terminal stage are the last two stages where surgery and loco-regional
therapy do not have a role.
Surgery when possible is the mainstay of therapy for HCC. Resection is considered fi rst line treatment option for patients with a single tumor and well preserved
liver function. For patient within Milan criteria or with mild portal hypertension not
suitable for liver transplant ation , resection can be performed though there is no
strong evidence for this strategy. Liver transplantation is considered fi rst line for
patients meeting Milan criteria who cannot undergo resection. Loco-regional therapy is considered if waiting list exceeds 6 months.
Local ablation is considered standard of care for patients with BCLC 0-A (very
early-early stages) with tumors not suitable for surgery . This advocacy is based on
studies showing good results with smaller tumors. Currently radiofrequency ablation ( RFA ) is considered the modality of choice due to evidence of better control
than percutaneous ethanol injection (PEI) [ 11 ]. Evidence with other modalities such
as microwave ablation (MWA) is lacking though their use is increasing [ 12 ]. RFA
can be performed by open surgery, through laparoscopic approach, or more commonly using the percutaneous approach under radiologic guidance. RFA works by
ionic agitation creating local rise in temperature and in the process causes cell death
through coagulative necrosis [ 13 ]. However, RFA has limitations, including size
threshold of the treated area and the “heat sink effect,” where tumor adjacent to
blood vessels is spared as the heat is carried away by the fl owing blood.
TACE has been recommended for patients with BCLC stage B (intermediate).
The use of TACE is recommended in part due to two radomized control trials (RCT)
that showed survival benefi t of TACE in unresectable HCC, though the numbers of
subjects were small and the chemotherapeutic agents used in each trial was different
[ 14 , 15 ]. TACE is a transarterial technique, usually through a common femoral arte-
rial approach, that delivers chemotherapeutic agent or agents through a catheter
placed in the hepatic artery feeder vessels to the tumor, followed by embolization
which blocks further fl ow to the tumor. The goal of this technique is to deliver a high
dose of chemotherapeutic agent to the tumor while sparing the rest of the liver
parenchyma (i.e., chemotherapy is injected directly into the tumor) and to decrease
washout of the agent (i.e., by embolization) thereby prolonging drug effect while
limiting systemic toxicity [ 13 ].
We seek to see whether there is any evidence comparing the use of ablative
therapy to TACE in patients who are in BCLC 0-A and BCLC B stages.
T.G. Van Ha
141
Search Strategy
A literature search of English language publications was performed in the time
period of 2000–2014. Publications were identifi ed on the subject of chemoembolization and radiofrequency ablation for hepatocellular carcinoma.
Terms used: Transarterial chemoembolization, TACE, chemoembolization, RFA ,
radiofrequency ablation, thermal ablation, AND hepatocellular carcinoma OR
HCC.
Databases used were PubMed and Embase.
Articles were excluded if they addressed surgical treatment of HCC or comparison between surgical resection TACE and/or RFA . In addition, studies involving
sorafenib or adjuvant and neoadjuvant chemotherapy were also excluded.
Results
No randomized control trials were identifi ed comparing RFA to TACE head to head.
There were three retrospective studies comparing RFA to TACE (Table 12.1 ).
Hsu et al. [ 16 ] retrospectively analyzed data that were prospectively collected in
an 8 year period, in two cohorts of patients who met the Milan criteria. Three hundred fi fteen patients underwent RFA and 215 received TACE. From each arm, 101
matched patients were selected to create a propensity score model. Long term survival signifi cantly favored the RFA group (P = 0.048). However, in the propensity
score model, there was no signifi cant difference in long term survival between the
two groups. The study also found that total tumor volume less than 11 cm 3 have
signifi cantly longer survival with RFA treatment (P = 0.032).
Kim et al. [ 17 ] reported a retrospective study of RFA versus TACE in the treat-
ment of single HCC smaller than 2 cm (BCLC very-early stage HCC). There were
165 patients treated initially with RFA and 122 patients who were initially treated
with TACE. There were no signifi cant differences in overall survival (P = 0.079).
However, there was a difference in response rates favoring the RFA group (100 %
vs. 95.9 %). In addition, the RFA group had a more favorable time to progression
(27 vs 18 months; P = 0.013).
Liu et al. [ 18 ] in a retrospective analysis of 424 patients undergoing RFA and 282
patients receiving TACE, all within Milan criteria, evaluated for overall survival .
Patients were stratifi ed by ECOG performance status (PS) into two cohorts, one
with ECOG PS 0 and the other with PS =/>1. Overall, the RFA patients had better
survival than the TACE patients with the 3 year survival of 71 % and 59 % respectively (P = 0.001). Of the initial patient population, 167 pairs of patients with PS of
0 and 68 pairs with PS of 1 or greater were entered into propensity score matching
analysis. For the PS 0 group, RFA had signifi cantly better survival then the TACE
group. However, in the analysis of the PS 1 or greater propensity matched patients,
there was no signifi cant difference in survival.
