Improving the Safety and Efficacy of Bimodal Electric Tissue Ablation

Improving the Safety and Efficacy of
Bimodal Electric Tissue Ablation
Thesis submitted to The University of Adelaide for the degree of
Master of Surgery
By
Leong Ung TIONG, MB.BS. (Adelaide)
Discipline of Surgery
School of Medicine
The University of Adelaide
Supervisors:
Professor Guy J. Maddern, PhD, FRACS (Principle Supervisor)
Professor Peter Hewett, MBBS, FRACS (Co-Supervisor)
1
Table of Contents
Page Number
Title
1
Table of Contents
2
Thesis Abstract
6
Statement of Declaration
8
Acknowledgements
9
Abbreviations
11
1. Introduction
13
2. Radiofrequency Ablation
15
2.1. History of Radiofrequency Ablation
15
2.2. Principles and Mechanisms of Action
15
2.3. Biological Effects of Hyperthermic Therapy
16
2.4. Radiofrequency Ablation Generators
17
2.5. Radio-Imaging in Radiofrequency Ablation
18
2.5.1. Pre-Ablation Imaging
18
2.5.2. Intra-Ablation Imaging
18
2.5.3. Post-Ablation Imaging
19
2.5.3.1.
U
Ultrasonography
2.5.3.2.
C
Computed Tomography
2.5.3.3.
Magnetic Resonance Imaging
2
M
19
20
20
2.5.3.4.
Positron Emission Tomography
2.6. Complications After Radiofrequency Ablation
P
21
21
2.6.1. Haemorrhagic Complications
21
2.6.2. Abdominal Infections
22
2.6.3. Biliary Tract Injury
23
2.6.4. Hepatic Vascular Injury
24
2.6.5. Liver Failure
25
2.6.6. Visceral Organ Injury
25
2.6.7. Skin Burns
27
2.6.8. Tumour Seeding
27
2.6.9. Miscellaneous
28
2.7. A Systematic Review of Survival and Disease Recurrence after
Radiofrequency Ablation for Hepatocellular Carcinoma
2.8. A Systematic Review of Survival and Disease Recurrence after
Radiofrequency Ablation for Hepatic Metastases
3. Electrolysis and Electrochemical Therapy
3.1. Animal Experiments
29
50
66
67
3.1.1. Tissue Temperature
67
3.1.2. 3 Water Content
67
3.1.3. 3 Elemental Concentrations
68
3.1.4. 3 Tissue pH
68
3.1.5. 3 Gas Productions
68
3.1.6. 3 Cellular Histological Changes
68
3
3.1.7. 3 Volume of Tissue Ablation
69
3.1.8. 3 Safety
69
3.2. Human Studies
70
3.3. Modifications and Innovations
70
3.4. Problems in Electrochemical Therapy
71
4. Bimodal Electric Tissue Ablation
4.1. Early Experimental Results
5. Rational for Current Research
5.1. Experiment 1: Does Bimodal Electric Tissue Ablation really work by
increasing tissue hydration?
5.2. Experiment 2: Where is the optimum place to put the anode in Bimodal
Electric Tissue Ablation?
5.3. Experiment 3: Can Bimodal Electric Tissue Ablation be incorporated into
the Cool-Tip RF System?
Experiment 1: Bimodal Electric Tissue Ablation – Effect of Reversing the
Polarity of the Direct Current on the Size of Ablation.
Experiment 2: Bimodal Electric Tissue Ablation – Ablation Size when the
Anode is Placed on the Peritoneum and the Liver.
Experiment 3: BETA compared to standard Radiofrequency Ablation using
the Cool-Tip RF System (Covidien, ValleyLab).
72
72
76
76
77
77
79
94
110
6. Area for Future Research
128
7. Conclusions
129
Appendix 1
131
Appendix 2
133
Appendix 3
135
4
Appendix 4
136
Appendix 5
137
Appendix 6
142
Appendix 7
146
Appendix 8
147
Appendix 9
149
Appendix 10
153
Appendix 11
158
Appendix 12
159
References
160
5
Thesis Abstract
Introduction:
Bimodal electric tissue ablation (BETA) is a new method of ablation, which combines the
process of electrolysis with radiofrequency ablation (RFA) to increase the size of tissue
ablations. The cathode of the electrolytic circuit is connected to the radiofrequency (RF)
electrode to increase the surrounding tissue hydration. This allows the RFA process to
continue for a longer period of time and therefore produce larger ablations. Previous research
has shown that BETA could produce larger ablations compared to standard RFA and that it
did not produce any significant short or long-term complications. The studies described here
aim to increase the knowledge on how BETA works to facilitate its translation into clinical
practice to treat liver tumours.
Materials & Methods
The first study tested whether BETA really acts by increasing the hydration of tissues around
the RF electrode. This was achieved by reversing the polarity of the electrolytic circuit, which
theoretically would produce smaller ablations compared to standard RFA. The second study
assessed where would be the best location (skin, parietal peritoneum or liver) for the anode of
the electrolytic circuit during a BETA process. The third experiment determined whether the
principle of BETA could be incorporated into the Cool-Tip RF system, which uses internallycooled electrodes (ICEs).
Results
The duration of ablation when the polarity of the electrolytic circuit was reversed (called
reversed polarity bimodal electric ablation, or RP-BEA) were significantly shorter compared
to standard RFA and BETA (48s vs. 148s and 84s respectively, p=0.004). Consequently the
size of ablations in RP-BEA was significantly smaller compared to RFA and BETA (9.1mm
vs. 13.4mm and 11.6mm, p=0.001). The second experiment showed that the size of ablations
were significantly larger when the anode of the electrolytic circuit was placed on the
peritoneum or the liver, compared to when it was placed on the skin (19.7mm and 17.9mm
6
vs. 12.4mm, p<0.001). Lastly, the third experiment showed that the principle of BETA could
be incorporated into the Cool-Tip RF system to produce significantly larger ablations
compared to standard RFA alone (23.1mm vs. 20.1mm, p<0.001).
Discussion
The results from this study confirmed the theory that BETA increases ablation size due to the
effects of increased tissue hydration around the RF electrode. The increased hydration delays
tissue desiccation during an ablation, thus allowing the process to continue for longer periods
of time, therefore producing larger ablations. The efficacy of BETA depends on good
electrical conductivity between the cathode and the anode of the DC circuit. Results from the
second study showed that BETA works best when the anode of the electrolytic circuit was
placed deep to the skin as the stratum corneum consisted of a layer of anucleated cells which
have high electrical resistivity. Lastly, BETA could be incorporated into the Cool-Tip RF
system (Covidien, ValleyLab), which is one of the popular RFA generators in the market.
This means that BETA could be readily incorporated into existing RF generators, therefore
facilitating its translation into the clinical settings.
7
Statement of Declaration
This work contains no material which has been accepted for the award of any other degree or
diploma in any University or other tertiary institution to Dr. Leong Ung TIONG and, to the
best of my knowledge and belief, contains no material previously published or written by
another person, except where due reference has been made in the text. I give consent to this
copy of my thesis when deposited in the University Library, being made available for loan
and photocopying, subject to the provisions of the Copyright Act 1968. The author
acknowledges that copyright of published works contained within this thesis (as listed below)
resides with the copyright holder(s) of those works. I also give permission for the digital
version of my thesis to be made available on the web, via the University’s digital research
repository, the Library catalogue, the Australasian Digital Theses Program (ADTP) and also
through web search engines, unless permission has been granted by the University to restrict
access for a period of time.
1. Tiong LU, Finnie JW, Field JBF, Maddern GJ. Bimodal Electric Tissue Ablation
(BETA) – Effect of Reversing the Polarity of the Direct Current on the Size of
Ablation (published online in the Journal of Surgical Research - 08 February 2011
(10.1016/j.jss.2011.01.013))
2. Tiong LU, Finnie JW, Field JBF, Maddern GJ. Bimodal Electric Tissue Ablation
(BETA): A study on Ablation Size when the Anode is placed on the Peritoneum and
the Liver (published online in the Journal of Surgical Research - 28 February 2011
(10.1016/j.jss.2011.01.061))
3. Tiong LU, Maddern GJ. A Systematic Review of Survival and Disease Recurrence
after Radiofrequency Ablation for Hepatocellular Carcinoma (published in the British
Journal of Surgery, September 2011; Vol 98 (9): 1210-1224)
4. Tiong LU, Field JBF, Maddern GJ. Bimodal Electric Tissue Ablation (BETA)
compared to the Cool-Tip RFA System. (accepted for publication by the Australian and New
Zealand Journal of Surgery)
Leong Ung TIONG
8
(6/10/2011)
Acknowledgements
I am thankful for the scholarships provided by the University of Adelaide (Australian
Postgraduate Award) and the Royal Australasian College of Surgeons (WG Norman
Research Fellowship) to make this research possible.
I am also most grateful to the following individuals who have provided invaluable assistance
to me during the course of my research. My work would never have been completed without
their contribution, and therefore my sincerest thanks to them.
First and foremost I would like to thank my supervisors Professor Guy Maddern and
Professor Peter Hewett who have been most supportive and encouraging during the course of
my research. Their constant mentorship ensured I stayed on track while allowing me a great
degree of independence to carry out my research work.
Dr. Martin Bruening for his support enabling me to work part-time at the Department of
Surgery (The Queen Elizabeth Hospital) to keep in touch with clinical practice.
Dr. Christopher Dobbins, who is a friend and a colleague, has been a valuable source of
information from the start of the project to the end. He was generous with advice and
suggestions to help me overcome the various obstacles common in surgical research. He
shared various tips on how to survive the transition from clinical practice into the world of
surgical research, which made it a less daunting experience for me.
The research staff at the Department of Surgery at The Queen Elizabeth Hospital: Ms.
Brooke Sivendra, Ms. Lisa Leopardi, Ms. Sheona Page and Ms. Sandra Ireland who have all
been invaluable to me as the ‘go to people’ whenever I had any administrative issues
concerning my research. Their kind assistance with the complex process of animal research
ethics applications was most appreciated.
9
Mr. Matthew Smith and the staff at the animal research laboratory (The Queen Elizabeth
Hospital) were also very accommodating and helpful with my research work especially with
anaesthetizing the research animals and providing post-operative care to them.
Dr. John Field from the Faculty of Health Sciences (University of Adelaide) provided vital
statistical support for this research project. Dr. John Finnie from the Institute of Medical and
Veterinary Services (IMVS) Adelaide provided histopathological support for this research.
Both provided their time and assistance willingly and freely, for which I am grateful.
Many thanks to Dr. Christopher Lauder who kindly taught me the various surgical procedures
and research techniques involving the research animals, and to Dr. Andy Strickland for
‘brain-storming’ with me.
Last but not least my utmost appreciation to my family for the support and encouragement
that kept me going through this research project.
Dr. Leong Ung TIONG
10
Abbreviations:
AC – alternating current
AFP – alpha-fetoprotein
ASA - American Society of Anaesthesiologists
BETA – bimodal electric tissue ablation
CLM – colorectal liver metastasis
CT – computed tomography
DC – direct current
ECT – electrochemical therapy
FDG – Fludeoxyglucose
HAI – hepatic artery infusion
HCC – hepatocellular carcinoma
HIFU – high intensity focused ultrasound
ICE – internally cooled electrode
IVC – inferior vena cava
LITT – laser interstitial thermal therapy
MCT – microwave coagulation therapy
MRI – magnetic resonance imaging
PAI – percutaneous acetic acid injection
11
PE – perfused electrode
PEI – percutaneous ethanol injection
PET – positron emission tomography
RCT – randomized controlled trials
RF – radiofrequency
RFA – radiofrequency ablation
RNA – ribonucleic acid
RP-BEA – reversed polarity bimodal electric ablation
TACE – trans-arterial chemo-embolization
US - ultrasonography
12
1. Introduction
Radiofrequency ablation (RFA) is currently one of the most popular thermal ablative
therapies for un-resectable liver cancers[1]. It uses alternating electric current (AC) at high
frequencies (200-1200 kHz) to generate thermal energy which causes coagulative necrosis of
the targeted tissues[1]. Besides liver cancers, RFA has also been used successfully to treat
other solid organ tumours including those of the lungs, kidneys, adrenals and the skeleton[2].
Electrochemical therapy (ECT) is another ablative therapy used around the world to treat
various malignancies. It uses a low energy direct electric current (DC) to drive an electrolytic
process at its two electrodes, the anode and the cathode, to produce various cytotoxic
chemicals which cause cellular necrosis[3, 4].
Both RFA and ECT have the advantage of being minimally invasive, with low risks of
morbidity or mortality[3-7]. However the efficacy of RFA, defined as the ability to
completely ablate a tumour, is limited by the small ablation size achievable. This leads to
higher local disease recurrence and lower survival rates compared to surgical resection[8].
ECT on the other hand, has the disadvantage of requiring a long period of time, up to several
hours to administer[9], which may not be practical in the current busy hospital practice.
Therefore, clinical outcomes after RFA and ECT for hepatic malignancies are still inferior
compared to curative surgery[3, 4, 10].
Recently a group of researchers have introduced a new local ablative therapy combining RFA
and ECT, which is called bimodal electric tissue ablation (BETA)[11-14]. BETA uses the
hydration effect produced at the cathode during ECT to enhance the efficacy of thermal
ablations produced by radio-frequency (RF) generators. Their research showed that BETA
was able to produce larger ablations compared to standard RFA[11, 14].
As BETA is a relatively new innovation, there were several questions that needed to be dealt
with before this technology could be introduced into the clinical setting. Firstly it had not
13
been proven that the capability of BETA to produce larger ablations was indeed due to the
increased tissue hydration secondary to the electrochemical reactions of the DC. Secondly,
there was the question of where would be the best placement of the anode, which in previous
research had been shown to cause local tissue injury. Lastly, it was not known whether the
principle of BETA could be incorporated into other types of RF generators in the market
besides the RF 3000 generator (Boston Scientific) used in previous studies.
This research consists of a series of animal experiments performed to answer the above
questions. A literature review on RFA and ECT was conducted, followed by a more detailed
discussion on BETA including its experimental results to date. Lastly the experimental
procedures were described and the results discussed followed by a concluding summary on
this new and promising technique of bimodal electric tissue ablation.
14
2. Radiofrequency Ablation (RFA)
2.1. History of RFA
The pioneering work on RFA was reported by the French scientist d’Arsonval in 1891[15].
d’Arsonval discovered that AC with frequencies over 250 kHz was able to produce heat in
living tissues without causing neuromuscular excitation. This led to the invention of
electrocautery and medical diathermy in the early 1900s[16-18]. Clark reported the use of
RFA to treat breast and skin cancers in 1911[17] and a decade later Cushing and Bovie
developed the “Bovie knife” to treat brain tumours[19]. In 1976 Organ reported the
interactions between AC and biological tissues[20]. He showed that AC at low power causes
ionic agitations in adjacent tissues, which subsequently produced heat by friction. Since then
RFA has been used for a multitude of conditions including cardiac arrhythmias and malignant
tumours in various parts of the body. McGahan et al and Rossi et al, from the United States
and Italy respectively, were two groups of researchers who first reported the use of RFA to
treat liver tumours in 1990[21, 22].
2.2. Principles and Mechanisms of Action
RFA refers to the use of AC that oscillates at high frequencies (300-500 kHz) to destroy
biological tissues[1, 23, 24]. In principle a closed-loop circuit is created by placing a
generator, a dispersive or grounding pad, a patient and a needle electrode in series. The
grounding pad is usually placed on the patient’s thigh, while the needle electrode is inserted
into the centre of the lesion to be ablated. When the RF generator is activated, an alternating
electrical field is generated within the patient between the grounding pad and the needle
electrode. The grounding pad must be sufficiently larger than the needle electrode, thus
ensuring that the electrical current is concentrated around the needle electrode. As biological
tissues have higher electrical resistance than the metal electrodes, the electrical currents will
cause ionic agitation within the cells adjacent to the needle electrode as they attempt to
follow the changes in directions of the alternating current. The ionic agitation will produce
frictional heat that subsequently destroys the tissue if the temperature rises to an adequate
level.
15
2.3. Biological Effects of Hyperthermic Therapy
The mechanism of tissue destruction in RFA is due to thermal coagulative necrosis. Tissue
temperature during RFA can increase up to 100°C. The volume of tissue destruction by
coagulative necrosis in RFA is governed by the temperature[25]. A model to describe the
distribution of heat in biological tissue known as the “Bioheat Equation” was described by
Pennes[26] in 1948, and subsequently simplified by Goldberg[27] to:
Coagulation necrosis = energy deposited x local tissue interactions - heat lost
Cellular homeostasis can maintain normal function at temperatures up to 40°C. At higher
temperatures (42-45°C), cells become more susceptible to injury e.g. chemotherapy or
radiotherapy[28]. However, even when exposed to these temperatures for prolonged periods
of time, viable cells could still be observed[28]. Irreversible cellular damage occurred when
cells were exposed to a temperature of 46°C for 60 minutes[29]. Exposure to temperatures
beyond 50-52°C will shorten the time required to cause lethal cell injury exponentially[30].
As temperatures reach 60-100°C, coagulation of protein and cellular death is near
instantaneous[27, 31, 32]. Temperatures greater than 100°C causes intra- and extra-cellular
water to boil, vaporize and the surrounding tissue to carbonize. The resultant gas and charred
tissues act as electrical insulators preventing further heat deposition. Hence the optimal target
temperature to achieve and maintain is between 50-100°C[33, 34].
Besides protein coagulation, thermal energy also produces vascular changes characterized by
microvascular cell swelling and disruption, intravascular thrombosis, and neutrophil
adherence to venular endothelium. A few experimental RFA studies also demonstrated
secondary anticancer immunity due to activation of tumour-specific T-lymphocytes[35].
These secondary effects may explain the ongoing tissue necrosis after cessation of RFA.
16
2.4. RFA Generators
There are a variety of different RFA generators available commercially, each with slightly
different configurations. Two of the more popular RF generators, which were used in this
research project, were the Cool-Tip RF System (Covidien, formerly ValleyLab) and the RF
3000 system (Boston Scientific). Each machine has its own ablation algorithm, monitoring
systems and needle electrodes.
1. Cool-Tip RF System (Covidien) – This generator is capable of producing 200 watts of
energy at 480 kHz. It uses internally cooled electrodes (ICEs), which come in the
straight single needle applicator or cluster systems (3 single electrodes spaced 5mm
apart and grouped equidistantly in a triangle). A peristaltic pump is used to circulate
chilled saline throughout the needle electrode. This reduces the tissue temperature
immediately adjacent to the electrode to prevent premature charring/desiccation. Each
ablation is started with baseline tissue impedance measurement and internal cooling
of the needle electrode for 1 minute before RFA[36], followed by maximal power
ablation. The generator continuously monitors tissue impedance and temperature
during an ablation process. When tissue impedance rises more than 10 Ohms (Ω)
above baseline, the ablation process is automatically paused for 15 seconds before the
generator delivers anymore energy[36]. The generator shuts itself automatically after
12-15 minutes[37]. The intermittent pauses when tissue impedance increases allows
gases adjacent to the electrode to dissipate while the internal cooling with saline
minimizes tissue charring, hence improving the delivery of energy to surrounding
tissues.
2. RF 3000 System (Boston Scientific) – This generator is also capable of producing up
to 200 watts of energy at 480 kHz. It uses expandable needles with an umbrella
configuration. The expandable needles increase the surface area of the electrode in
contact with the liver tissues, thus increasing the size of ablations. This machine
requires the operator to set the power output manually in a stepwise incremental
manner to avoid early tissue boiling and charring[37]. Power output is stopped
automatically when “roll-off” occurs, defined as when tissue impedance rises
significantly and prevent further conduction of electricity. After a brief pause, a
second cycle of RFA is started at a lower power setting. The whole ablative process
finishes when the second roll-off occurs. The expandable electrode system can
achieve ablation sizes between 3-5cm[24].