12 Which Is Better Local Therapy for HCC, RFA or TACE?
142
Table 12.1 Studies comparing RFA to TACE directly
Studies HCC size
RFA cohort
(Number of
patients)
TACE cohort
(Number of
patients) Overall survival (%) RFA/ TACE
Median TTP
(months)
RFA/ TACE
Tumor
regression %
RFA/ TACE
Hsu et al. [
16 ] Within Milan Criteria 315 215 3 years: 72/63 Not given Not given
5 years:
55/43 (p = 0.048)
Propensity Score
analysis
101 101 3 years: 60/55 Not given Not given
5 years: 41/36 (p = 0.476)
Kim et al. [
17 ] <=2 cm 165 122 3 years: 27/18 100/95.9
86.7/75.4
5 years: 74.5/63.1 (p = 0.079)
Liu et al. [
18 ] Within Milan Criteria 424 282 3 years:
71/59 (p = 0.001)
PS 0 319 197 77/63 (p = 0.006)
PS >=1 105 85 38/47 (p = 0.812)
PS ECOG Propensity score, TTP Time to progression
T.G. Van Ha
143
One additional study [ 19 ], though not a comparative analysis, evaluated patients
who were eligible for RFA but instead underwent TACE. The study retrospectively
analyzed 114 patients, who would have qualifi ed for RFA, with HCC, the largest
less than 5 cm in diameter up to three nodules who have undergone TACE as initial
treatment. Many of these patients were treated when RFA was not readily available.
The 1-, 3-, 5-year survival rates were 80 %, 43 %, and 23 % respectively, which the
authors concluded as being comparable to historical rates of survival for RFA
treated patients.
Recommendations
RFA has been shown to be effective in the treatment of HCC with tumor size </=
3 cm with good complete response rate of 90 %. As tumor size increases, there is a
decrease in the response rate to RFA. Though complete ablation can be achieved
with medium size tumors, from 3 to 5 cm, tumors larger than 5 cm have poor
response rate [ 13 ]. RFA is also not recommended in central locations where risk of
bile duct or vascular injury is high. Tumors abutting large vessel can be less effective as the fl ow of blood can carry the heat away and therefore offer protection to the
adjacent tumor margin [ 20 ]. Additionally, peripheral lesions adjacent to other
organs such as bowel or pericardium, should not undergo ablation if protective measures such as hydro-dissection or CO 2 insuffl ation cannot be adequately provided
[ 21 , 22 ]. TACE, on the other hand, received validation through two RCT and numer-
ous meta-analysis as having a survival benefi t in the treatment of unresectable HCC
[ 14 , 15 , 23 ].
The EASL-EORTC Clinical Practice Guidelines
The EASL-EORTC clinical practice guidelines recommend that the BCLC staging
system, as described above be used for prognostic prediction and treatment allocation [ 7 ]. Surgical treatments include hepatic resection and liver transplantation .
Resection is considered fi rst line treatment for patients with solitary tumors and
very well preserved function, defi ned as normal bilirubin level and either hepatic
venous pressure gradient </= 10 mmHg or platelet count >/= 100,000 plt/mcL. For
patients with multifocal tumors, within the Milan criteria but not suitable for transplantation, resection could be performed, but no defi nitive recommendation can be
made at this point due to lack of prospective comparison with loco-regional therapies. Liver transplantation is considered fi rst line treatment option for patients
within Milan criteria but not candidates for surgical resection. Loco-regional treatments can be considered if the waiting list exceeds 6 months, even though long term
outcomes are uncertain due to level of available evidence.
12 Which Is Better Local Therapy for HCC, RFA or TACE?
144
According to the guidelines, local ablation is considered fi rst line treatment
option for patients with early stage HCC who are not candidates for surgical resection . Percutaneous ethanol injection has been shown to be inferior to RFA in lesions
larger than 2 cm and is associated with high recurrence rate in lesions larger than
3 cm. Therefore, RFA is preferred over PEI as an ablative technique [ 24 ], but PEI
can be employed where use of RFA is not possible. Other ablative therapies including microwave ablation and cryoablation are being used but strong evidence is currently lacking. Though there are studies comparing RFA and surgical resection of
small solitary HCC, the results are mixed and ablation could not be recommended
as alternative therapy to hepatic resection . TACE is recommended as fi rst line treatment for intermediate stage HCC, more specifi cally, those with multinodular HCC
but without cancer related symptoms, vascular invasion, or extrahepatic spread.
Although there is a lack of defi nitive evidence, chemotherapeutic agents recommended are doxorubicin and cisplatin and that TACE can be repeated 3–4 times per
year. To minimize affecting non-tumoral hepatic tissue in an attempt to preserve
liver function, it is also recommended that superselective chemoembolization, i.e.
treatment limited to tumoral feeder vessels and sparing vessels to normal liver, be
used.