17
2.5. Radio-Imaging in RFA
Radio-imaging plays a critical role in the field of local tumour ablation throughout the whole
treatment process. In the pre-operative setting, radio-imaging is used to estimate the size of
the lesion and the anatomical location. Intra-operatively, it is used to guide electrode
placement and real-time monitoring of the ablative process. Finally, it is used to assess the
efficacy of tumour ablation post-procedure to ensure that the entire tumour is destroyed.
2.5.1. Pre-ablation Imaging
Various imaging modalities (ultrasonography (US), computed tomography (CT) and
magnetic resonance imaging (MRI)) can be used in the pre-operative setting based on
availability, operators’ preference and experience, and the individual characteristics of the
patients and lesions. However almost all patients these days will receive contrast-enhanced
CT or MRI scans to allow accurate tumour localization and volume calculations. Contrast
enhanced scans are also useful for comparison with the post-operative scans to detect residual
un-ablated tumour tissue.
2.5.2. Intra-ablation Imaging
Ultrasonography (US) is one of the most popular modalities used because it is inexpensive,
easy to use and safe. US has a major role in guiding the placement of the electrodes
regardless of whether RFA is conducted percutaneously, laparascopically or intraoperatively. However real-time monitoring of the ablative process using conventional Bmode US is unreliable as it can potentially under- or over-estimates the completeness of
tumour ablation. This is because the hyperechoic focus observed around the distal electrode
tip is a result of gas micro-bubbles from the vaporization of intracellular water in the heated
liver tissue, instead of the coagulated tissue per se[38]. Boehm et al reported that any fatty
tissue surrounding a tumour quickly becomes hyper-echogenic during RFA which makes
visual monitoring of the actual tumour during ablation impossible[39].
18
2.5.3. Post-ablation Imaging
Repeat scans should be performed soon after RFA (between 1-4 weeks), to detect any
residual tumour so that re-treatment can be planned, and then at regular intervals afterwards
(every 3-6 months) to detect any progressive or new tumours[40]. The general consensus on
the imaging feature that suggests complete tumour ablation is the disappearance of previously
seen vascular enhancement on contrast enhanced imaging[41]. However, radio-pathologic
correlation study have shown that contrast-enhanced CT/MRI is accurate to only within 2-3
mm[27]. These techniques are limited by their spatial resolution in detecting small foci of
peripheral tumour which are potential sources of tumour recurrence[24]. Therefore, all RFA
should include a 1 cm ablative margin of normal tissues to ensure complete eradication of
malignant tumour[24].
2.5.3.1.
Ultrasonography
Conventional US is reported to be unreliable in assessing therapeutic efficacy of RFA, and is
difficult to use for assessing tumours in the hepatic dome. Raman et al[42] studied the radiopathologic correlation of US in RFA, and found that early US is poorly correlated with and
tends to under-estimate the true size of the ablated lesion. RFA produces an echogenic cloud
on US that quickly dissipates when the procedure is terminated, leaving a predominantly
hypoechoic lesion with a smaller central echogenic nidus[27]. New technology such as colour
and power Doppler US have improved their efficacy, but it is still an inadequate
discriminator of ablated versus viable tissues [27]. Micro-bubble US contrast agents have
been used to differentiate between perfused and non-perfused tissue and allow more an
accurate detection of residual tumour after RFA in both hepatocellular carcinomas (HCC) and
liver metastases[43]. Recent research has seen the development of contrast-enhanced
wideband harmonic gray-scale sonography – which further improved the colour and power of
Doppler US by cancelling signals from stationary tissues to show only signals generated by
microbubble contrast agents[44]. This has enabled the examination of tumour perfusion flow
and significantly increased the accuracy of US in the detection and characterization of liver
lesions[45]. Meloni et al reported a study which found contrast-enhanced pulse inversion
harmonic sonography more sensitive than contrast-enhanced power Doppler sonography in
the detection of residual tumour (83.3% vs. 33.3%, p<0.05)[46]. In a study comparing
contrast-enhanced gray scale harmonic US and contrast enhanced CT performed within 1
19
month after RFA for HCC, Choi et al reported equal efficacy between the two modalities
[47]. However, contrast enhanced axial imaging (CT or MRI) is still considered the most
sensitive modality, and hence the gold standard, in assessing RFA efficacy for patients with
HCC [46].
2.5.3.2.
Computed tomography
Multi-phasic helical CT has been shown to accurately differentiate between ablated and
viable residual tumour[41]. Cha et al[38] compared CT vs. US, and reported that unenhanced CT had the best correlation to pathologic size (r = 0.74), followed by contrastenhanced CT (r= 0.72) and sonography (r= 0.56). Contrast enhanced CT performed best in
characterizing the shape of the lesion, but tends to over-estimate the ablated zone because of
the ischaemic areas peripheral to the ablated lesion. Ablated tissues appeared as
homogenously hypo-attenuating area having well defined borders. In early scans taken soon
after RFA, the volume or size of the ablation should be equal to the pre-procedure scans, or
ideally larger to achieve the 1 cm ablative margin. These early scans may also show a rim of
hyper-attenuation around the ablated lesion during the arterial phase which corresponds to an
inflammatory reaction to the thermal damage seen at histopathologic examination[48]. This
hyperaemic rim, which gradually dissipates with time, may limit the detection of residual
tumour tissue in the periphery.
2.5.3.3.
Magnetic Resonance Imaging
Un-enhanced T1- and T2-weighted MRI after RFA produces heterogeneous signal intensity
within the ablated lesion[27]. This variability in signal intensity throughout the ablated region
is most likely caused by an uneven evolution of the necrotic area and the host response to
thermal damage ablated tissues appearing as areas with low signal intensity on T2-weighted
spin-echo images. Therefore contrast-enhanced MRI is recommended to assess therapeutic
efficacy of RFA. Viable tumour cells produce moderately hyper-intense signals on T2weighted images associated with corresponding enhancement on contrast-enhanced T1weighted images[49]. Coagulation necrosis appears as a markedly hypo-intense area with loss
of gadolinium enhancement on dynamic post-contrast scans[50]. Any viable residual tumours
show the typical and similar signal intensity and enhancement compared to the pre-RFA
scans. Similar to CT scans, the rim of enhancement surrounding the ablated tumour
corresponding to inflammatory reactions can be observed. However in contrast to CT, this
enhancement may persist up to several months after ablation. A new technology currently in
20
evaluation is the use of “heat-sensitive” sequences to monitor the ablation procedure in realtime[51].
2.5.3.4.
Positron Emission Tomography
Functional imaging with FDG radionuclide scanning has been gaining popularity. The avid
uptake of fluorine-18-labelled deoxyglucose (18F-FDG) by tumour tissue has been used to
accurately detect residual disease by positron emission tomography (PET)[52]. A concern
with PET scans is the possibility of false-positive results as the inflammatory cells and tissues
after RFA can display signals similar to tumour tissues. However, a study by Khandani et
al[53] showed that an early PET scan (within 48 hours of RFA) infrequently showed
inflammatory uptake. They concluded that early PET after RFA might be useful by indicating
macroscopic tumour-free margin as total photopenia and macroscopic residual tumour as
focal uptake. Donckier et al[54] reported PET to be more accurate in detecting residual
tumour tissue compared to contrast-enhanced helical CT.
2.6. Complications after RFA
RFA has been shown to be a safe procedure in various studies published in the literature. Its
morbidity (2.2-10.6%) and mortality rates (0.3-1.4%) are much lower compared to surgical
resection[5, 6], therefore making RFA a very useful option for patients who have multiple comorbidities or at high surgical risks[6]. Obviously the risks are much greater if RFA is used
during or in combination with surgical resection. The overall mortality and morbidity rates
have been reported to be 7.5% and 50-60% respectively[6]. As RFA becomes increasingly
popular, several large series have been published reporting the complications encountered
after RFA of hepatic tumours[5, 6, 55, 56].
2.6.1. Haemorrhagic Complications
Bleeding is one of the most common complications following radio-frequency treatment of
liver tumours. The mechanisms involved include coagulopathy as a result of underlying
hepatic impairment such as cirrhosis[57], mechanical trauma from the needle electrode
during placement, and thermal injury to adjacent hepatic vessels.
21
Mulier et al[57] reported a total of 60 out of 3670 (1.6%) cases of abdominal bleeding, of
which 0.7% were intra-peritoneal, 0.5% sub-capsular, 0.2% intra-hepatic while the rest were
abdominal wall and non-specific haemorrhage (0.2%). Akahane et al[55], in a study of 1000
RF treatments for 2140 lesions in 664 patients, reported a rate of 0.2% for haemorrhage
requiring transfusion. De Baere et al[5] reported a 0.3% rate of sub-capsular haemorrhage in
their study involving 312 patients who had a total of 350 procedures. In a large multi-centre
trial in Italy involving 2,320 patients with 3,554 lesions, Livraghi et al[6] reported that the
rate of peritoneal bleeding requiring intervention was 0.3%. In the Korean Study Group of
RFA involving 1139 patients, the prevalence of haemorrhage was 0.46% [58].
Several key precautions have been identified to reduce the risk of bleeding after RFA. Imageguided electrode placement is mandatory for accurate tumour targeting and to avoid large
vessels [56]. Cauterization of the electrode track has also been shown to reduce the risk of
haemorrhage [59]. In a review by Mulier et al[57], none of the 214 patients who had
cauterization of their electrode track experienced haemorrhage, compared to 10 of 1036 (1%)
of patients who did not have cauterization and bled.
2.6.2. Abdominal Infections
Abdominal infections are usually the result of enteric bacterial contamination after a RF
treatment. Factors increasing the risk of abdominal infections include abnormal biliary tract
anatomy (e.g. bilio-enteric fistula or anastomosis) leading to bacterial colonization and a
compromised immune system (e.g. type 2 diabetes mellitus).
Mulier et al[57] reported a total of 42 abdominal infections in 3670 patients (1.1%), of which
34 (0.9%) were hepatic abscesses. Four patients died as a result of sepsis; two from hepatic
abscesses, one from peritoneal Staphylococcus aureus infection and one from septic ascites.
de Baere et al[5] reported a 2% rate of hepatic abscess in his study involving 350 procedures
in 312 patients. In this study, all three patients who had bilio-enteric anastomoses developed
hepatic abscesses. In the Italian multi-centre study, six (0.3%) cases of intra-hepatic
22
abscesses were identified, of which two were diabetic and three had bilio-enteric anastomoses
[6]. Choi et al[60] reported that hepatic abscesses developed after 13 ablations in 13 patients
out of a total of 751 procedures (1.7%). Their analysis revealed that three factors were
associated with significantly higher rates of hepatic abscesses; pre-existing biliary
abnormality (p = 0.0088), tumour with retention of iodized oil from previous transcatheter
arterial chemoembolization (OR=3.381, p = 0.040), and treatment with an internally cooled
electrode system (OR=12.434, p = 0.016). In the multi-centre Korean study, hepatic abscess
was the most common complications with a prevalence of 0.66%[58].
Early diagnosis of abdominal infections can be challenging, as patients often experience lowgrade temperature and mild leukocytosis as part of the post-ablation syndrome. Several
reports indicated that the fever, associated with post-ablation syndrome, usually lasts 1-9
days[56]. Therefore, one should be suspicious of an infective process if fever persists for
longer than two weeks[56]. The commonest microorganisms that have been identified in
abscesses after hepatic ablation include Escherichia coli, Clostridium perfringens,
Streptococcus D and Enterococcus[61]. Treatment modalities include percutaneous aspiration
and antibiotics; a logical choice would be amoxycillin plus clavulanate that is active against
these microorganisms.
2.6.3. Biliary Tract Injury
The main bile ducts are protected by the heat-sink effect of the portal vein and the hepatic
artery that run along-side them[62]. However biliary tract injury can occur when the blood
flow to the liver is decreased by Pringle’s manoeuvre, portal vein thrombosis or vascular
injury. Aggressive heating of central hepatic tumours adjacent to the porta hepatis to
overcome the heat-sink effect of the larger vessels can also damage the biliary tract[58].
Previous studies reported that only bile ducts adjacent to small (<3mm) thrombosed blood
vessels are destroyed[63].
In Mulier’s review, a total of 38 out of 3670 (1%) patients experience biliary tract
complications, of which 18 (0.5%) were biliary strictures and 7 (0.2%) were bilomas[57]. In
23
another study, Kim et al[64] reported that bile duct changes occurred in 69 of 571 (12%)
treatments and 66 of 389 (17%) patients. The average time interval to the discovery of bile
duct change was 1.6 months, and 69 of the patients (87%) had no progression of the injury
[64]. All the bile duct changes noted in this study occurred peripheral to or within the
ablation zones. The most common biliary tract changes seen were upstream biliary tract
dilatation peripheral to the ablation zone (57 patients or 82.6%) followed by biloma (four
patients or 5.8%) [64]. Eight patients (11.4%) had both features on follow-up imaging scans
[64]. In the Italian study involving 2320 patients, biliary tract strictures occurred in six
(0.3%) patients including one patient who needed a stent, and three (0.1%) patients developed
bilomas of which one required drainage [6]. The Korean study of 1139 patients reported three
bilomas (0.20%) and one biliary tract stricture (0.07%) [58].
Two methods have previously been described to prevent biliary tract injury during RFA of
central tumours. The first method involved the prophylactic insertion of a biliary stent [65],
while the second method involved cooling the biliary ducts with chilled saline [66]. There are
concerns however, that these methods might introduce bacterial contamination into the biliary
tract resulting in infective complications [56].
2.6.4. Hepatic Vascular Injury
Vascular thrombosis after RFA occurred most commonly in small vessels <4mm[67] whereas
vessels >4mm were usually spared because of the “heat sink” effect of blood flow[63].
However, thrombosis can occur in hepatic vessels >4mm if blood flow is reduced, for
example by the Pringle’s manoeuvre[68], or in someone who has poor hepatic reserve[57].
Traumatic injury of the hepatic vessels can also occur from insertion of the electrodes.
Mulier’s review reported 22 (0.6%) cases of hepatic vascular damage, of which nine were
portal vein thrombosis, two hepatic vein thrombosis, nine hepatic artery damage and two
unspecified hepatic infarction[57]. Three out of the nine portal vein thromboses resulted in
death[57]. They found that RFA with the Pringle’s manoeuvre increased the risk of portal
vein thrombosis compared to RFA without the Pringle’s manoeuvre (2.1% versus 0.2%,)[57].
24
One patient with hepatic artery damage had extensive hepatic infarction resulting in
death[57]. De Baere et al reported 11 (3%) cases of vascular thromboses after RFA – five
hepatic vein, three segmental portal vein and three portal trunk (all patients with portal trunk
thromboses passed away)[5]. They found a significantly higher rate of portal vein thrombosis
when RFA was performed in combination with the Pringle’s manoeuvre in cirrhotic (two of
five patients) compared to non-cirrhotic livers (0 of 54 patients) (p<0.00001)[5]. Livraghi et
al reported nine patients who developed arterioportal shunt discovered incidentally on
follow-up CT scans, and one patient who developed portal hypertension, portobiliary fistula,
hemobilia, phlebitis, and acute thrombosis, with portal venous cavernous transformation[6].
Akahane reported a 0.4% rate of portal vein thrombosis[55].
2.6.5. Liver Failure
Liver failure is a rare but serious complication of RFA. The common causes of hepatic failure
reported in the literature are portal vein thrombosis and excessive ablation[56].
Mulier reported 29 (0.8%) patients who developed hepatic failure, of which seven (0.2%)
were fatal and 22 (0.6%) were mild[57]. Four of the fatal cases were secondary to central
vascular thrombosis, and the other three due to over-estimation of liver reserve[57]. de Baere
reported one case of fatal liver failure after radiofrequency treatment combined with a right
hemi-hepatectomy[5]. The Italian study reported three (0.1%) cases of rapid hepatic
decompensation (all in HCC) with one resulting in death, and 11 (0.5%) patients, all with
liver cirrhosis, experienced transient hepatic decompensation[6]. The Korean study reported
only one (0.09%) case of hepatic failure[58].
2.6.6. Visceral Organ Injury
RFA has been reported to cause iatrogenic injury to various intra-abdominal organs and
structures such as the gallbladder, small and large bowel, stomach, kidneys, diaphragm and
the abdominal wall. Recognized risk factors for visceral organ injury include the use of high
power RF generator and prolonged ablation time. Ablation of sub-capsular tumours or a
central tumour abutting vital structures also increases the risk of iatrogenic thermal injury.
25
Percutaneous RFA has a higher risk compared to either laparascopic or open RFA[56],
especially if the patient has abdominal adhesions from previous abdominal surgery.
Mulier et al reported a total of 19 (0.5%) cases of visceral organ injury among 3670 patients,
all of which occurred in patients who received percutaneous RFA; five cholecystitis, five
diaphragmatic burns, two colonic burns, one gastric burn, one jejunal burn, two renal burns,
two abdominal burns and one non-specified burn[57]. In the Italian report, major visceral
thermal injury occurred in seven (0.3%) patients – six colonic perforations (four who had
previous bowel resection), and one cholecystitis[6]. Ten (0.4%) patients had minor
complications secondary to visceral thermal injury – six asymptomatic gallbladder wall
thickening, three thickening of the diaphragm and one direct damage to renal tissue without
clinical sequelae[6]. The Korean study reported three (0.3%) cases of complications which
could be attributed to thermal injury – one diaphragmatic injury, one gastric ulcer and one
renal infarction[58]. In the study reported by de Baere, there was one (0.3%) case of colonic
perforation, which resulted in death[5]. Akahane et al reported three (0.5%) cases of
iatrogenic thermal injury from RFA out of 664 patients – one each for gastric, duodenal and
colonic perforation[55].
Awareness of the risk of iatrogenic thermal injury to intra-abdominal organs is critical to safe
RFA. Some authors contraindicated RFA of tumours closer than one cm to other intraabdominal organs[69]. They proposed that RFA in these cases be performed either by
laparascopic or open surgery. Several studies in animal models reported that full thickness
burns of the stomach and the small and large intestines could occur if the edge of the RFA
lesion was less than one cm from the surface of the liver[70]. Therefore sub-capsular tumours
should be approached via either laparascopic or open surgery, where these organs can be
separated from the liver[71]. Another method which has been investigated was peritoneal
saline instillation to create an artificial insulating barrier between the surface of the liver and
adjacent structures[72].
26
2.6.7. Skin Burns
Reports of dispersive pad skin burns are increasing with the introduction of high-power RF
generators. Most cases are superficial first and second degree burns, but third degree burns do
occur as well[57]. Specific precautions and care must be taken when placing the dispersive
pads to ensure there is good contact between the skin and the dispersive grounding pad. It is
now recognized that multiple dispersive pads are required to minimize the risk of skin burns,
especially when using high-power RF generators or if the RFA continued for a prolonged
period of time. Goldberg’s experimental study on animals investigated the variables affecting
safe dispersive grounding system for RFA and concluded that up to four 100 cm2 dispersive
pads should be used instead of one[73]. These pads should be placed at equi-distance from
the electrode and with the long edge facing the active electrode.
Dispersive pad skin burns occur in 0.6% in the review by Mulier[57], 0.5% in Akahane’s[55]
report, 0.2% in Rhim’s[58] Korean study, 0.2% in Livraghi’s[6] Italian study and 1.4% in de
Baere’s[5] study.
2.6.8. Tumour Seeding
Several theories responsible for tumour seeding have been proposed. Cancerous cells could
be deposited along the insertion track by the electrode itself during removal, or spread by
bleeding which occurred as a complication of the procedure[57]. Sudden increases in the
intra-tumoral pressure, which might happen during RFA[57] or when an interstitial saline
infusion RF system is used[74], can force cancerous cells into the vascular systems[75].
Pre-procedure tumour biopsy was also found to increase the risk of tumour seeding[76].
Llovet reported a 12.5% rate of electrode track seeding, and identified several factors
associated with this phenomenon - no cauterization of the electrode tract upon removal,
poorly differentiated tumour cells, and a perpendicular approach to sub-capsular tumours[75].
Other researchers have reported a much lower rate of tumour seeding – 0.2%[57], 0.5%[6],
0.6%[77] and 2.8%[78].
27
A practical step to reduce the risk of tumour seeding includes cauterizing the electrode track
during its removal after RFA. Llovet et al cauterized all electrode tracks except for four subcapsular tumours, and tumour seeding occurred in all of them[75]. Similarly, radio-imaging
support is necessary to ensure accurate electrode placement to prevent multiple repositioning. If the electrode has to be re-positioned to enable a complete ablation, then each
electrode track should be cauterized.
2.6.9. Miscellaneous Complications
Numerous other complications and adverse events had been reported following RFA albeit in
a very small number of cases. In Mulier’s review, there were 0.8% pulmonary complications
(including pneumo-haemothorax and pleural effusion), 0.4% cardiac complications
(arrhythmias, myocardial infarction and cardiac failure), 0.2% coagulopathy, 0.1% renal
failure, 0.2% myoglobinaemia/myoglobinuria and 0.1% hormonal complications (carcinoid
crisis, hyperglycaemia and Addisonian crisis)[57]. Other rare complications that have been
reported include renal infarction[58], sepsis[78], transient ischemic attack[78], cardiac
arrest[6],
hypoxaemia[5],
haemoperitoneum[78],
plexopathy[57], and gastrointestinal tract bleeding[57].
28
central
hyperthermia[57],
brachial
Title of Thesis: Improving the Safety and Efficacy of Bimodal Electric Tissue Ablation (p.31)
Student Name: Dr. Tiong, LU
CHAPTER 2.7
A Systematic Review of Survival and Disease Recurrence after
Radiofrequency Ablation for Hepatocellular Carcinoma
Leong Tiong (MBBS), Guy Maddern (FRACS, PhD)
Department of Surgery, The Queen Elizabeth Hospital
University of Adelaide, SA
Australia
British Journal of Surgery - September 2011; Volume 98 (9): 1210-1224
NOTE:
This article was published as:
"Systematic review and meta-analysis of survival and
disease recurrence after radiofrequency ablation for
Hepatocellular Carcinoma"
29
Title of Thesis: Improving the Safety and Efficacy of Bimodal Electric Tissue Ablatio
Student Name: Dr. Tiong, LU
Statement of Authorship
Title of Paper: A Systematic Review of Survival and Disease Recurrence after
Radiofrequency Ablation for Hepatocellular Carcinoma
British Journal of Surgery – September 2011; Volume 98 (9): 1210-1224
Dr. Leong Ung Tiong (Candidate)
Performed literature search, data collection and wrote the manuscript.
I hereby certify that the statement of contribution is accurate.
Professor Guy Maddern
Supervised the development of work, helped in data interpretation, manuscript evaluation and
acted as the corresponding author.
I hereby certify that the statement of contribution is accurate and I give permission for the
inclusion of the paper in the thesis
30
2.7. Systematic Review of Survival and Disease Recurrence after Radiofrequency
Ablation for Hepatocellular Carcinoma
Introduction
Hepatocellular carcinoma (HCC) is the 5th most common cause of cancer in the world and
the 3rd most common cause of cancer related-death[10, 79, 80]. Surgical resection and liver
transplantation are the only curative options available for these patients, with 5-year survival
rates between 36-70% and 60-70% respectively[81-84]. However only 10-20% of these
patients have resectable disease[85-87]. Factors precluding surgery include extra-hepatic
metastases, vascular invasion, high-risk anatomic location, excessive size or number of
lesions, insufficient remnant liver to support life, or co-morbid conditions[10, 88]. Lack of
liver donors compounds the problem. If untreated, the median survival for these patients is 612 months[89, 90], with few surviving beyond 3 years[91]. Systemic chemotherapy can
increase the median survival of patients with un-resectable HCC to approximately 14
months[92]. However chemotherapy is toxic with unpleasant side effects and less than ideal
disease control capabilities.
There has been a surge of interest in local ablative therapy for un-resectable liver cancers
worldwide in the past 2 decades, which includes cryotherapy, percutaneous ethanol injection
(PEI), percutaneous acetic acid injection (PAI), laser induced thermal therapy (LITT), highintensity focused ultrasound (HIFU), microwave ablation and radiofrequency ablation (RFA).
Among these, RFA has been the most widely investigated therapeutic option for unresectable liver cancers[1]. It has been shown in numerous large series that RFA is safe, with
minimal morbidity and mortality. RFA has also been shown to achieve satisfactory local
response rate, with >80% complete ablation in most studies[93]. It also significantly
improves overall survival when compared to other modalities e.g. chemotherapy or PEI[86].
General consensus guidelines from North America and Japan where RFA has been used
extensively for HCC recommend that RFA be used for ≤3 HCC which are ≤3cm in diameter
[86, 94, 95].
31
A major drawback of RFA is the high disease recurrence rate seen in patients who received
this treatment. This could have an adverse effect on patient survival, and is the main reason
why RFA is considered inferior to surgery for the treatment of resectable disease. Early RFA
results were limited by the small ablation size achievable, and the lack of sensitive radioimaging modalities to assess treatment response.
Intense research over the last 2 decades has produced impressive results. Higher-powered
radiofrequency generators[96] and modifications to the electrodes[97-99] have enabled
ablation sizes up to 6-7 cm in diameter in animal models. Whereas only lesions <3 cm were
treatable with RFA in the past, physicians now can ablate tumours up to 5 cm and still
achieve a 0.5-1 cm ablative margin[100-104]. These advances have opened the door to more
patients who previously were considered “untreatable” and whose options were only
palliation or chemotherapy.
The majority of reports in the literature are case-series, with few randomized controlled trials
comparing RFA to other interventions especially surgical resection. One reason for this is that
the long term outcomes after RFA for liver cancers are considered inferior to resection;
therefore randomizing patients with resectable liver cancers to RFA would be un-ethical. This
review aims to examine the survival and disease recurrence rates after RFA for HCC over the
past decade.
Methods:
A literature search was conducted using Medline (Jan 2000 – week 3 Nov 2010), EMBASE
(Jan 2000 – week 49 2010), Cochrane Central Register of Controlled Trials (Jan 2000 - 4th
Quarter 2010), Cochrane Database of Systematic Reviews (2005 to November 2010),
Cochrane Methodology Register (Jan 2000 - 4th Quarter 2010), Database of Abstracts of
Reviews of Effects (Jan 2000 - 4th Quarter 2010) as per the search terms in Table 1 without
language restriction.
32
1. Catheter Ablation/ or radiofrequency ablation
2. RFA
3. hepatocellular carcinoma or Carcinoma, Hepatocellular/
4. primary liver cancer
5. 1 or 2
6. 3 or 4
7. 5 and 6
8. limit 7 to (comment or editorial or letter or meta analysis or "review")
9. metastas* or Neoplasm Metastasis/
10. 7 not 8 not 9
11. limit 10 to (humans and yr="2000 -Current")
Table 1. Search terms used for literature search
Inclusion criteria for studies were as follows (1) Participants – patients with HCC. Patients
who received other therapies (e.g. liver resection, PEI, chemotherapy etc.) prior to RFA for
their HCC were included as data in this area is lacking. (2) Intervention – RFA with any of
the commercially available RFA generators or needle designs. (3) Comparative interventions
– surgical resection, chemotherapy and/or other ablative treatment e.g. PEI, MCT, LITT. (4)
Outcomes data (measured from the time of intervention) including survival rates (overall
median survival, median survival at 1-, 3-, and 5-years, and median disease free survival),
and disease recurrence rates (calculated per patient when data available). Three types of
disease recurrences were recorded; ablation site (tumour recurrence at the site of ablation),
intra-hepatic (tumour recurrence in the liver away from the site of ablation), and extra-hepatic
(tumour recurrence outside the liver). (5) Types of study – randomized controlled trials,
quasi-randomized controlled trials and non-randomized comparative studies were included in
the review. In addition meeting abstracts and each article’s bibliography identified above
were cross-referenced for relevant publications. Only articles reporting survival and/or
disease recurrence >12 months were included in this review. Articles which reported a
combination of RFA with other treatment modalities (e.g. surgery, chemotherapy, other local
33
ablative therapy) were also included. (6) Exclusion criteria – articles were excluded if the
outcome data could not be clearly attributed to each specific intervention (e.g. RFA vs.
resection) or disease (e.g. HCC vs. liver metastases). Meta-analysis, review articles, case
series, letters/comments and editorials were also excluded. Methodological qualities of all
RCTs were assessed using both the Cochrane Collaboration’s tool[105] for assessing risk of
bias and the Jadad scoring system[106].
Studies
Adequate
Sequence
Generation
Allocation
Concealment
Blinding
(observer)
Blinding
(patient)
Adequate
follow-up
Jadad
Score
Lencioni
(2003)[107]
Yes
Yes
NP
NP
Yes
3
Lin (2004)[108]
Yes
Yes
NP
NP
Yes
3
Lin (2005)[109]
Yes
Yes
NP
NP
Yes
2
Shiina
(2005)[110]
Yes
NR
NP
NP
Yes
3
Shibata
(2006)[111]
NR
Yes
NP
NP
NR
1
Ferrari
(2007)[112]
Yes
NR
NP
NP
NR
2
Zhang
(2007)[103]
Yes
Yes
NP
NP
Yes
3
Brunello
(2008)[113]
Yes
Yes
NP
NP
Yes
3
Cheng
(2008)[114]
Yes
Yes
NP
NP
Yes
3
Yang (2008)[115]
NR
NR
NP
NP
NR
1
Morimoto
(2010)[116]
Yes
NR
NP
NP
NR
2
Chen (2006)[117]
Yes
NR
NP
NP
Yes
3
Table 2. Assessment of Bias in RCTs included. NR=not reported, NP=not possible
34
There were 5 RCT comparing RFA to PEI for HCC which were pooled together for a metaanalysis using the RevMan 5.1 software[118]. The data were analyzed using the random
effect model of Dersimonian and Laird[119]. The results were reported as pooled risk ratios
with 95% confidence interval. Heterogeneity between studies was assessed using χ2 test with
significance set at p<0.100[120]. The patients in the other studies were too heterogenous for
any meaningful meta-analysis.
Results
A total of 43 articles were included in this review including 12 RCT and 31 non-randomized
comparative studies (Figure 1). The 12 RCTs in this review had moderate methodological
quality, with a mean Jadad score of 2.5 (range 1-3; Table 2). Ten trials described appropriate
methods of generating the sequence of randomization[103, 107-110, 112-114, 116, 117],
while 7 reported methods of allocation concealment[103, 107-109, 111, 113, 114]. Four trials
did not report loss to follow-up[111, 112, 115, 116]. Due to the differences in the nature of
the interventions studied in the RCTs, double blinding was virtually impossible. Patients
treated with RFA could be broadly divided into 2 groups; “un-resectable HCC” and
“resectable HCC”. The patient survival and disease recurrence rates were shown in
Appendices 1-8.
35
Potentially relevant studies identified in the
literature search and screened for retrieval
(n=1990)
362 articles excluded – duplicates
Studies retrieved for more detailed evaluation
(n=1628)
Potentially appropriate studies to be included
in the systematic review (n=266)
1362 articles excluded – failed
inclusion/exclusion criteria or not
related to RFA for HCC after
reading title/abstract
223 articles excluded - failed
inclusion/exclusion criteria after
reading full text.
Studies included in the systematic review
(n=43)

12 Randomized controlled trials

30 comparative studies

1 case series
Figure. 1 Quorum chart
1.
Outcomes after RFA for Un-Resectable HCC
There were 30 comparative studies published in the past 10 years which reported survival and
disease recurrence rates after RFA (used in various combinations with PEI or TACE) for
patients with un-resectable HCC. In some studies RFA was used in combination with surgery
for patients whose disease was otherwise not treatable by resection alone.
36
1.1.
RFA vs. Resection
1.1.1. Within Milan Criteria (Appendices 5 & 6)
There were 16 non-randomized studies comparing RFA to resection for the treatment of
HCC. Eight of these articles included only patients within Milan criteria[121-128]. These
patients were treated with RFA instead of resection because of: (1) patient preferences, (2)
severe co-morbidities, and (3) insufficient post-operative hepatic remnant. The total number
of patients was 928 in the RFA and 708 in the resection group. Median tumour size ranged
from 1.8-2.1 (mean 2.4-3.65) cm in the RFA and 2.0-2.7 (mean 2.5-4.0) cm in the resection
group. Median disease free survival rates at 1-, 3-, and 5-years in the RFA group were 7883%[124, 128], 36-59%[122, 124, 128], and 17-25%[122, 124, 128]. The corresponding
figures for the resection group were 80-83%[124, 128], 47-64%[122, 124, 128], and 2238%[122, 124, 128]. Median overall survival rates at 1-, 3-, and 5-yr in the RFA groups were
96-100%[121, 123-126, 128], 53-92%[121-126, 128], and 41-77%[122, 124, 126-128], and
in the resection group were 91-99%[121, 123-126, 128], 57-92%[121-126, 128], and 5480%[122, 124, 126-128]. Ablation site and intra-hepatic disease recurrence rates in the RFA
group were 7-24%[121, 123, 124, 126, 127] and 28-68%[121, 123, 126, 128], while those in
the resection group were 0-10%[121, 123, 124, 126, 127] and 33-51%[121, 123, 126, 128].
All 8 studies showed no significant differences in overall survival rates between the RFA and
resection groups. However patients treated with resection had significantly lower local
disease recurrence rates[126, 127, 129], and higher disease free survival[124, 128].
1.1.2. Outside Milan Criteria (Appendices 5 & 6)
Eight articles included patients outside the Milan criteria in their comparison between RFA
(n=797 patients) and resection (n=712 patients)[100, 130-136]. Because of larger numbers
and sizes of tumours, 4 of the studies combined RFA with TACE[130, 132, 135, 136]. The
median tumour sizes were 3.0-4.6 cm and 4.6-7.4 cm in the RFA and resection group,
respectively. In 2 studies, tumours size was >3cm in more than 70% of patients[100, 134].
Median overall survival rates at 1-, 3-, and 5-year in the RFA group were 78-98%[100, 13137
134, 136], 33-94%[100, 131-134, 136], and 20-75%[100, 131-133, 135, 136]. The
corresponding figures in the resection group were 75-97%[100, 131-134, 136], 64-93%[100,
131-134, 136], and 31-81%[100, 131-133, 135, 136]. Median overall survival was 28-51
months and 37-57 months in the RFA and resection groups, respectively[100, 130, 133].
Median disease free survival was 16-25 months and 36-53 months in the RFA and resection
groups, respectively[100, 132]. The ablation site, intra-hepatic and extra-hepatic disease
recurrence rates were 3-15%[131, 133, 134, 136], 25-59%[131-134, 136] and 12-21%[131,
132] in the RFA group; compared to 0-2%[133, 136], 28-37%[132, 133, 136] and 13%[132]
in the resection group.
Three studies found that patients treated with resection had better overall and disease
free survival compared to those treated with RFA. The survival benefits, however, were
generally limited to patients with Child-Pugh A cirrhosis and single HCC >3 cm[100, 134,
135].
1.2.
RFA vs. PEI for Un-Resectable HCC[103, 107-110, 113] (Appendices 1 & 2)
Five RCTs compared RFA (n=354 patients) to PEI (n=347 patients) for the treatment of unresectable HCC. The mean tumour diameter was 2.42-2.9 cm and 2.25-2.8 cm in the 2 groups
respectively. Meta-analysis of these trials showed that patients treated with RFA had better 1and 3-yr overall survival than those treated with PEI (Fig. 2 & 3). RFA was associated with
significantly better disease free survival rates at 1-and 3-yr; 74-86% and 37-43%, compared
to the PEI group; 61-77% and 17-21% respectively[107-109]. Disease recurrence rates at the
ablation site were significantly lower in the RFA group (2-14%) compared to the PEI group
(11-35%)[107-110].
38
RFA
Study or Subgroup
PEI
Risk Ratio
Events Total Events Total Weight
Risk Ratio
M-H, Random, 95% CI
Brunello 2008
4
70
10
69
13.6%
0.39 [0.13, 1.20]
Lencioni 2003
0
52
2
50
1.9%
0.19 [0.01, 3.91]
Lin 2004
11
52
15
52
36.7%
0.73 [0.37, 1.44]
Lin 2005
11
62
16
62
36.1%
0.69 [0.35, 1.36]
4
118
7
114
11.7%
0.55 [0.17, 1.84]
347 100.0%
0.62 [0.41, 0.94]
Shiina 2005
Total (95% CI)
Total events
354
30
M-H, Random, 95% CI
50
Heterogeneity: Tau² = 0.00; Chi² = 1.61, df = 4 (P = 0.81); I² = 0%
0.01
0.1
1
10
100
Favours experimental Favours control
Test for overall effect: Z = 2.27 (P = 0.02)
Figure 2. RFA vs. PEI for Un-Resectable HCC (Survival at 1-Year)
RFA
Study or Subgroup
PEI
Risk Ratio
Events Total Events Total Weight
Risk Ratio
M-H, Random, 95% CI
Brunello 2008
52
70
52
69
31.2%
0.99 [0.81, 1.20]
Lin 2004
34
52
46
52
28.5%
0.74 [0.59, 0.92]
Lin 2005
24
62
36
62
16.8%
0.67 [0.46, 0.97]
Shiina 2005
46
118
63
114
23.4%
0.71 [0.53, 0.93]
297 100.0%
0.79 [0.65, 0.96]
Total (95% CI)
Total events
302
156
197
Heterogeneity: Tau² = 0.02; Chi² = 7.04, df = 3 (P = 0.07); I² = 57%
Test for overall effect: Z = 2.41 (P = 0.02)
M-H, Random, 95% CI
0.01
0.1
1
10
100
Favours experimental Favours control
Figure 3. RFA vs. PEI for Un-Resectable HCC (Survival at 3-Years)
In another RCT Zhang et al[103] compared the efficacy of RFA + PEI versus RFA alone in
treating un-resectable HCC. A total of 67 patients received RFA + PEI where absolute
alcohol was injected into the tumour followed by RFA, whereas in the 2nd group 66 patients
received RFA only. The RFA + PEI group had significantly better overall survival with 1-, 2, 3-, 4-, and 5-year survival being 95.4%, 89.2%, 75.8%, 63.3%, and 49.3%, compared to the
RFA only group; 89.6%, 68.7%, 58.4%, 50.3% and 35.9% respectively (p<0.05). Local
tumour progression rates were also significantly lower in the RFA + PEI group compared to
the RFA only group (6.1% vs. 20.9%, p=0.01). Sub-group analyses revealed that RFA + PEI
39
improved overall survival of patients with tumours between 3.1-5.0 cm in diameter, but not
for tumours ≤3.0 cm or 5.1-7.0 cm.
1.3.
RFA vs. TACE (Appendices 3 & 4)
Three RCTs compared RFA to RFA + TACE. The data could not be pooled due to the
heterogeneity of patient populations and inclusion/exclusion criteria.
Cheng et al[114] conducted a RCT comparing RFA + TACE (n=96) vs. RFA-only (n=100)
vs. TACE-only (n=95) for patients with up to 3 HCC ≤7.5cm in diameter. The average largest
tumour diameter in the 3 groups was approximately 5.0 cm, while duration of follow-up was
35.8, 24.6 and 25.4 months respectively. Complete tumour response, overall survival,
disease-free survival and disease recurrence were significantly better in the RFA + TACE
group compared to either RFA or TACE alone.