Other Recommendations
Similar to EASL recommendations, CEPO, an oncologist group of specialists who
provide evidence based guidelines for clinicians in the province of Quebec, Canada,
recommends that TACE be considered standard of practice for palliative treatment
of HCC in eligible patients [ 25 ]. CEPO also states that DEB-TACE be considered
an alternative and equivalent treatment to TACE. Bland embolization and radioembolization are not considered standard treatments for HCC currently by either group.
Sorafenib, an oral agent, inhibitor of multi-tyrosine kinase, is the only systemic
drug that has shown survival benefi t [ 26 ] and it is recommended for patients with
well-preserved liver function (Child-Pugh A) and with advanced HCC, or tumors
progressing on loco-regional therapies. No recommendation can be made with
sorafenib in Child-Pugh B patients at this point.
Outside these recommendations, there are a few RCT favoring the use of
TACE/ RFA combination therapy over RFA alone. In a meta-analysis [ 27 ] consisting
of 7 RCTs that included 571 patients who were treated with TACE and RFA or RFA
alone, found that there was a signifi cant differences in the 1- and 3-year survival
rates favoring the combination group. Recurrence free survival at 1 and 3-year also
favors the combination group.
In a more recent publication, a meta-analysis consisting of 12 studies and 1952
patients comparing clinical outcome of small HCC among the various treatment,
divided the study group into two different cohorts [ 28 ]. One arm consisted of
patients receiving surgical resection and the other arm patients undergoing nonsurgical loco-regional treatment or treatments including RFA , PEI, TACE, and
T.G. Van Ha
145
TACE plus RFA combination. The results showed that there were no signifi cant
survival advantage at 1 and 3 year, but the 5 year survival rate favored the surgical
resection group. However, no signifi cant difference was noted in the 1 or 5 year
progression free survival. In addition, there was a signifi cant decrease in the incidence of adverse events in the surgical resection group and the local recurrence rate
was signifi cantly higher in the non-surgical group. The authors acknowledged that
the number of trials of non-surgical ablation to be insuffi cient and that the number
of cases undergoing PEI and TACE were also insuffi cient to compare the nonsurgical modalities to each other. This publication illustrates the lack of suffi cient
evidence to suggest one non-surgical technique over another in the treatment of
small HCC.
As seen above, there are only a few head to head studies of RFA vs. TACE and
no RCT. However, due to available evidence, there are recommendations that for
tumors that are non- resectable , RFA should be performed if the tumors are in early
stages or smaller than 3 cm, and for intermediate tumors, TACE should be used as
palliative treatment. From the few studies directly comparing the two treatment
techniques above, it appears that for the patients within Milan criteria, there is survival advantage for patients undergoing RFA over TACE. However in one study this
advantage is no longer seen in the propensity score model and is seen in only in the
ECOG PS 0 group and not the PS 1 or greater group. For the study involving tumors
less than 2 cm, there was no difference in overall survival though there was a difference in tumor response rate. However, in this study the results were not straightforward as there was signifi cant crossover in terms of subsequent treatments [ 18 ].
What these studies suggest is that RFA is superior in survival advantage for
patients with good performance status. Additionally, RFA appears to be more effective in terms of tumor response rate in early HCC and total tumor volume of less
than 11 cm 3 . TACE, though recommended as palliative therapy, should be considered in patients with tumors who might not qualify for RFA otherwise, due to contraindications, such as central tumors close to large bile duct s, or tumors adjacent to
other organs [ 16 – 18 ].
Another treatment gaining acceptance in the treatment of HCC is combination
therapy, TACE followed by RFA . This therapy makes use of the synergistic effect of
TACE, which blocks blood fl ow the tumor and can extend the ablated area when
followed by RFA soon after, among other potential effects.
A Personal View of the Data
For small tumors, RFA appears to be effective in achieving complete response.
However, for tumors approaching 5 cm, the response rate and survival rate advantage diminish. With tumors 5 cm or larger, RFA results are rather poor and therefore
TACE should really be used for palliation. When tumors qualify for possible RFA
but due to contraindication to thermal ablation, TACE is a reasonable alternative.
Combination of TACE followed by RFA appears to increase the effectiveness of
12 Which Is Better Local Therapy for HCC, RFA or TACE?
146
RFA over RFA alone and this treatment might very well be recommended in the
future for intermediate size HCC if RCT can substantiate the preliminary results.
Recommendations
Loco-regional therapy is for patients who are not eligible for surgical resection and
who are on transplant list with wait time longer than 6 months.
For patients with very early and no contraindication to RFA ,
• RFA should be fi rst line treatment.
• If RFA not possible, consider TACE as a reasonable alternative.
For patients with early HCC (within Milan)
• RFA if possible.
• Consider TACE/ RFA combination if largest lesion approaching 5 cm to increase
tumor response rate.
• TACE if RFA not possible.
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12 Which Is Better Local Therapy for HCC, RFA or TACE?