Yang et al[115] randomized 78 patients to RFA (n=12, median size 5.2 cm), TACE (n=11,
median size 6.4 cm), RFA + TACE (n=24, median size 6.6 cm) and RFA + TACE + lentinan
fungal abstract (n=31, median size 6.5 cm). Patients in the last group had significantly better
median survival (28 months) and lower ablation site and intra-hepatic disease recurrence rates
(18%) compared to the others.
Morimoto et al[116] randomized patients with single HCC 3.1-5.0 cm to RFA (n=18, mean
size 3.7 cm) or RFA + TACE (n=19, mean size 3.6 cm). After a mean follow-up of 31
months, the RFA + TACE group had significantly lower disease recurrence rate at the
ablation site than the RFA group (6% vs. 39%, p=0.012). There were however no significant
differences in the median survival rates at 1- and 3-years.
40
Two retrospective comparative studies also showed that the combination therapy of RFA +
TACE produced significantly longer overall and disease free survival, and lower disease
recurrence rates compared to RFA alone[137, 138].
Only 2 studies compared RFA to TACE alone. Chok et al[139] compared 51 patients treated
with RFA to 40 patients receiving TACE and found no significant differences in overall
survival rate at 1- and 2-years, or median disease free survival. On the other hand Murakami
et al[140] reported that patients treated with RFA (n=105) had lower rates of disease
progression/recurrence compared to TACE (n=133).
1.4.
RFA vs. LITT (Appendices 5 & 6)
Ferrari et al[112] randomized patients to RFA (n=40) or LITT (n=41) for single HCC ≤4cm
or up to 3 HCC ≤3cm. Mean tumour size of the tumours in the 2 groups were 2.67 cm and
2.89 cm respectively. No significant differences between the 2 groups were found in ablation
site and intra-hepatic disease recurrence rates, median disease free survival, or median
survival rate at 1-yr, 3-yr, and 5-years. Sub-group analysis, however, showed that Child-Pugh
A patients (HR 0.18, p=0.017) and those with tumour ≤2.5cm (HR 0.18, p=0.018) had better
survival rates when treated with RFA compared to LITT.
1.5.
RFA vs. MCT (Appendices 5 & 6)
Three observational studies compared RFA (n=171 patients) to MCT (n=151 patients). Mean
tumour sizes were 1.6-2.6 cm in the RFA, and 1.7-2.6 cm in the MCT group. No significant
differences between the 2 groups were found in disease recurrence, disease free survival or
overall survival rates in 2 studies[141, 142], but one study[143] reported that patients treated
with RFA had significantly higher median survival rates at 1-, 3- and 4-years compared to
MCT (100%, 70% and 70% vs. 89%, 49%, 39%, p=0.018).
41
1.6.
RFA vs. RFA + Interferon (Appendices 5 & 6)
A matched case-control study compared RFA + interferon therapy (n=43 patients, median
tumour size 1.8 cm) for patients with Child-Pugh A cirrhosis and up to 3 HCC ≤3cm to RFA
(n=84 patients, median tumour size 1.5 cm) alone[94]. Interferon therapy was started after
confirmation of complete response to RFA, and continued for a median duration of 4.7 years.
Patients in the RFA only group received conventional anti-inflammatory therapy consisting
of ursodeoxycholic acid or strong neo-minofagen C. Five year overall survival rate was
significantly higher in the RFA + interferon group compared to RFA-only group (83% vs.
66%, p=0.004), and lower intra-hepatic disease recurrence rates were lower (56% vs. 71%,
p=0.04).
In another study interferon maintenance therapy after RFA in patients with HCC and HCV
positive RNA conferred better overall survival rate (5-yr; 90% vs. 70%, p=0.0181), and
maintained Child-Pugh A classification for a longer period of time (37 vs. 32 months,
p=0.0025) compared to those patients not taking the drug[127].
2.
Outcomes after RFA for Resectable HCC (Appendices 7 & 8)
One RCT[117] and three comparative articles[144-146] were identified. As data on RFA for
resectable HCC is lacking, a recently published large series[137] was also included to provide
a comprehensive evidence review with a total of 680 patients.
2.1.
Resectable 1st episode HCC (Appendices 7 & 8)
Chen et al[117] randomized patients to RFA (n=90) or surgery (n=90) for single resectable
Child-Pugh A HCC ≤5.0 cm in diameter. Fifty-two percent and 47% of the patients had
tumours ≤3cm in the RFA and resection groups respectively. Nineteen (21%) patients
withdrew consent for RFA post-randomization, and received surgical resection instead.
Analyses of RFA vs. resection including and excluding these 19 patients showed that both
modalities produced comparable overall and disease-free survival rates. Similar outcomes
were achieved regardless of tumour diameter (≤3.0 cm or 3.1-5.0 cm). Surgical resection was
42
associated with higher morbidity rates (55.6% vs. 4.2%, p<0.05), and longer hospital stay
(19.7 days vs. 9 days, p<0.05) compared to RFA.
Two comparative studies looked at the same topic. Montorsi et al[146] compared 40 patients
who had surgical resection to 58 patients who received RFA for a single HCC nodule <5.0
cm in diameter. Baseline patient characteristics were comparable between the 2 groups, and
the average follow-up period was approximately 2 years in both groups. Complete response
after RFA was achieved in 55 patients (95%); 2 patients required TACE and 1 had a
subsequent resection. The RFA group had higher rates of intra-hepatic tumour recurrence
compared to the resection group (35% vs. 30%, p=0.018), but there were no statistically
significant differences in 1-, 2-, 3- and 4-year survival rates (p=0.139).
Abu-Hilal et al[144]compared resection versus RFA in patients with resectable uni-focal
HCC <5.0 cm in diameter and found no significant differences in 1-, 2-, and 5-year overall
survival (p=0.302). However median disease free survival was longer in the resection group
compared to RFA (35 vs. 10 months, p=0.028). Local tumour recurrence was significantly
higher in the RFA group (30% vs. 4%, p=0.001). Multivariable analyses showed that RFA
was associated with reduced overall (HR=4, p=0.014) and disease-free survival (HR=2.3,
p=0.022)
In 224 patients with Child-Pugh A cirrhosis and resectable single HCC ≤5.0 cm with no
extra-hepatic or vascular invasion managed with RFA as first line treatment, median disease
free survival was 48 months[137]. The median overall survival and disease free survival rates
at 5-and 10-years were 60%and 34%, and 36%and 18% respectively.
2.2.
Resectable Recurrent HCC (Appendices 7 & 8)
Liang et al[145]compared percutaneous RFA (n=66) versus repeat resection (n=44) for
recurrent technically resectable HCC. Inclusion criteria were; <3 lesions, <5.0 cm diameter,
no other treatment apart from previous hepatectomy for HCC, no evidence of tumour
43
invasion into major portal vein/hepatic vein branches, and Child-Pugh A/B cirrhosis.
Complete response was achieved in 65 patients (98%) who received RFA; 1 patient was
treated with TACE after 2 failed ablation attempts. Four patients in the resection group
received TACE; 2 for ruptured tumour during surgery and 2 for inadequate resection margin.
No significant differences in overall survival, disease free survival or disease recurrence rates
were found between the 2 interventions. Repeat resection was associated with more major
complications compared to RFA (68% vs. 3%, p<0.005). No significant difference between
the survivals of patients treated with repeat hepatectomy or RFA for recurrent tumors ≤3 cm
(p=0.62) or >3 cm (p=0.57) was found.
3.
Techniques and equipment
3.1.
Comparison of percutaneous and laparoscopic/open RFA (Appendices 5 & 6)
Khan et al[101] compared percutaneous to “surgical RFA” in 228 patients with up to 3 HCC
≤5.0 cm. Percutaneous RFA was performed in 117 patients, while 111 patients had “surgical
RFA” (open=91 patients, laparoscopic=20 patients). More patients in the “surgical RFA”
group had cirrhosis (95% vs. 74%, p<0.001), and higher AFP levels (776ng/ml vs. 193ng/ml,
p=0.05). Thirty-six percent of patients in the percutaneous RFA group had previous liver
resection compared to 19% in the “surgical RFA” group (p=0.03). Both approaches had
similar overall, disease free survival and disease recurrence rates for tumours ≤3 cm.
However for tumours >3 cm, “surgical RFA” had significantly better median survival rates
than percutaneous RFA at 1-year (92% vs. 81%, p=0.03) and 3-years (68% vs. 42%, p=0.03)
respectively.
3.2.
RFA generator (Appendices 5 & 6)
In the only RCT available, Shibata et al[111] compared the internally-cooled electrode (CoolTip RF system, Radionics) to the expandable LeVeen electrode (RF 2000 generator, Boston
Scientific) in 74 patients with up to 3 HCC ≤3 cm. Multiple electrode insertions were used to
treat tumours >2.5 cm. No significant differences were found in complete ablation rates,
overall or disease-free survival, or disease recurrence rates between the 2 groups.
44
Lin et al[147] prospectively compared 100 patients with up to 3 HCC ≤4 cm in diameter
treated with 4 different RF generators and their respective electrodes which can ablate an area
of 3.0-5.0 cm (25 patients per group, mean tumour size 2.6 cm). Complete tumour response
rates were 91% in the RF 2000 group and 97% in the other 3 groups (p=ns). There were no
significant differences in disease recurrence, median overall survival or disease free survival
rates at 1- and 2-years between groups.
Seror et al[148] compared RFA for HCC during 2 different periods of time; from 2000-2002
forty-five patients were treated with internally-cooled electrodes (Cool-tip; Radionics/Tyco,
Burlington, Massachusetts), and from 2002-2004 forty-four patients were treated with the
perfused electrode (PE) (Berchtold/Integra, Tuttlingen, Germany). Only patients with ChildPugh A/B cirrhosis and up to 3 HCC ≤3.0 cm were included in the study, with no significant
baseline differences in patient or tumour characteristics. Complete ablation rate was 96% in
both groups, but only 15% of tumours treated with internally-cooled electrodes required
multiple RF applications to achieve complete ablations, compared to 72% of tumours treated
with the PE (p<0.00005). Treatment with the PE was also associated with higher rates of
intra-hepatic disease recurrence compared to the ICEs (64% vs. 31%, p<0.01). Median
overall survival at 1-year, 2-years, and ablation site disease recurrence rates were not
significantly different between the 2 groups.
Discussion
This review showed that RFA could achieve good clinical outcomes for un-resectable HCC.
A meta-analysis of 5 RCTs showed that RFA was better than PEI, with higher overall and
disease-free survival rates. Data on RFA compared to LITT or MCT were inconclusive, with
some studies reporting no significant differences between these ablative modalities, while
others showed better results after RFA. A combination of RFA + TACE has been shown to
be superior compared to RFA only therapy. More recently some clinicians have started using
RFA for resectable early HCC within Milan criteria (≤3 HCC < 3cm) and produced
comparable results as surgical resection. Lastly a comparison of different RFA electrodes and
generators showed no significant differences in disease-free or overall survivals.
45
Current RFA capabilities are limited by the size of coagulation that can be achieved in one
RFA application, which leads to incomplete treatment response and consequently higher rates
of tumour recurrence. The inability to completely ablate “larger” tumours, or tumours in high
risk locations[149] e.g. adjacent to large hepatic vessels or in sub-capsular areas compounds
the problem and these are adverse prognostic factors for tumour recurrences. The high local
tumour recurrence rates could have a negative influence on patient survival in the long term,
and is one of the main reasons why RFA is associated with inferior outcomes compared to
surgical resection[150]. In a large series by Kim et al, the ablation site recurrence rates
significantly increased from 0% (when the ablation margin around the tumour was >3 mm) to
6%, 19%, and 23% when the ablation margin was 2-3 mm, 1-2 mm and <1 mm
respectively[151].
There has been a clear evolution in the use of RFA for hepatic malignancies in the past
decade. In the early 2000s, the use of RFA was limited by the size (≤3.0 cm) and number
(<3) of lesions. The rate of successful complete ablation of a tumour, as measured by nonenhancement of the tumour during contrast-enhanced CT scan, is mainly dependent on its
size[131]. The local tumour recurrence rate after RFA can be up to 40-50%[152, 153], and is
directly related to the incapability to completely ablate a larger lesion. Rhim et al reported a
complete ablation rate of 96.7% for HCC and a 5-year survival rate of 58%[154]. When used
for larger tumours, the complete ablation rate and the long-term outcomes predictably
deteriorated. Chen et al[155]reported an overall complete response rate of 95% after RFA for
hepatic malignancies, and found that the success rate fell to 85 % for tumours >3.5 cm. The
response rates were also lower when tumours were adjacent to the gallbladder (86.3%) and
the bowels (83.3%) respectively.
With better equipment and understanding, the indication for RFA continues to expand, while
maintaining satisfactory outcomes. Clinicians are now commonly using RFA to treat hepatic
tumours >3.0 cm in size, with some even treating tumours >5.0 cm with satisfactory
results[100, 103, 156]. The number of lesions has ceased to become an absolute
46
contraindication to RFA[157]. A multi-modal approach to the treatment of HCC (e.g. RFA +
PEI or TACE) has improved the efficacy of RFA for tumours >3.0 cm[103, 114-116].
RFA has its own distinct advantages compared to surgical resection of HCC. It is minimally
invasive and has much lower rates of morbidity and mortality compared to surgery. Most of
the RFA are performed as day procedures. In addition, RFA is a versatile tool which has
proven to be very useful as it can be performed percutaneously, laparoscopically, and/or in
combination with surgical resection. The combination of RFA and surgical resection provides
a curative option to many patients who previously had inoperable tumours (e.g. bilobar
disease)[158-160].
Furthermore RFA has been used as a “bridging therapy” for patients with HCC while
awaiting liver transplant. Due to scarcity of organ donors, there is a high patient dropout rate
(10-30%) while waiting for liver transplantation[82, 161, 162]. Several studies have found
that pre-transplant treatment with RFA can reduce the dropout rate to 10-20%[82, 163]. In a
prospective study by Mazzaferro et al, RFA was found to be a safe and effective bridging
therapy to liver transplantation as there was no rapid HCC deterioration, tumour seeding or
vascular invasion during the pre-transplant period[164].
Another area where RFA would be useful is for the treatment of recurrent HCC[138, 145,
165]. Several studies have shown that the intra-hepatic tumour recurrence rate after resection
for HCC could be as high as 70% at 5-years[166-169]. Although repeat resection could
provide an effective treatment, it is limited to only 10-30% of the patients[170-173].
Some clinicians are concerned by the much higher tumour recurrence rates, and lower disease
free and overall survival rates in patients who received RFA compared to surgical resection.
Currently there are few “head to head” comparisons between RFA versus surgery in
technically resectable HCC. The majority of the literature available reported results where
RFA was used to treat “un-resectable” tumours which were, most of the time, associated with
advanced disease (e.g. Child-Pugh B/C HCC, or bilobar tumours) or the patient was too sick
47
to undergo surgery. These are adverse prognostic factors which could have a negative
influence on the patients’ outcomes, and therefore comparing RFA to surgery in these
different groups of patients is akin to comparing “apples to oranges”.
The capability of RFA to completely ablate a tumour is the most important principle
underlying its recent success in achieving survival parity with resection, albeit with the strict
criterion that the tumour size is 3.0 cm or less. As the results of this review show, there are no
significant differences in survival rates between RFA and resection for HCC within Milan
criteria[121-128]. When RFA was used for tumours outside Milan criteria, there were
significantly lower overall and disease free survival rates compared to resection[100, 134,
135].
There are now at least 5 reports[117, 137, 144-146], including 1 RCT[117], where RFA was
used to treat small resectable HCC in a carefully selected group of patients (early HCC within
Milan criteria). The results from these reports showed comparable overall survivals between
RFA and surgery, although there is a significantly higher tumour recurrence rate in the
former. Whether the higher tumour recurrence rates have any effect on the overall well-being
and health related quality of life of patients remains to be investigated. Tumour recurrences
under these circumstances can generally be re-treated, which might explain the comparable
overall survival rates between RFA and resection found in these reports.
As research progress continues in the field of RFA, there is little doubt that its indication for
use will broaden to include resectable HCC in the near future. However this progress must be
based on solid evidence from randomized controlled trials.
Addendum
Since the publication of this review article in the British Journal of Surgery, it has been
brought to the authors’ attention that one of the randomized controlled trials included in this
systematic review has since been retracted by its publisher[114]. The reasons for the
48
retraction was because of concerns regarding the validity of the study[174]. The authors were
not aware that this article has been retracted as it was retrieved for inclusion in this systematic
review before the notice of retraction was issued.
The authors subsequently re-analyzed the data of this systematic review, excluding the
retracted article, and found that this did not change the main findings or the conclusion of this
paper. Therefore no significant changes were made to this systematic review.
49
2.8. Systematic Review of Survival and Disease Recurrence after Radiofrequency
Ablation for Hepatic Metastases
Introduction
Liver cancer is the fifth most common malignancy worldwide and the third most common
cause of cancer related deaths[10]. Colorectal liver metastasis (CLM) is the most common
cause of secondary liver metastases where approximately 50% patients with colorectal cancer
will develop liver metastases, 25% as synchronous[175] and 25% as metachronous[176]
disease. Surgical resection is the only curative options available for these patients, with 5year survival as high as 58%[159, 177]. However, only 20% of these patients have resectable
disease[88]. Factors precluding surgery include extra-hepatic metastases, high risk anatomic
location, excessive size or number of lesions, in-sufficient remnant liver to support life, or comorbid conditions[10, 88]. If untreated, the median survival for these patients is 6-12
months[89, 90], with few surviving beyond 3 years[91]. Adjuvant chemotherapy can increase
the median survival to approximately 20 months. However, chemotherapy is toxic with
unpleasant side effects and less than ideal disease control capabilities.
There has been a surge of interest in local ablative therapy for un-resectable liver cancers
worldwide in the past 2 decades, which includes cryotherapy, PEI, LITT, HIFU, MCT and
RFA. Among these, RFA has been the most widely investigated therapeutic option for unresectable liver cancers[1]. It has been shown in numerous large series that RFA is safe, with
minimal morbidity and mortality. RFA has also been shown to achieve a satisfactory local
response rate, with >80% complete response (defined as negative contrast-enhanced CT scan
post-RFA) in most studies[93]. It also significantly improves overall survival when compared
to other modalities e.g. chemotherapy or PEI[86].
A major drawback of RFA is the high local tumour recurrence rate seen in patients who
received this treatment. This could have an adverse effect on patient survival, and is the main
reason why RFA is considered inferior to surgery for the treatment of resectable liver
50
cancers. Early RFA results were limited by the small ablation size achievable, and the lack of
sensitive radio-imaging modalities to assess treatment response.
Intense research over the last two decades has produced impressive results. Higher-powered
radiofrequency generators and modifications to the electrodes can produce ablation sizes up
to 6-7 cm in diameter. Whereas only lesions <3 cm were treatable with RFA in the past,
physicians now can ablate tumours up to 5 cm and still achieve a 0.5-1 cm ablative margin
[100, 103, 156]. These advances have opened the door to more patients who previously were
deemed “un-treatable” and whose options were only palliation or chemotherapy. Recent
results are showing that the gap between RFA and surgery for liver cancer is narrowing.
This systematic review aims to examine the results of RFA for hepatic metastases over the
past decade in terms of patient survival and disease recurrence.
Methods
A literature search was conducted using Medline (Jan 2000 – week 3 Nov 2010), EMBASE
(Jan 2000 – week 49 2010), Cochrane Central Register of Controlled Trials (Jan 2000 - 4th
Quarter 2010), Cochrane Database of Systematic Reviews (2005 to November 2010),
Cochrane Methodology Register (Jan 2000 - 4th Quarter 2010), Database of Abstracts of
Reviews of Effects (Jan 2000 - 4th Quarter 2010) as per the search terms in Table 3 without
language restriction.
51
1. Catheter Ablation/ or radiofrequency ablation.mp.
2. RFA.mp.
3. Liver Neoplasms/ or Neoplasm Metastasis/ or liver metastas*.mp.
4. hepatic metastas*.mp.
5. 1 or 2
6. 3 or 4
7. 5 and 6
8. limit 7 to (comment or editorial or letter or meta analysis or "review")
9. hepatocellular carcinoma.mp. or Carcinoma, Hepatocellular/
10. 7 not 8 not 9
11. limit 10 to (humans and yr="2000 -Current")
Table 3. Search terms used for literature search
Inclusion criteria were as follows: (1) Participants – individuals with hepatic metastases of
any origin. (2) Intervention – RFA with any generator or needle designs. (3) Comparative
interventions – surgical resection, chemotherapy and/or other ablative treatment e.g. PEI,
cryoablation, MCT, LITT, HIFU. (4) Outcome data (measured from the time of intervention)
includes survival rates (overall median survival, median survival at 1-, 3-, and 5-years, and
median disease free survival), and disease recurrence rates (calculated per patient). Three
types of disease recurrences were recorded; ablation site (tumour recurrence at the site of
ablation), intra-hepatic (tumour recurrence in the liver away from the site of ablation), and
extra-hepatic (tumour recurrence outside the liver). (5) Types of study – randomized
controlled trials, quasi-randomized controlled trials and non-randomized comparative studies
were included in the review. Case series reporting more than 50 patients receiving RFA were
also included to provide a comprehensive evidence summary of the outcomes after RFA for
hepatic metastases. In addition meeting abstracts and each article’s bibliography identified
above were cross-referenced for relevant publications. Only articles reporting survival and/or
disease recurrence were included in this review. Articles which reported a combination of
RFA with other treatment modalities (e.g. surgery, chemotherapy, other local ablative
52
therapy) were also included. (6) Exclusion criteria – articles were excluded if the outcome
data could not be clearly attributed to each specific intervention (e.g. RFA vs. resection) or
disease (e.g. HCC vs. liver metastases). Meta-analysis, review articles, letters/comments and
editorials were also excluded.
Results
A total of 39 articles were identified and included in this review (Figure 4 – Quorum chart),
of which only 10 were comparative studies. Twenty-nine articles reported RFA for CLM, 8
for various liver metastases, while one article each was identified for neuroendocrine and
breast cancer liver metastases. No RCT of RFA for hepatic metastases was identified. No
meta-analysis could be performed due to the heterogeneity in treatment modalities and patient
populations. The patients who were treated with RFA could be broadly divided into 2 groups;
“un-resectable hepatic metastases” (Appendices 9 & 10) and “resectable hepatic metastases”
(Appendices 11 & 12).
53
Potentially
relevant
studies
identified in the literature search
and screened for retrieval
(n=1591)
272 articles
duplicates
excluded-
Studies retrieved for more
detailed evaluation
(n=1319)
Potentially appropriate studies to
be included in the systematic
review (n=149)
1170 articles excluded –
failed
inclusion/exclusion
criteria or not related to RFA
for hepatic metastases after
reading title/abstract
(n=149)
110 articles excluded - failed
inclusion/exclusion criteria
after reading full text.
Studies included in the systematic
review (n=39)

29
–
colorectal
metastases

1 – neuroendocrine liver
metastases

1 – breast
metastases

8 – various liver metastases
cancer
liver
liver
Figure 4. Quorum chart
Outcomes after RFA for Un-Resectable Hepatic Metastases (Appendices 9 & 10)
There were 34 articles which reported the results of RFA for liver metastases. Analysis of
these articles showed 3 distinct ways of RFA utilization; RFA-only, RFA + resection, and
RFA + chemotherapy.
54
RFA for Un-resectable Hepatic Metastases [102, 155, 178-200]
Twenty-five studies reported the outcomes after RFA for liver metastases, involving a total of
2446 patients. The median largest tumour diameter in the studies ranged from 1.2-3.7 (mean
1.5-5.2) cm, whereas median follow-up was between 14-42 (mean 17-33.2) months. The
median survivals reported in 15 studies were between 25-52 months[178, 182, 183, 185-191,
195-198, 201]. The 1-, 3-, and 5-year median survival rates were 72.5-96% [102, 153, 155,
179, 180, 183, 184, 189, 190, 198, 199, 202], 25.1-68%[102, 153, 155, 156, 179, 180, 183,
184, 189, 190, 199, 200, 202], and 5-48%[156, 179, 189-191, 197, 198, 200, 202]
respectively. The rates of ablation site, intra-hepatic distant and extra-hepatic disease
recurrence were 9.7-47.2%[153, 155, 179, 181, 184, 185, 187, 190, 191, 194-200, 203], 962%[179-181, 190, 191, 195, 197, 200], and 5-54%[179, 180, 190, 191, 195, 197, 199, 200]
respectively.
Recently Gillams et al[188] published the largest series of RFA for CLM (median size 3.5
cm) in 2009 involving 309 patients. One hundred and fifteen patients (37%) had extra-hepatic
disease, while 292 (94.5%) patients had chemotherapy with no/partial response. Forty-eight
(15.5%) patients had previous liver resection. The patients were stratified into 2 groups based
on the number and size of tumours; group 1: ≤5 tumours ≤5 cm, and group 2: >5 tumours >5
cm. The overall median survival, 3-, and 5-yr median survival were 58%, 26%, and 39
months for group 1, and 29%, 5%, and 25 months for group 2 respectively (p<0.05). The
authors found that the number/size of tumour and the presence of extra-hepatic disease were
significant risks for worse survival in both uni- and multi-variate analysis. Sub-group analysis
55
showed that patients with ≤3 tumours <3.5 cm had the best outcome, with 5-year survival rate
of 33%.
Berber et al[197] compared laparoscopic RFA (n=68) to resection (n=90) in a group of
patients with solitary CLM. Median follow-up was 23 and 33 months for the 2 groups
respectively. The sizes of the tumours in the 2 groups were similar (3.7 cm vs. 3.8 cm,
p=0.9). All patients treated with laparoscopic RFA had un-resectable disease; and 26 of them
had extra-hepatic disease. No peri-operative mortality was reported. The complication rates
were 2.9% in the RFA group and 31.1% in the resection group. The authors reported a
median survival of 24 months for RFA patients with extra-hepatic disease, 34 months for
RFA patients without extra-hepatic disease, and 57 months for patients who had resection
(p<0.0001). Median disease free survival was 9 months in the RFA group versus 30 months
in the resection group (p<0.0001). There was no significant difference in the 5-year median
survival rate between the RFA and the resection group (30% vs. 40%, p=0.35) however. A
Cox proportional hazards model analysis showed that larger tumour size (>30mm vs.
<30mm, HR=1.6, p<0.0008) is a risk for worse outcome, while the type of intervention (RFA
vs. resection, HR=1.24, p=0.16) is not. A sub-group analysis of ASA I-II patients without
extra-hepatic disease who had RFA compared to those who had resection showed no
significant difference in median survival (49 months vs. 59 months, p=0.9).
Hur et al[200] retrospectively analyzed 67 patients with single CLM treated with either
resection (n=42) or RFA (n=25). Median size of the tumours was 2.6 and 2.5 cm in the
resection and RFA groups respectively. They reported that overall the disease recurrence and
survival rates were significantly better in the resection group compared to RFA. However
56
sub-group analysis showed that for patients with tumours <3 cm, there were no significant
differences in the overall survival or disease free survival between resection and RFA.
In an article published in 2005 Berber et al[195] examined 53 patients who had 192 “unusual
tumours” (cancers other than HCC, colorectal or neuroendocrine liver metastases) exclusive
to the liver treated with laparoscopic RFA. The majority of the patients had sarcoma (n=18)
or breast cancer (n=10). Disease recurrence at the site of ablation was 17% after a mean
follow-up of 24 months. The overall median survival was 33 months for the whole group.
Based on these results, the authors concluded that patients with “liver-exclusive disease” are
suitable candidates for RFA.
In 2007 Mazzaglia et al[198] reported the results of laparoscopic RFA for neuroendocrine
liver metastases. This is the largest case series to date involving neuroendocrine liver
metastases in 63 patients (384 tumours, mean size 2.3 cm). Nearly half of the patients (49%)
received medical and/or radiation therapy and 38% had extra-hepatic disease. Fifty-seven
percent of the patients were symptomatic pre-operatively. One week after RFA treatment,
92% of these patients reported at least partial symptom relief, and 70% had significant or
complete relief. After a mean follow-up of 33.6 months, 6.3% of the patients had disease
recurrence at the ablation site. Median survival was 46.8 months, whereas 1-, 2- and 5-yr
median survivals were 91%, 77% and 48% respectively.
Meloni et al[190] reported a series of 52 patients (87 tumours, mean size 2.5 cm) who were
treated with RFA for breast cancer liver metastases. Only patients with <5 tumours ≤5 cm
57
were included in the study. Ninety percent of the patients had no or partial response to
chemotherapy and/or hormonal therapy. Overall median survival after RFA was 29.9 months,
whereas median survival rates at 1-, 3-, and 5-years were 68%, 43% and 27% respectively.
Disease recurrence rates at the ablation site, intra-hepatic and extra-hepatic were 25%, 53%
and 54% respectively after a median follow-up of 19.1 months.
RFA + Regional/Systemic therapy for Liver Metastases [204, 205]
Scaife et al[204] reported a prospective series of 50 patients with colorectal liver metastases
(median largest diameter 2 cm) who received RFA in conjunction with hepatic artery infusion
chemotherapy (HAI) of continuous-infusion floxuridine (0.1 mg/kg days 1–7) and bolus
fluorouracil (12.5 mg/kg days 15, 22, and 29). Sixty-two percent of the patients completed
the full course of the chemotherapy. Post-operative morbidity and mortality rates were 18%
and 2% respectively. After a median follow-up period of 20 months, 32% of patients were
disease-free. The rates of disease recurrence at the ablation site, intra-hepatic and extrahepatic were 10%, 30% and 48% respectively. Although there were 31 patients who received
resection at the same time of RFA, this did not significantly affect the disease recurrence
rates.
Machi et al[205] reported the use of RFA in 100 patients with un-resectable CLM (mean
diameter 3 cm), either as first-line treatment (n=55) followed by chemotherapy or as secondline intervention after failed chemotherapy (n=45) which consisted of fluorouracil plus
leucovorin and/or irinotecan. The overall median survival was 28 months, and 1-, 3-, and 5years median survival were 90%, 42%, and 30.5% respectively. Uni-variate analysis showed
58
that RFA had significantly better median survival when used as first-line therapy compared to
it being used as 2nd-line therapy (48 vs. 22 months, p=0.0001).
In the article by Siperstein et al[206] RFA was used to treat 234 patients with un-resectable
CLM (mean diameter 3.9 cm), and who displayed disease progression despite chemotherapy.
The median overall survival was 24 months, and 3-, and 5-years median survival were 20.2%
and 18.4% respectively. They reported better median survival for patients with ≤3 versus >3
tumours (27 vs. 17 months, p=0.0018), and whose tumour diameter was ≤3 cm versus >3 cm
(28 vs. 20 months, p=0.07). Twenty four percent of the patients had extra-hepatic disease
during the first ablation, although this did not affect median survival compared to those
without extra-hepatic disease (20% vs. 25%, p=0.34). The types of chemotherapy regimens
(5-FU-leucovorin vs. FOLFOX/FOLFIRI vs. bevacizumab) also did not affect survival
(p=0.11).
RFA + Resection for Hepatic Metastases [158, 159, 207-210]
Six studies reported the outcomes after RFA was used together with surgical resection in 442
patients. The median tumour diameter ablated was between 1.0-2.5 cm, and median followup between 21-27.6 months. The median survival was 36-45.5 months[207, 211], whereas the
1- and 3-year median survival rates were 83-92% [207, 210], and 30-47% [207, 208, 210,
212] respectively. The disease recurrence rates at the ablation, intra-hepatic and extra-hepatic
sites were 2.3-17.4% [207, 209, 211, 212], 10.3-60.7% [207-209, 211, 212] and 30.2-46.2%
[207, 208, 211, 212] respectively.
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Pawlik et al[158] published the outcomes of RFA combined with hepatic resection in 172
patients with multi-focal hepatic malignancies (72.1% CLM) which were considered to be
un-resectable by conventional standards. Both procedures were performed during 1 operation
where 387 tumours were resected and 350 tumours ablated. After a median follow-up period
of 21.3 months, the rates of local tumour progression, intra-hepatic distant recurrence and
extra-hepatic metastases were 2.3%, 38.8% and 53% respectively. The median overall
survival was 45.5 months. The overall mortality and morbidity rates were 2.3% and 19.8% in
this series. Patients with CLM had worse survival compared to non-CLM (median survival 37
vs. 59 months, p=0.03). The authors found that tumours >3 cm had adverse effects on
survival (HR=1.85, p=0.04).
Abdalla et al[159] reported 418 patients with CLM who received 1 of 4 different treatment
modalities; hepatic resection (n=190), RFA + resection (n=101), RFA only (n=57) or
chemotherapy only (n=70). RFA-only treatment was associated with significantly higher
rates of local tumour progression and intra-hepatic distant recurrence when compared to RFA
+ resection or hepatic resection (p<0.001). However there was no significant differences in
the rates of extra-hepatic metastases between the 3 groups (p=ns). Hepatic resection provided
significantly better outcomes when compared to the other treatment groups in terms of
overall and recurrence-free survival. When compared to hepatic resection in a multi-variate
analysis, treatment by RFA + resection (HR 2.14, p=0.004) or RFA only (HR 2.79,
p<0.0001) were risk factors for decreased overall survival. The authors also analyzed the
results of RFA + resection, RFA-only versus chemotherapy-only which might be the more
comparable groups considering that the patients in these groups technically had “unresectable” tumours. Both the RFA + resection and RFA only groups had significantly better
60
results when compared to the chemotherapy group with a median 4-year overall survival rate
being 36%, 22% and 8% respectively (p=0.002).
More recently Gleisner et al[160] published their results of patients who had hepatic
resection (n=192), RFA + resection (n=55) or RFA-only (n=11) therapy for CLM. The
authors found that the patients who underwent resection had the best overall and disease-free
survival. The median overall survival for the resection group versus the RFA + resection
group was 73.4 months and 38.1 months respectively (p<0.001). The median disease-free
survival was 19.5 months versus 10.2 months respectively (p<0.001).
In contrast, in the article published by Leblanc et al[209], there were no statistically
significant differences in median survival at 2-years between patients with liver metastases
who received RFA + resection (n=28) versus those who had resection (n=37) only (68% vs.
83%, p=ns). There were also no significant differences in median disease-free survival
between the 2 groups of patients (12 vs. 18 months, p=ns).
Outcomes after RFA for Resectable Hepatic Malignancies (Appendices 11 & 12)
Three articles were identified involving a total of 245 patients. Two articles[213, 214]
involved only patients with CLM, and 1 article[215] with mixed hepatic malignancies.
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Livraghi et al[215] used percutaneous RFA to treat 88 patients with 134 resectable colorectal
liver metastases. Inclusion criteria were: age ≤75 years, lesion numbers ≤3, and size ≤4 cm in
diameter. Eighty percent of the patients had received chemotherapy, and 24% had previous
hepatic metastasectomy prior to RFA. Complete response rate was achieved in 53 (60%)
patients. After a median follow-up of 33 months, 40% of patients developed local tumour
recurrence whereas 10% and 6.8% developed new intra-hepatic and extra-hepatic recurrence
respectively.
Otto et al[214] was the first to report the results of percutaneous RFA for first episode
resectable colorectal liver metastases compared to surgical resection. As part of their
institutional clinical pathway, patients who developed colorectal liver metastases within 12
months of their colorectal surgery were treated preferentially with RFA. Exclusion criteria for
RFA were; tumour diameter >5 cm, number of lesions >5, superficial lesions, or lesions in
proximity to large vessels or bile ducts. Patients who were previously treated with liver
resection, ablative therapy or portal vein embolization, or who received down-staging
chemotherapy were also excluded from analysis. There were 28 patients in the RFA group,
and 82 in the surgical resection group, with an average tumour diameter of 3 cm (range: 1–5
cm) and 5 cm (range: 1–14 cm) respectively. The complete response rate after the first RFA
was 100%. The authors reported that the patients in the RFA group had significantly higher
rate of local tumour recurrence (32% vs. 4%, p<0.001), but similar rates of intra-hepatic
(50% vs. 34%, p=0.179) and extra-hepatic tumour recurrence (32% vs. 37%, p=0.820)
respectively. However most patients with local tumour recurrence in the RFA group were
amenable to further intervention compared to the resection group (50% vs. 27%, p=0.012),
therefore leading to similar rates of estimated 5-year survival (48% vs. 51%, p=0.961).
62
Elias et al[213] used percutaneous RFA to treat 47 patients (107 tumours) with resectable
hepatic tumour recurrences after previous hepatectomy. This article was included in this
systematic review although the number of patients was less than 50 (as per inclusion criteria)
because it is only one of the 3 articles available in the literature where RFA was used to treat
resectable disease. Therefore its data would be of significant value to clinicians treating
hepatic malignancies. In the article only patients with <5 lesions and maximal tumour
diameter <3.5 cm were included in the study. Twenty-nine (62%) patients had CLM and 5
(11%) had HCC. The average tumour diameter and follow-up period were 2.1 cm and 14.4
months respectively. The authors reported a mortality rate of 2% (n=1, portal vein
thrombosis) and a morbidity rate of 9%. Following the first RFA 26 patients developed a
second recurrence after an average of 5.5 months in the liver of which 18 were amenable to
repeat RFA. Six of the 18 patients developed a third recurrence after 3.4 months of which 4
were treated with repeat RFA. The rate of local tumour progression, intra-hepatic distant
recurrence and extra-hepatic metastases were 31.9%, 21.3% and 31.9% respectively. The
median overall survival rates at 1- and 2-years were 88% and 55% respectively. The authors
compared this cohort to a matched group of patients who received repeat resection in the
same institution of which the survival rates were 84% and 60% respectively. The authors
suggested that RFA could be an alternative to repeat resection for hepatic tumour recurrences
considering its low morbidity and mortality, and the similar rates of overall survival between
the 2 therapies. The study only reported short term results up to 2 years however.
Discussion
Current RFA capabilities are limited by the size of coagulation that can be achieved which
leads to incomplete ablations and consequently higher rates of local tumour recurrence. The
inability to completely ablate “larger” tumours, or tumours in high risk locations (e.g.
adjacent to large hepatic vessels or in sub-capsular areas) compounds the problem and are
adverse prognostic factors for local tumour recurrences. In addition most hepatic
malignancies are irregular in shapes which mean part of them may escape ablation. For these
larger and irregularly shaped tumours, multiple electrode insertions and ablations are usually
required to produce complete necrosis of the whole lesion including a 1 cm ablation margin,
which is not always easy to accomplish leading to incomplete ablation.
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Some clinicians are concerned over the much higher rates of local tumour recurrences and
lower disease-free and overall survival in patients who received RFA compared to surgical
resection. It should be noted that there are few “head to head” comparisons between RFA
versus surgery for resectable hepatic malignancies. The majority of the literature available
reported results where RFA was used to treat “un-resectable” tumours which were, most of
the time, associated with advanced disease (e.g. Childs-Pugh B/C HCC, or bilobar tumours)
or the patient was too sick to undergo surgery. These are adverse prognostic factors which
could have a negative influence on the patients’ outcomes, and therefore comparing RFA to
surgery in these different groups of patients is akin to comparing “apples to oranges”.
One intrinsic flaw of RFA is the high local tumour recurrence rate which can be up to 3040% [153], which is related to the capability to completely ablate a lesion. The complete
ablation rate of RFA, as measured by non-enhancement of the tumour during contrastenhanced CT scan, is directly related to the size of the tumour. For tumours where a higher
rate of complete ablation could be achieved, the 5-yr median survival rates could be up to
68.5% [216]. When used for larger tumours, the complete ablation rate and the long term
outcomes predictably became worse. In the article published by Chen et al [155] who
reported an overall complete ablation rate of 95% after RFA for hepatic malignancies, the
authors found that the success rate fell to 85 % for tumours >3.5 cm. The complete ablation
rates were also lower when the tumours were adjacent to the gallbladder (86.3%) and the
bowels (83.3%) respectively. The high local tumour recurrence rates and its adverse influence
on patients’ survival in the long term is the main reason why RFA is inferior compared to
surgical resection. Several studies have shown that when limited to tumours <3 cm, there
were no statistically significant differences in disease-free or overall survival rates between
RFA and resection[217, 218].
The evolution in the RFA technology has been phenomenal in the past decade. In the early
2000s, the use of RFA was limited by the size (≤3 cm) and number (<5) of lesions. With
better equipment and understanding, the indication for RFA continues to expand while
maintaining satisfactory outcomes. Ahmad et al [181] examined patient outcomes when they
64
were treated with a first generation RFA needle electrode (3 cm ablation diameter) compared
to a newer needle design (5 cm ablation diameter). Baseline patient and disease burden
(tumour numbers and sizes) characteristics were similar between the 2 groups of patients.
Their results showed that after a median follow-up of 26.2 months, the patients treated with
the newer RFA electrode had better disease free survival (16 vs. 8 months, p<0.01) and lower
rates of disease recurrence at the ablation site (5.2% vs. 17.4%, p<0.04). Clinicians are now
commonly using RFA to treat hepatic tumours >3 cm in size, with some even treating
tumours >5 cm with satisfactory results [100, 103, 156]. The number of lesions has ceased to
become an absolute contraindication to RFA.
RFA has its own distinct advantages compared to surgical resection of hepatic malignancies.
It is minimally invasive when performed percutaneously and has much lower rates of
morbidity and mortality compared to surgery. Most of the RFA are performed as day
procedures with patients leaving the hospital on the same day. In addition, RFA is a versatile
tool which has proven to be very useful to the hepatic surgeon as it can be performed
percutaneously, laparoscopically, or in combination with surgical resection. The combination
of RFA and surgical resection provides a curative option to patients who have inoperable
tumours by conventional standards (e.g. bilobar disease) [158-160, 207, 209, 210].
There is now at least 1 report [214] where RFA was compared to surgery for resectable
colorectal liver metastases. This report involved a carefully selected group of patients with
strict inclusion and exclusion criteria. The authors found that there was no statistically
significant difference in 3-yr median survival (67% vs. 60%, p=0.93) between the 2 groups.
However there are several potential biases to consider in this paper. Firstly the treatment
protocol used by the author is part of their clinical pathway to treat patients with CLM, and
not a randomized trial. Secondly the size of the tumours were significantly larger in the
surgery compared to the RFA group (5 cm vs. 3 cm, p=0.004), and lastly there were only 28
patients in the RFA group. Nevertheless this article has increased the evidence that perhaps
the time for a randomized controlled trial comparing RFA to surgery for resectable hepatic
malignancies has arrived.
65
3. Electrolysis and Electrochemical Therapy (ECT)
Electrolysis is the passage of a direct electric current through an ionic substance in a suitable
solvent, resulting in chemical reactions at the electrodes and separation of materials. This
process is used for a variety of purposes including treating malignant tumours in humans,
which is known as ECT. Various types of electrodes have been used and reported in the
literature, the most common of which is made of platinum[11, 219-221]. The low energy DC
polarizes the two electrodes, causing electron transfer from the cathode to the anode. The
anode will attract negatively charged ions (e.g. Cl-) while the cathode will attract positively
charged ions (e.g. Na+ and K+). The main chemical reactions occurring at the anode are[4,
222, 223]:
2 Cl- Cl2 + 2e2 H2O  O2 + 4H+ + 4eThere are several possible outcomes from a combination of the various ions above. The Cl2
and O2 can be liberated as gases. The H+ can react with Cl- to form HCl which increases the
acidity of the surrounding tissue. Finally all three by-products (H+, O- and Cl-) can combine
to form HOCl (hypochlorous acid). As a result the pH of the tissue around the anode becomes
more acidic [224-226].
The main chemical reaction at the cathode is [4]:
2H2O + 2e → H2 + 2OHThe hydrogen is liberated as a gas which is evident as rigorous bubbling, whereas the sodium
ions combine with hydroxyl ions (OH-) to form NaOH. This makes the tissue pH more basic
[224-226].
The products of the chemical reactions above are responsible for the cellular necrosis seen in
ECT. Species produced at the anode and cathode are mainly transported to the surrounding
tissue by diffusion due to concentration gradients, and by migration (charged species) due to
the potential gradient.
66
Chlorine, a powerful oxidant, and hypochlorous acid (HOCl) can both cause lethal injuries to
the surrounding cells [221]. The hydrogen ions released from the hydrolysis of water
molecules decrease the tissue pH, causing complete cellular necrosis when the pH is less than
six[222, 223]. The tissues around the cathode become more basic as a result of the liberated
hydroxyl (OH-) species. Tissue necrosis is complete when the pH is more than nine[222,
223].
Apart from the chemical insults described above there is evidence that other mechanisms of
cellular injury are actively involved, for example disturbances in blood flow and oxygenation
to the tumour. Jarm et al inserted ECT electrodes into healthy tissue on opposite ends, and 5
mm away from a mice fibrosarcoma tumour model[227]. The distance between the electrodes
and the tumour edge prevented the toxic chemicals from directly affecting the neoplastic
cells. They found that low level DC (0.6mA for 60 minutes) resulted in damaged or occluded
blood vessels at the insertion sites of the electrodes, leading to severe reduction in tissue
perfusion, extensive extravasation of blood cells and focal areas of necrosis in the tumours.
3.1. Animal Experiments
3.1.1. Tissue Temperature
Thermal energy has been shown to have no role in the cellular necrosis seen in ECT. Baxter
et al studied the relationship between ECT and tissue temperature in rat (2-4 mA) and porcine
(20-50 mA) livers [225]. The tissue temperature in the rat liver remained the same, but the
temperature in the pig liver increased by 4.2 degrees (p<0.01) after ECT. However the
average tissue temperature in the pig liver was 45.2 degrees at the end of ECT, which would
not be high enough to cause cellular necrosis by hyperthermia.
3.1.2. Water Content
Studies in animals have shown that water moves from the anode to the cathode. Li et al found
that the water content was 76% around the cathode, compared to 71% at the anode and 73%
67
in an untreated part of a canine liver model after 124 coulombs of DC was passed between
two platinum electrodes[228, 229].
3.1.3. Elemental Concentrations
The different polarity between the anode and the cathode will cause movements of the
different elemental ions. Negatively charged ion e.g. Cl- will move towards the anode,
whereas positively charged ions e.g. Na+, K+ will move towards the cathode [228, 229]. The
concentrations of multivalent ions e.g. Cu2+, Mg2+ and Ca2+ did not change much, because
their larger size is inversely proportional to the velocity of their movements [228, 229].
3.1.4. Tissue pH
Various chemical reactions occur around the anode and the cathode during ECT. The
elements H+, Cl- and O- around the anode can react to forms two types of acids; HCl and
HOCl. The element Na+ can react with OH- to form the alkali, NaOH. Tissue pH around the
anode becomes acidic, whereas that around the cathode becomes basic. The changes in tissue
pH were thought to be the main mechanism of cellular destruction during ECT. A study
published by Finch et al reported that tissue pH can be used to reliably monitor tissue
ablation in a porcine liver model[222]. Total cellular necrosis was observed when tissue pH
was less than six or more than nine[222]. Tissue pH during ECT could be as low as 2.1 at the
anode, and as high as 12.9 at the cathode[228, 229].
3.1.5. Gas Production
The main gas produced at the anode is chlorine, whereas that at the cathode, is hydrogen[228,
229].
3.1.6. Cellular Histological Changes
Histopathologic study showed marked dehydration of the hepatocytes around the anode with
pyknotic nucleus and small or absent cytoplasm[230]. The tissues around the cathode showed
cellular oedema, nuclear and cytoplasmic swelling with occasional disruption of the plasma
membranes.
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Histological studies in liver models showed a sharp demarcation between necrotic and normal
hepatic tissues. Necrotic cells appear as featureless, eosinophilic hepatocytes lacking
glycogen vacuoles[222, 231]. There was total destruction of cellular membrane, cytoplasmic
structures and the nuclei[232]. This zone of coagulative necrosis was surrounded by a rim of
actively proliferating cells (which included fibrobroblast and biliary ductules) with
neutrophilic infiltration[222, 231]. The necrotic area is gradually replaced by fibrotic tissues
and the scar contracts as healing occurs[231]. It was observed that ECT produced an area of
wedge-shaped infarct, with the apex at the site of the electrode placement and the base
extending towards the edge of the liver. These wedge-shaped infarcts were likely secondary
to vessel thrombosis induced during the ECT, and could be seen at both the anode and the
cathode sites[219].
3.1.7. Volume of Tissue Ablation
There is a linear relationship between the volume of liver tissue destroyed and the amount of
DC energy administered[219, 226]. The higher the ECT dose (measured in Coulombs) which
is given, the larger the volume of tissue destruction. The volume of tissue destruction was
found to be greater at the anode compared to the cathode[219].
3.1.8. Safety
Long-term studies in pigs showed that ECT was well tolerated and produced no major
adverse effects on the liver functions. The liver enzymes, aspartate transaminase, alanine
transaminase and gamma-glutamyltransferase, were elevated after ECT but returned to
baseline level after one week[233].
ECT was found to be remarkably safe around blood vessels. Wemyss-Holden et al studied
the effect of ECT around major vasculatures by inserting the electrodes into, and adjacent to
the hepatic veins of six pigs before administering 100 coulombs of DC[231]. No major
bleeding complications were encountered, and despite gas bubbles entering the hepatic veins
and inferior vena cava IVC, all animals recovered well post-operatively.
69
3.2. Human Studies
There is relatively sparse data on the clinical use of ECT in human beings, with no
randomized controlled trials reported in the literature. Most of the data originates from China,
with three case series published in 1994. Xin et al reported the use of ECT in 388 patients
with various types of tumours, both benign and malignant[234]. However due to the
heterogeneity of the study population, the results were not easily interpretable or applicable to
clinical practice. Wang et al used ECT to treat 74 patients with HCC ranging from 3-20 cm
with a 1-year survival rate of 33%[235]. Lao et al treated 50 patients with HCC ranging from
3.5-21 cm with a 1-year survival rate of 69%[236]
3.3. Modifications/Innovations
Lin et al investigated the effect of saline injection on increasing the efficacy of ECT[237]. He
compared the size of tissue ablation after injection of water, 0.9%, 3% or 26% saline versus
no injection during ECT in an ex-vivo porcine liver model. It was postulated that the
interstitial saline injection would lower electrical impedance and allow more electrical
current to pass through to the target tumour. In addition the increased water and electrolytes
concentration would enhance the electrochemical reactions. They found that the volume of
tissue destruction was 8.1 times greater in the 26% saline group compared to control.
Several studies have found that placing the electrodes at least 2 cm apart produced
significantly bigger volumes of tissue destruction compared to if the electrodes were placed
closer to each other [221, 226, 238]. It was postulated that placing the electrodes near each
other would result in mixing of the electrochemical products to re-form water and sodium
chloride, therefore reducing the cytotoxic effects of ECT.
70
3.4. Problems in ECT
The main problem encountered in ECT is that each treatment takes a long time to complete as
it depends on the diffusion of various cytotoxic chemicals to produce cellular necrosis. Hinz
et al took an average of 31 minutes to ablate of volume of 1.5cm3 of liver using ECT,
whereas ablation using RF took only four minutes[232]. In addition, they had to use four
electrodes (two cathodes and two anodes) for the ECT, compared to a single electrode
insertion for RFA[232]. In a case report published by Fosh et al, ECT for a 4.2 cm x 4.2 cm x
2.6 cm HCC took 288 minutes to complete[9]. In the case series reported by Wang et al and
Lao et al, the ECT treatment took between 1.5 to five hours to complete[235, 236].
71
4. Bimodal Electric Tissue Ablation (BETA)
Bimodal electric tissue ablation (BETA) is a new method of local ablative therapy utilizing
the electrochemical reactions of the DC to enhance the efficacy of RFA. BETA utilizes the
hydration effect produced at the cathode in the DC circuit to enhance the efficacy of thermal
ablations produced by RF generators.
It had been shown that during electrolysis, water was attracted to the cathode evident as local
tissue swelling around this electrode[7, 239]. Early BETA studies in porcine livers showed
that the liver would appear congested, and fluid would ooze out from its surface while
microscopically, the cells exhibited marked intra-cellular swelling compared to standard
RFA[12]. This property of the cathode is utilized in combination with standard RFA with the
aim of postponing tissue charring and carbonization around the RF electrode which are the
limiting factors in producing bigger ablations. This hydration effect allows RFA to continue
for a longer period of time, therefore producing larger ablation zones. Increasing the water
content in the tissue around the active electrode also improves electrical conduction allowing
thermal energy to be distributed more evenly throughout the whole tumour which is to be
ablated.
4.1. Early Experimental Results
In 2007 Cockburn et al[11] published a study investigating the effect of applying increasing
amounts of DC before and during RFA of porcine liver. Nine volts of DC was applied for
increasing duration of time (0, 30, 60, 90, 120, 300, 600, 900 seconds) before the RF 3000
generator was started at 20W, and both the DC and RF circuit was then allowed to run
simultaneously until roll-off. This new setup produced larger ablations when compared to
standard RFA (p<0.001).
In 2008 Dobbins et al published a study comparing the ablative size of BETA compared to
standard RFA using a 3.5 cm multi-tined LeVeen electrode[14]. Nine volts of DC was
provided for 15 minutes, after which the RF 3000 generator was switched on to provide 80W
72
of power. Both the DC and RF current were allowed to run until roll-off occurred; defined as
impedance higher than 700Ω or power output less than 5W. BETA was shown to produce
significantly larger ablations compared to standard RFA (27.78 mm vs. 49.55 mm, p<0.001).
The average treatment duration in BETA was significantly longer compared to standard RFA
(1115 seconds vs. 249 seconds, p<0.001).
Dobbins et al subsequently investigated the long term morbidity and pathological features of
BETA in a pig liver model[12]. Each procedure was started with 9V of DC for five minutes,
after which the RF circuit was started with 20W power output and both circuits allowed to
run simultaneously. Six ablations were produced in each of the 10 pigs used in the study,
after which two pigs were euthanatized at two days, two weeks, two months and four months
respectively. The pigs had their bloods taken at different time periods depending on their
survival, and upon sacrifice, their internal organs were examined for any abnormalities. The
authors found no significant changes in haemoglobin, total white cell count, creatinine,
albumin, bilirubin, alkaline phosphatase, alanine transaminase or gamma-glutamyltransferase
compared to baseline. There was a transient rise in serum aspartate transaminase, alkaline
phosphatase and C-reactive protein in the immediate post-operative period which normalized
after two days. The only complication reported was the occurrence of local tissue injury at the
site of the anode which manifested as full thickness skin necrosis. BETA was noted to
produce coagulative necrosis which healed from the periphery of the lesion towards the
centre. This feature was similar to that produced by standard RFA and electrochemical
therapy.
In all animal experiments performed so far, BETA had proven to be safe, except for the full
thickness skin necrosis at the site where the anode was placed. This was not unexpected
considering previous experiments involving ECT had shown that various cytotoxic chemicals
were produced at the anode, including acidic hydrogen ions and chlorine. Chlorine reacts
with water to form hypochlorous acid, chloride and hydrogen ions. As a result of these
reactions, the pH in the vicinity of the anode drops to around 1-2 with lethal consequences to
the surrounding cells and tissues. Such a complication is clearly unacceptable in humans and
before BETA could be used in the clinical setting, its safety feature needs to be improved
further.
73
Dobbins et al proceeded to investigate an alternative method to use as the anode with the aim
of preventing skin injury[13]. They hypothesized that by increasing the surface area of the
anode, it will reduce the current density in the adjacent tissue, therefore reducing the risk of
local tissue injury. He replaced the scalpel blade used in the earlier studies with a dispersive
grounding pad similar to the ones used for electro-surgical units. This had the advantage of
being easily available, and could be conveniently placed on the skin which was attractive
considering that many RFA procedures are carried out percutaneously. Dobbins et al
compared the severity of tissue injury occurring at the anode (scalpel blade versus dispersive
pad) and also the diameter of the ablation achieved, with standard RFA as the control. They
reported only mild skin erythema in three out of the six pigs where the dispersive pads were
used as the anode. These changes resolved completely in all three animals after 48 hours.
Post-mortem histopathologic examination showed that tissues at the site of dispersive pads
placement showed no significant changes compared to controls. Full thickness skin necrosis
was observed in all animals where scalpel blades were used. The ablation size was largest
when scalpel blades were used compared to dispersive pads (2.5 cm vs. 1.8 cm, p<0.001). A
possible explanation for this observation was that the outer skin of the pigs was very thick,
and a poor conductor of electricity. Therefore, the electrical resistance to the flow of DC was
greater when a dispersive pad was used as the anode on the skin compared to a scalpel blade
inserted subcutaneously. As a result, less water would accumulate around the cathode leading
to earlier charring and desiccation of tissue. This meant roll-off would have occurred sooner,
producing smaller ablation sizes. The ablations using dispersive pads were however, still
significantly larger when compared to standard RFA (1.8 cm vs. 1.533 cm, p<0.001).
Continuous effort is being made to further improve the efficacy of BETA. Recently a multinational group of researchers published an article on dose optimization study on BETA in an
ex-vivo bovine liver model. Tanaka et al[240] used similar circuitry modifications as
described by Dobbins et al, namely a DC generator attached to a Boston Scientific RF 3000
generator to allow ECT and RFA to run separately but also concurrently. The cathode was
connected to a 3 cm LeVeen RFA electrode via a 100mH inductor. The return electrode of
the RF generator and the positive electrode of the DC generator were attached to a metallic
basin into which the liver was placed. Electrolysis was performed for 15 minutes with three
74
different voltage settings (2.2V, 4V and 9V) prior to any RFA. After that the RFA was started
while allowing the DC energy to flow continuously. The RFA was performed using three
different protocols: (1) stepwise increase pattern where the RFA was started at 40W and
increased by 10W every 30 seconds up to 80W; (2) 40W fixed without increase in power; and
(3) 80W fixed without increase in power. The procedure was continued until roll-off occurred
twice.
The authors found that pre-treatment with 4.5V or 9V DC combined with RFA using either
the 40W fixed or step-wise increase protocol produced ablation volumes nearly twice as large
as the control or the 2.2V group (p=0.009). However, there were no significant differences in
ablation sizes when comparing the 4.5V to the 9V groups. The duration of RFA was
significantly shorter in the 40W step-wise increase protocol compared to the fixed 40W
protocol (296s vs. 423s, p=0.028) in the 4.5V DC group. There were no significant
differences in the duration of ablation when comparing the 4.5V to the 9V DC group.
In summary, the step-wise increase RF protocol produced ablation volumes comparable to
the 40W fixed protocol. The latter however, took a significantly longer time to produce. In
addition pre-treatment with a DC set at 4.5V produced ablation volumes comparable to a 9V
DC, but the total amperage applied was approximately half as much. These observations led
the authors to conclude that a combination of a step-wise increase RF protocol with a DC
current of 4.5V is the optimum BETA setting to increase coagulation volume and, at the same
time, minimize procedure duration in ex-vivo bovine liver.
75
5. Rationale for the Current Research
5.1. Experiment 1: Does BETA really work by increasing tissue hydration?
It is not known exactly how BETA works. It has not been definitively proven yet that the
capability of BETA to produce larger ablations was indeed due to the increased tissue
hydration secondary to the DC. It is also not known how much the DC can increase the
hydration of tissues adjacent to the cathode. Existing data shows that electrolysis only
increased the water content at the cathode by approximately 3%[228, 239]. However, the DC
was run for a significantly longer period of time (69 minutes[228], 48 hours [239]) compared
to what was utilized in BETA. This “pre-treatment with DC” in BETA must not be prolonged
or it will make the whole procedure too time-consuming for clinical use.
One simple method to investigate the above question, whether BETA produced larger
ablations by increasing the tissue moisture, is to reverse the polarity of the DC. The anode,
instead of the cathode, is attached to the RF electrode and its effect on tissue ablation studied.
There are several different reactions that occur at the anode compared to the cathode besides
the net movement of water molecules from the former to the later. Due to the different
polarity, cations (e.g. Na+ and K+) will move towards the cathode, whereas anions (Cl-) move
towards the anode[228, 229]. Chloride can be liberated as chlorine gas, or react with H+
and/or O- to form HCL or HOCL respectively. These acids greatly reduce the tissue pH and is
one of the main mechanisms of cellular destruction seen in ECT. At the cathode the water
molecule is broken down to liberate hydrogen gas, and the by-product hydroxyl ions react
with sodium ions to form the alkali sodium hydroxide. Therefore, the tissue pH at the cathode
rises which will also cause cellular destruction, although to a lesser extent compared to the
anode.
Apart from the net movement of water molecules from the anode to the cathode, all the other
reactions and by-products of electrolysis should not have any effect on the RFA. Therefore, if
the hypothesis put forward by Cockburn et al and Dobbins et al is correct, then reversing the
polarity of BETA would produce smaller ablations compared to standard RFA or BETA as
the anode would cause tissue desiccation.
76
5.2. Experiment 2: Where is the optimum place to put the anode?
One of the important questions in BETA is where to place the anode. Dobbins et al reported
full thickness skin necrosis and abscess formation when the anode is placed in the
subcutaneous tissues[12]. This problem was solved by attaching the anode to the skin using
electrosurgical dispersive pads[13]. However the ablations produced were significantly
smaller due to the higher electrical impedance in the skin. Therefore a new option is required
where the anode can be placed to maximize the benefit of BETA, and yet minimize the local
tissue injury.
Evidence in the literature suggests that the tissue with the highest electrical impedance in the
body is the skin, more specifically the stratum corneum of the epidermal layer[241]. This
would explain the observation that placing the anode on the skin surface resulted in smaller
ablations. It was postulated that bypassing the skin layer and putting the anode below it
would overcome this problem.
In the second experiment, the peritoneum and the liver were studied as alternate locations to
place the anode. ECG dots were used instead of a needle electrode to increase the surface
area in contact with the tissues with the aim of minimizing local tissue injury.
5.3. Experiment 3: Can BETA be incorporated into the Cool-Tip RF System?
Previous research on BETA using the RF 3000 System (Boston Scientific) has shown that it
could significantly increase the duration and size of ablations compared to standard RFA. The
RF 3000 System has the “roll-off” as its end-point, which means that the ablation stops
automatically when the tissue impedance has risen too high to allow further electrical
conductance. Another popular RF system on the market is the Cool-Tip RF System
(Covidien), which uses time as its end-point during an ablation. The manufacturer’s
recommended protocol suggests switching the generator to the “impedance mode” to provide
maximum power for 12 minutes ablation. In this “impedance mode” the generator
continuously monitors tissue impedance, and will stop power output for 15 seconds when the
impedance rises more than 10 Ohms above baseline values. This, in addition to the internal
77
cooling of the electrode using chilled-saline, minimizes tissue charring and allows better
energy distribution throughout the whole tumour.
It was not known whether the principle of BETA could be incorporated into the Cool-Tip RF
System (Covidien) to increase the size of ablations compared to standard RFA only, which
was the objective of the third experiment.
78
Title of Thesis: Improving the Safety and Efficacy of Bimodal Electric Tissue Ablation
Student Name: Dr. Tiong, LU
CHAPTER 5:
Experiment 1
Bimodal Electric Tissue Ablation (BETA) – Effect of Reversing the
Polarity of the Direct Current on the Size of Ablation
Tiong LU (MBBS)‡, Finnie JW (BVSc, PhD, FRCVS)*, Field JBF (PhD, AStat)†, Maddern
GJ (PhD, MS, MD, FRACS)‡
‡Department of Surgery, The Queen Elizabeth Hospital, Adelaide, Australia
*SA Pathology, Institute of Medical and Veterinary Science, Adelaide, Australia
†University of Adelaide Faculty of Health Sciences & Basil Hetzel Institute, Adelaide,
Australia
Journal of Surgical Research 2011 – accepted paper
79
Title of Thesis: Improving the Safety and Efficacy of Bimodal Electric Tissue Ablation
Student Name: Dr. Tiong, LU
Statement of Authorship
Title of Paper: Bimodal Electric Tissue Ablation (BETA) – Effect of Reversing the Polarity
of the Direct Current on the Size of Ablation
Journal of Surgical Research 2011 – accepted paper
Dr. Tiong, LU (Candidate)
Planned and performed experiment, data collection and analysis, and prepared the
manuscript.
I hereby certify that the statement of contribution is accurate.
Dr. Finnie, JW
Performed histo-pathological analysis of specimens
I hereby certify that the statement of contribution is accurate and I give permission for the
inclusion of the paper in the thesis
80
Title of Thesis: Improving the Safety and Efficacy of Bimodal Electric Tissue Ablation
Student Name: Dr. Tiong, LU
Dr. Field, JBF
Performed power calculation for sample size and statistical analysis on the experimental data
obtained
I hereby certify that the statement of contribution is accurate and I give permission for the
inclusion of the paper in the thesis
Prof. Maddern, GJ
Supervised the development of work, helped in data interpretation, manuscript evaluation and
acted as the corresponding author.
I hereby certify that the statement of contribution is accurate and I give permission for the
inclusion of the paper in the thesis
81
Experiment 1: Bimodal Electric Tissue Ablation (BETA) – Effect
of Reversing the Polarity of the Direct Current on the Size of
Ablation
Introductions
Radiofrequency ablation (RFA) is increasingly used to treat liver tumours (e.g. HCC and
liver metastases) especially in cases where the tumours are technically un-resectable[89, 242245]. One major limitation of this technique is the excessively high rate of local tumour
progression which can be up to 30-40%[153, 246]. This limitation is related to the
incapability of RFA to achieve complete ablation of a liver tumour[194, 247]. It has been
shown in numerous studies that successful complete ablations in smaller sized tumours (≤30
mm) were associated with lower rates of local tumour progression (<10%)[107, 123, 159,
248, 249]. Livraghi et al[216] published a case series in 2008 where they reported a total of
218 patients with single HCC ≤20 mm in diameter who were treated with RFA. They
reported a sustained complete ablation rate of 97.2% after a median follow-up of 31 months,
and 5-year survival rate of 68.5%. When the size of the tumour increases, the success rates of
complete ablation reduce therefore leading to a high local disease recurrence rate[250].
Multiple RF generator and electrode modifications have been made to produce larger
ablations to overcome this problem, however none have yet to prove 100% effective. Highpowered generator capable of delivering higher energy output [96, 249], cold-saline perfused
needle electrode [251], saline enhanced electrode [250, 252], and multi-tined needle electrode
[253] are some of the examples of recent innovations in the field of RFA.
More recently the combination of DC with RFA to increase the size of tissue ablation was
introduced[11-14]. This is in a sense a combination of electrolysis and RFA, although the
underlying principle is slightly different from the conventional electrolytic therapy.
82
The process of electrolytic therapy to treat liver tumours has been investigated extensively
[220, 221, 224-226, 238]. The anode was conventionally inserted into the centre of the
tumour to be ablated as it produces larger area of necrosis compared to the cathode. The
mechanisms of cellular necrosis have been attributed to various processes including changes
in tissue pH levels [222, 230], release of toxic gases (chlorine and hydrogen), and the
occlusion of vessels feeding the tumour [227].
During the electrolytic process, it was noted that the tissues surrounding the anode would
become desiccated, while those surrounding the cathode would become oedematous with
water [239, 254]. Therefore, there is a net movement of the water molecules to the tissues
adjacent to the cathode. It was this “hydrating” property of the cathode that forms the
underlying principle in BETA.
Cockburn et al and Dobbins et al postulated that increasing the hydration of the liver tissues
around the active RF electrode would reduce the tissue temperature during ablation[11-14].
This would delay tissue desiccation and allow the ablation process to continue for a longer
period of time therefore, produce larger ablations. This combination of the cathode belonging
to a DC circuit together with a RF electrode is called bimodal electric tissue ablation (BETA),
and it has been shown to produce significantly larger ablations compared to standard RFA.
It is not known exactly how BETA works, and it has not yet been proven that the capability
of BETA to produce larger ablations was indeed due to the increased tissue hydration
secondary to the DC. It is also not known how much the DC can increase hydration of tissues
adjacent to the cathode. Existing data has shown that electrolysis only increases the water
content at the cathode by approximately 3% [228, 229]. However, that DC was run for a
significantly longer period of time (69 minutes [228], 48 hours [239]) compared to what was
utilized in BETA. This “pre-treatment with DC” in BETA must not be too long or else it will
make the whole procedure too time-consuming for clinical use.
83
One simple method to investigate the above question, whether BETA works by increasing the
tissue moisture, is to reverse the polarity of the DC. The anode, instead of the cathode, is
attached to the RF electrode and its effect on tissue ablation studied. There are several
different reactions that occur at the anode compared to the cathode besides the net movement
of water molecules from the former to the later. Due to the different polarity, cations (e.g.
Na+ and K+) will move towards the cathode, whereas anions (Cl-) move towards the anode
[228, 229]. The chloride can be liberated as chlorine gas, or react with H+ and/or O- to form
HCL or HOCL respectively. These acids greatly reduce the tissue pH and this is one of the
main mechanisms of cellular destruction seen in electrolytic therapy. At the cathode the water
molecule is broken down to liberate hydrogen gas, and the by-product hydroxyl ions react
with sodium ions to form the alkali sodium hydroxide. Therefore, the tissue pH at the cathode
rises which causes cellular destruction, although to a lesser extent compared to the anode.
Apart from the net movement of water molecules from the anode to the cathode, all the other
reactions and by-products of electrolysis should not have any effect on the RFA. Therefore, if
the hypothesis put forward by Cockburn and Dobbins is correct, then reversing the polarity of
BETA will produce smaller ablations compared to standard RFA or BETA as the anode will
cause tissue desiccation.
This study aims to investigate the size of ablation when the polarity of DC is reversed,
namely the anode is combined with the RF electrode. This new combination is abbreviated to
RP-BEA (reversed polarity bimodal electric ablation) throughout the rest of the thesis to
distinguish it from standard RFA and BETA.
Materials and Methods
This study was performed in the animal laboratory at The Queen Elizabeth Hospital
(Adelaide) using domestic female white pigs each weighing approximately 50 kg. All
animals were admitted to the experimental facility a minimum of two days before the
experiment for acclimatization. The animals were housed in individual pens, maintained at 23
+/- 1ºC, at ambient humidity. Lighting was artificial, with a 12-hour on/off cycle. The air
84
exchange rate and airflow speed complied with the Australian code of practice for the care
and use of experimental animals. The pigs were fed and watered ad libitum (standard grower
diet of 0.7 g of available lysine per mega-Joule of digestible energy, with a digestible energy
content of 14 MJ/kg). Water quality was suitable for human consumption.
Preoperatively, the pigs were fasted for 12 hours. Each pig was sedated with an intramuscular injection of ketamine (0.5 mg/ kg). General anaesthetic was induced and maintained
using of 1.5% isofluorane mixed in oxygen. An endotracheal tube was placed to maintain the
airway and a temperature probe was placed inside the endotracheal tube to monitor core
temperature of the animal. The pig was placed on a warming pad in the base of its cradle to
assist in temperature homeostasis. An oxygen saturation probe was placed on the pigs tongue
to monitor oxygen saturations. Throughout the procedure, recordings for pulse, temperature,
oxygen saturations, end-tidal carbon dioxide levels and cardiac rhythm was monitored. The
pig received 0.9% normal saline solution through an intravenous line throughout the course
of the procedure.
The abdomen was cleaned with iodine solution and square-draped with sterile towels. A midline incision was made from the xiphi-sternum to the umbilicus. The falciform ligament was
divided and the liver mobilized inferiorly. The porcine liver exhibits deep fissures that divide
it into left lateral and medial and right lateral and medial lobes. Additionally, the short
quadrate lobe and the caudate process are present centrally[255].
All experimental
procedures were carried out in the liver tissue thick enough to accommodate the whole
ablation. The surrounding organs were protected and packed away with moist gauze packs.
Three different ablations were carried out on each pig as follows:
1.
Standard RFA only
2.
BETA-skin – with the anode attached to the skin using ECG dots
3.
RP-BEA – with the cathode attached to the skin using ECG dots
85
A Boston Scientific RF 3000 generator was used to provide the radiofrequency energy.
Aluminium rods measuring 40x2 mm were used as the RF electrode and were inserted 20
mm into the liver tissue. The grounding pad for the RF 3000 generator was placed on the
inner thigh of the animals’ hind-leg.
A generic AC/DC adaptor was used to provide the DC. In BETA the cathode of the AC/DC
adaptor was connected to the RF electrode wiring using a 1 mH inductor. This inductor
allows the flow of the DC into the radiofrequency circuit, but prevents the leakage of
alternating current from the RF 3000 generator into the DC circuit. Therefore the needle
electrode of the RF 3000 generator and the cathode of the DC circuit are one and the same.
The anode of the DC circuit was attached to the skin using a standard ECG diagnostic
electrode (ECG dots). In RP-BEA the polarity of the DC circuit was reversed; therefore the
anode was connected to the RF electrode, and the cathode attached to the skin via ECG dots.
For the first procedure, only the RF energy was delivered to the liver tissue. The RF 3000
generator was started to deliver 40 watts of power until “roll-off” occurred – defined as when
power output was less than 5 watts or tissue impedance was more than 700 Ohm. The total
ablation time for each procedure was recorded. For the second and third procedure 9 volts of
DC was provided to the liver tissue for 10 minutes before the RF 3000 generator was
switched on. This 10 minutes of 9V DC is called the “pre-treatment” phase. Thereafter both
electrical circuits were allowed to run concurrently until “roll-off” occurred.
A thermocouple was inserted 10 mm into the liver tissue along the RF electrode track, and
temperature recordings were taken at the following 4 different time-points:
1.
Baseline – before the start of any procedures
2.
Pre-treatment – after 10 minutes of DC, before the start of RFA
3.
Highest temperature achieved during ablation
4.
End temperature – when “roll-off” occurred
86
Upon completion of the procedure the abdomen was inspected for any signs of haemorrhage
or injuries to the liver and the surrounding organs. The abdominal wall was closed in layers
using 1/0 Maxon for the fascia and 3/0 Caprosyn for the skin. The wound edges were
infiltrated with 20 ml of 0.5% bupivacaine and the anaesthesia was reversed. A single dose of
noracillin (0.3 mg/kg) was given intra-muscularly. The pigs were also provided with intramuscular injections of buprenorphine (0.5 mg/kg) 12-hourly, and ketoprofen (3mg/kg) daily.
Once self-ventilation recommenced, the endotracheal tube was removed and the pigs returned
to an individualized, warm pen and closely monitored for signs of distress until it was awake
and able to stand. Food and water was supplied so the pigs could recommence eating as soon
as they wished.
At 48 hours, the pigs were sacrificed under anaesthesia by lethal intravenous injection of
sodium pentobarbitone. The liver and the surrounding organs were inspected for signs of
injury or haemorrhage. After death skin biopsies were taken from the areas where the ECG
dots were placed and put in 10% buffered formalin. The livers were then harvested and the
ablation zones resected in their entirety. The axial diameter (parallel to the electrode insertion
track) and two transverse diameters (at right angles to each other) were measured between the
white zones of the ablation. The liver specimens were then placed in 10% buffered formalin
and subjected to histological examination under haematoxylin and eosin stain. Photographs
were taken of the areas where the ECG dots were placed before and after the procedure, and
at 48 hours when the animals were sacrificed.
Animal research ethics approval was obtained from the Institute of Medical and Veterinary
Service (IMVS) and the University of Adelaide animal ethics committee. The study
conformed with the Code of Practice for the Care and Use of Animals for Scientific Purposes
2004 and the South Australian Prevention of Cruelty to Animals Act 1985.
87
Results
Ten pigs were used in this study and all tolerated the procedures well and survived 48 hours
until euthanasia. There were no signs of haemorrhage or injury to the surrounding organs
when the abdomen was re-opened to harvest the liver.
The study outcome measures are shown in Table 4. There was a statistically, but not
clinically, significant difference in the baseline temperature of the liver tissue between the
RFA compared to the BETA and RP-BEA groups (37.5°C vs. 37.9°C and 37.8°C, p<0.001).
Ten minutes of DC at 9 V did not produce statistically significantly changes in the tissue
temperature in the BETA or the RP-BEA group when compared to each other (37.8°C and
37.9°C respectively, p=0.11), or to their baseline temperature. The highest tissue temperature
recorded during the ablation process in the RFA, BETA and RP-BEA groups were 87.1°C,
73.3°C and 71.6°C respectively; the differences did not achieve statistical significance
(p=0.07). Similarly, there were no statistically significant differences in the end temperature
(when ablation “rolled-off”) between the 3 groups (p=0.18).
The duration of ablation was significantly longer in the RFA and BETA group compared to
the RP-BEA groups (148s and 84s and 48s, p=0.004).
The sizes of ablations were smaller in all three dimensions in RP-BEA compared to standard
RFA (Table 4). The transverse diameter A & B, and the axial diameter in RP-BEA were
12.5mm, 9.1mm and 18.1mm; which were significantly smaller than those produced by
standard RFA (15.8mm, 12.4mm and 22.3mm respectively; p<0.05). The transverse diameter
B and the axial diameter were also significantly smaller in RP-BEA compared to BETA-skin
(9.1mm vs. 11.6mm, p=0.001; and 18.1mm vs. 21.4mm, p=0.006).
88
Standard RFA
BETAskin
RP-BEA
p-value
Temperature
Baseline (°C)
37.5 a
37.9 b
37.8 b
<0.001
Pre-treatment (°C)
n/a
37.8
37.9
0.11
Highest (°C)
87.1
73.3
71.6
0.07
End (°C)
78.5
67.6
68.2
0.18
148 a
84 a
48 b
0.004
Transverse diameter A
15.8 a
13.2 a,b
12.5 b
0.04
Transverse diameter B
13.4 a
11.6 a
9.1 b
0.001
Axial diameter
22.3 a
21.4 a
18.1 b
0.006
Duration of Ablation (seconds)
Size of ablation (mm)
Table 4. Tissue temperature, duration of ablation and size of ablation in the Standard RFA, BETA-skin and RPBEA groups respectively.
In four animals (Pig 1-4) small skin ulcers (2-3 mm) were noted after RP-BEA where the
cathode was placed on the skin (Figure 5). In Pig 4 the skin ulcer healed completely after 48
hours at euthanasia and was no longer macroscopically evident. Microscopic examination
showed variable extent of coagulation necrosis of the epidermal layer. Some sections showed
only intra-epidermal necrosis of stratum spinosum with intact stratum corneum and stratum
basale. Other sections however showed extensive coagulation necrosis of the whole
epidermal layer down to the upper dermis. There was minimal inflammatory reaction in the
dermal layer. After the BETA-skin procedure, there were no macroscopic or microscopic
changes to the skin where the anode was placed (Figure 5.a).
Macroscopic examination of the RP-BEA liver specimens showed cylindrical lesions clearly
demarcated from the surrounding viable tissues (Fig. 6.a). Immediately adjacent to the
89
electrode track was a rim of tissue of pale discoloration corresponding to an area of
coagulation necrosis. Surrounding this area of coagulation necrosis is a thin envelope (1-2
mm) of hyperaemic zone where viable cells could still be found. Microscopic examination
revealed a central haemorrhagic wound track with widespread disruption of hepatic cords and
individualisation of degenerate and necrotic hepatocytes (Fig. 6.b). In more severely injured
parts of the wound track, there was coagulation necrosis of hepatocytes with preservation
only of cellular outlines. At the periphery of the track, there was sometimes a mild to marked
neutrophilic reaction and, in many wound tracks, a severe necrotising vasculopathy,
sometimes attended by thrombosis. The mentioned features are similar to those seen in
standard RFA and BETA-skin liver specimens (Fig. 7 & 8).
Figure 5 (a) & (b)
Figure 6 (a) & (b)
90
Figure 7 (a) & (b)
Figure 8 (a) & (b)
Discussion
BETA and RP-BEA work in a similar way to RFA, which uses thermal energy to cause
cellular coagulation necrosis. The main purpose of combining the cathode of the DC circuit
with the RF electrode is to increase tissue hydration which will delay premature tissue
desiccation, therefore allowing the ablation process to continue for a longer period of time
and produce larger ablations.
91
It can be inferred from the results of this experiment that it was the hydrating effect of the DC
at the cathode that improved the efficacy of BETA, therefore leading to the larger ablation
size compared to standard RFA. Reversing the polarity of the DC, as in RP-BEA, desiccated
the liver tissues, causing “roll-off” to occur earlier compared to standard RFA.
An observation in this study worth noting is that the sizes of ablations were similar in
standard RFA and BETA-skin. This is in contradiction to the results obtained by Dobbins et
al who reported that BETA produced larger ablations than standard RFA (18 mm vs. 15.33
mm, p=0.001)[13]. There were some differences between their study protocol and the current
one. Dobbins et al ran 9V of DC for 15 minutes, compared to 10 minutes in this study. In
addition they set the RF 3000 generator to deliver 80 W of energy, compared to 40 W in this
study. Lastly, Dobbins et al used a much larger electro-surgical grounding pad, as compared
to the ECG dots used here. These different protocols could explain the conflicting results
described above.
There were no differences in the temperature profiles between the three ablation groups
investigated. Previous studies on electrolysis found minimal changes in tissue temperature of
approximately 4 °C[225]. In the current study, although the p<0.001 for baseline temperature,
the difference was only 0.4 °C and therefore not clinically significant. After 10 minutes of
DC at 9V, the pre-treatment tissue temperature essentially remained unchanged compared to
baseline levels. There was no pre-treatment temperature for the RFA group as DC was not
used. Although the average highest- and end-temperatures were much higher (14-16 °C) in
the RFA compared to the BETA and RP-BEA group, the differences were not statistically
significant. The reason for this observation is not clear. One possible explanation is that the
DC interfered with the circuitry of the thermocouple, which measures temperature based on
electrical conductivity. However, the thermocouple was always checked before and after each
procedure and found to be functioning properly. The thermocouple was always inserted 10
mm into the liver tissue along the same track as the RF electrode. However there is always
the possibility that the location and distance of the thermocouple from the RF electrode was
different across the study groups.
92
It is also not clear why or how the first four pigs developed skin ulcers where the cathode was
attached to the skin using ECG dots during RP-BEA. Histological examination under H&E
stains showed features of coagulation necrosis involving mostly the superficial epidermal
layer, but with some focal areas of full epidermal necrosis. The process of electrolysis itself
can cause tissue injury, mainly due to increased pH levels from the accumulation of sodium
hydroxide. Conventional electrolytic therapy takes a much longer time to cause cellular
injury, usually in the order of several hours. In this study, the whole process of RP-BEA took
on average only 10.8 minutes (10 minutes pre-treatment with DC + average ablation duration
48 seconds). A leakage of the alternating current from the RF 3000 generator into the DC
circuit leading to thermal injury is also a possibility, although less likely for several reasons.
Firstly, no skin injury was observed where the anode was attached to the skin using similar
ECG dots in the BETA group. Secondly and most importantly, these skin ulcers were only
observed in the first four pigs. If the fault was indeed due to electrical leakage, one would
expect to see the skin ulcers in all 10 pigs.
In conclusion this study showed that RP-BEA (which combines the anode of a DC circuit to
the RF electrode) leads to a shorter duration of ablation and smaller ablation size compared to
standard RFA and BETA. The anode desiccated the tissues adjacent to it, leading to the
observations as described above. Therefore the theory that BETA (which combines the
cathode of a DC circuit to the RF electrode) increases ablation size due to the effects of
increased tissue hydration around the RF electrode is correct.
93
Title of Thesis: Improving the Safety and Efficacy of Bimodal Electric Tissue Ablation
Student Name: Dr. Tiong, LU
CHAPTER 5:
Experiment 2
Bimodal Electric Tissue Ablation (BETA): A study on Ablation Size
when the Anode is placed on the Peritoneum and the Liver
Tiong LU (MBBS)‡, Finnie JW (BVSc, PhD, FRCVS)*, Field JBF (PhD, AStat)†, Maddern
GJ (PhD, MS, MD, FRACS)‡
‡Department of Surgery, The Queen Elizabeth Hospital, Adelaide, Australia
*SA Pathology, Institute of Medical and Veterinary Science, Adelaide, Australia
†University of Adelaide Faculty of Health Sciences & Basil Hetzel Institute, Adelaide,
Australia
Journal of Surgical Research 2011 – accepted paper
94
Title of Thesis: Improving the Safety and Efficacy of Bimodal Electric Tissue Ablation
Student Name: Dr. Tiong, LU
Statement of Authorship
Title of Paper: Bimodal Electric Tissue Ablation (BETA): A study on Ablation Size when the
Anode is placed on the Peritoneum and the Liver
Journal of Surgical Research 2011 – accepted paper
Dr. Tiong, LU (Candidate)
Planned and performed experiment, data collection and analysis, and prepared the
manuscript.
I hereby certify that the statement of contribution is accurate.
Dr. Finnie, JW
Performed histo-pathological analysis of specimens
I hereby certify that the statement of contribution is accurate and I give permission for the
inclusion of the paper in the thesis
95
Title of Thesis: Improving the Safety and Efficacy of Bimodal Electric Tissue Ablation
Student Name: Dr. Tiong, LU
Dr. Field, JBF
Performed power calculation for sample size and statistical analysis on the experimental data
obtained
I hereby certify that the statement of contribution is accurate and I give permission for the
inclusion of the paper in the thesis
Prof. Maddern, GJ
Supervised the development of work, helped in data interpretation, manuscript evaluation and
acted as the corresponding author.
I hereby certify that the statement of contribution is accurate and I give permission for the
inclusion of the paper in the thesis
96
Experiment 2: Bimodal Electric Tissue Ablation (BETA) – A
Study on Ablation Size When the Anode is placed on the
Peritoneum and the Liver
Introduction
Surgical resection is the gold standard treatment for resectable liver cancers e.g. HCC and
liver metastases. However, only 20% of liver cancers are amenable to surgical resection[88,
256, 257]. RFA is a technique that is increasingly used to treat un-resectable liver tumours. It
is a minimally invasive therapy with low morbidity and mortality rates, and can be performed
percutaneously in a “day-surgery” setting. However the long term outcomes of RFA for liver
tumours are inferior to surgical resection due to the high local tumour recurrence rates. This
is related to the incapability of RFA to achieve complete ablation of the whole tumour,
especially when the size of the tumour is >3 cm[185, 258, 259].
Numerous modifications have been made to both the RF generator and the electrode design to
increase the size of tissue ablation achievable.
One recent discovery is BETA which
combines the cathode of a DC circuit to the RF electrode to increase the size of tissue
ablation[11-14]. The cathode will increase the hydration of the tissues around it which will
delay tissue desiccation and “roll-off” during an ablation. Therefore, it allows the ablation
process to continue for a longer period of time resulting in larger ablations.
BETA is still a new technique in the field of ablative therapy, therefore, its safety and
efficacy profile needs to be ensured before its use can be translated into the clinical setting.
One of the problems with BETA identified in a previous study was the tissue injury
associated with the positive electrode (anode). In their animal studies, Dobbins et al attached
the anode to a scalpel blade which was inserted into the subcutaneous tissue which
subsequently resulted in a full thickness skin necrosis[12]. In retrospect this was not
unexpected considering that in previous experiments involving electrolytic therapy, various
cytotoxic chemicals were shown to be produced at the anode including acidic hydrogen ions
97
and chlorine[224-226]. Chlorine reacts with the hydrogen ions and water to form
hydrochloric and hypochlorous acid[224-226]. As a result of these reactions, the pH in the
vicinity of the anode drops to around 1-2 with lethal consequences to the surrounding
cells[224-226]. A complication such as this is clearly unacceptable in humans.
Dobbins et al proceeded to investigate an alternative method to use the anode with the aim of
preventing skin injury[13]. They hypothesized that increasing the surface area of the anode it
will reduce the current density per centimetre square of tissue, thereby reducing the risk of
local tissue injury. They replaced the scalpel blade with a dispersive grounding pad similar to
the ones used for electro-surgical units. This had the advantage of being easily available, and
could be conveniently placed on the skin which was attractive considering that many ablative
therapies are carried out percutaneously. Dobbins et al compared the severity of tissue injury
occurring at the anode (scalpel blade versus dispersive pad), and also the diameter of the
ablations achieved. Standard RFA were also performed as controls. They reported mild skin
erythema in three out of the six pigs where the dispersive pads were used as the anode. These
changes resolved completely in all three animals, and at 48 hours during post-mortem
examination the tissue at the site where the dispersive pads were used showed no changes
compared to controls. Full thickness skin necrosis was observed in all animals where scalpel
blades were used. However the size of ablation was significantly smaller when the dispersive
pads were used compare to the scalpel blade (1.8 cm vs. 2.5 cm, p<0.001). A possible
explanation for this observation was that the outer skin of the pigs was very thick, and is a
poor conductor of electricity. This leads to greater resistance to the flow of direct current
when the dispersive pad was placed on the skin compared to the scalpel blade inserted
subcutaneously. Therefore less water would accumulate in the tissues around the cathode
leading to earlier tissue desiccation and roll-off, and resulting in smaller ablation sizes.
Thus an alternative solution is required which maximizes the benefits of the DC, while
minimizing the complications. This study investigated two alternative sites to place the
anode, one on the internal abdominal wall (parietal peritoneum) and another on the liver, in
order to improve the efficacy and safety profile of BETA.
98
Materials and Methods
This study was performed in the animal laboratory at The Queen Elizabeth Hospital
(Adelaide) using domestic female white pigs each weighing approximately 50 kg. All
animals were admitted to the experimental facility a minimum of two days before the
experiment for acclimatization. The animals were housed in individual pens maintained at
23±1 ºC at ambient humidity. Lighting was artificial with a 12-hours on/off cycle. The air
exchange rate and airflow speed complied with the Australian code of practice for the care
and use of experimental animals. The pigs were fed and watered ad libitum (standard grower
diet of 0.7 g of available lysine per mega-Joule of digestible energy, with a digestible energy
content of 14 MJ/kg). Water quality was suitable for human consumption.
Pre-operatively, the pigs were fasted for 12 hours. Each pig was sedated with an intramuscular injection of ketamine (0.5 mg/ kg). General anaesthetic was induced and maintained
using of 1.5% isoflurane mixed in oxygen. An endotracheal tube was placed to maintain the
airway and a temperature probe was placed inside the endotracheal tube to monitor the core
temperature of the animal. The pig was placed on a warming pad in the base of its cradle to
assist in temperature homeostasis. A pulse oximeter was placed on the pigs tongue to monitor
oxygen saturations. Throughout the procedure temperature, oxygen saturations, end-tidal
carbon dioxide levels, heart rate and cardiac rhythm were monitored. The pig received 0.9%
normal saline solution through an intravenous line throughout the course of the procedure.
The abdomen was cleaned with iodine solution and square-draped with sterile towels. A midline incision was made from the xiphi-sternum to the umbilicus. The falciform ligament was
divided and the liver mobilized inferiorly. The porcine liver exhibits deep fissures that divide
it into left lateral and medial and right lateral and medial lobes. Additionally, the short
quadrate lobe and the caudate process are present centrally[255]. All experimental procedures
were carried out in the liver tissue thick enough to accommodate the whole ablation. The
surrounding organs were protected and packed away with moist gauze packs.
Four different ablation configurations were carried out in each pig as follows:
99
1.
Standard RFA only.
2.
BETA-skin – with the anode attached to the skin using ECG dots. The anode was
always placed on the left side and 10 cm away from the midline incision.
3.
BETA-peritoneum - with the anode attached to the parietal peritoneum using ECG
dots. The anode was always placed on the internal abdominal wall on the left side and 10 cm
away from the midline incision.
4.
BETA-liver - with the anode attached to the liver using ECG dots. The anode was
always placed on the surface of the liver away from the RF electrode.
A Boston Scientific RF 3000 generator was used to provide the radiofrequency energy.
Aluminium rods measuring 4 x 0.2 cm were used as the RF electrode and were inserted 2 cm
into the liver tissue. The grounding pad for the RF 3000 generator was placed on the inner
thigh of the animals’ hind-leg.
A generic AC/DC adaptor was used to provide the DC. In BETA the cathode of the AC/DC
adaptor was connected to the RF electrode wiring using a 1 mH inductor. This inductor
allows the flow of the DC into the RF circuit, but prevents the leakage of alternating current
from the RF 3000 generator into the DC circuit. Therefore the needle electrode of the RF
3000 generator and the cathode of the DC circuit are one and the same. The anode of the DC
circuit was attached to the three different places as described above using a standard ECG
diagnostic electrode (ECG dots).
For the first procedure, only the RF energy was delivered to the liver tissue. The RF 3000
generator was started to deliver 40 watts of energy until “roll-off” occurred – defined as when
power output was less than 5 watts or tissue impedance was more than 700 Ohm. The total
ablation time for each procedure was recorded. For the second, third and fourth procedure, 9
volts of DC was provided to the liver tissue for 10 minutes before the RF 3000 generator was
switched on. This 10 minutes of 9V DC is called the “pre-treatment” phase. Then both
electrical circuits were allowed to run concurrently until “roll-off” occurred.
100
A thermocouple was inserted 1 cm into the liver tissue along the RF electrode track, and
temperature recordings were taken at the following 4 different time-points:
1.
Baseline – before the start of any procedures
2.
Pre-treatment – after 10 minutes of DC, before the start of RFA
3.
Highest temperature achieved during ablation
4.
End temperature – when “roll-off” occurred
Upon completion of the procedure the abdomen was inspected for any signs of haemorrhage
or injuries to the liver and the surrounding organs. The abdominal wall was closed in layers
using 1/0 Maxon for the fascia and 3/0 Caprosyn for the skin. The wound edges were
infiltrated with 20 mL of 0.5% bupivacaine and the anaesthesia was reversed. A single dose
of noracillin (0.3 mg/kg) was given intra-muscularly. The pigs were also provided with intramuscular injections of buprenorphine (0.5 mg/kg) 12-hourly, and ketoprofen (3mg/kg) daily.
Once self-ventilation recommenced, the endotracheal tube was removed and the pigs returned
to an individualized, warm pen and closely monitored for signs of distress until awake and
able to stand. Food and water was supplied so the pigs could recommence eating as soon as
they wished.
At 48 hours, the pigs were sacrificed under anaesthesia by lethal intravenous injection of
sodium pentobarbitone. The liver and the surrounding organs were inspected for signs of
injury or haemorrhage. After death biopsy specimens were taken from the spots where the
anodes were placed (skin, parietal peritoneum and the liver) and put in 10% buffered
formalin. The livers were then harvested and the ablation zones resected in their entirety. The
axial diameter (parallel to the electrode insertion track) and two transverse diameters
(perpendicular to each other) were measured between the white zones of the ablation. The
liver specimens were then fixed in 10% buffered formalin for examination under
haematoxylin and eosin (H&E) stain. Photographs were taken of the areas where the ECG
101
dots were placed before and after the procedure, and at 48 hours when the animals were
sacrificed.
Animal research ethics approval was obtained from the Institute of Medical and Veterinary
Service (IMVS) and the University of Adelaide animal ethics committee. The study
conformed with the Code of Practice for the Care and Use of Animals for Scientific Purposes
2004 and the South Australian Prevention of Cruelty to Animals Act 1985.
Results
Ten pigs were used in this study and all tolerated the procedures well and survived 48 hours
until euthanasia. There were no signs of haemorrhage or injury to the surrounding organs
when the abdomen was re-opened to harvest the liver.
The study results can be seen in Table 5. The baseline temperatures of the liver tissue were
essentially the same between all the groups although there were statistically, but not
clinically, significant differences. Ten minutes of 9V DC did not produce significant changes
in the tissue temperature in the BETA-skin, BETA-peritoneum or the BETA-liver group
when compared to one another (37.8°C, 38.6°C and 38.5°C respectively, p=0.11), or to their
baseline temperature. The highest tissue temperature recorded during the ablation process in
the RFA, BETA-skin, BETA-peritoneum and the BETA-liver groups were 87.1°C, 73.3°C
and 88.7°C and 84.7°C respectively; the differences did not achieve statistical significance
(p=0.21). Similarly there were no statistically significant differences in the end temperature
(when ablation “rolled-off”) between the four study groups (p=0.39).
102
BETA-
BETA-
BETA-
skin
peritoneum
liver
37.5 a
37.9 c
37.5 a,b
37.8 bc
0.002
Pre-treatment (°C)
n/a
37.8
38.6
38.5
0.11
Highest (°C)
87.1
73.3
88.7
84.7
0.21
End (°C)
78.5
67.6
79.5
78.2
0.39
154 a,b
84 a
220 b
214 b
0.006
Transverse diameter A
15.8 b
13.2 a
20.8 c
18.5 c
<0.001
Transverse diameter B
13.4 a
11.6 a
18.5 b
17.3 b
<0.001
14.6 b
12.4 a
19.7 c
17.9 c
<0.001
22.3
21.4
24.5
23.7
0.09
RFA
p-value
Temperature
Baseline (°C)
Duration
of
ablation
(seconds)
Size of ablation (mm)
Average transverse
diameter
Axial diameter
Table 5. Each variable was examined using a randomised block analysis of variance with pigs as blocks.
Duration was analysed on a log scale. The table gives the mean for each treatment. The mean followed by the
same letter are not significantly different from each other (at p=0.05, using Fisher’s protected least significant
differences).
The duration of ablation in the BETA-peritoneum and BETA-liver groups was 220 seconds
and 214 seconds respectively, which were significantly longer than the BETA-skin group (84
seconds). The duration of ablation in the standard RFA group (154 seconds) was not
significantly different from those in the BETA-skin, BETA-peritoneum or BETA-liver
groups.
103
The transverse diameter A and B in the BETA-peritoneum and BETA-liver groups were
significantly larger when compared to the RFA and BETA-skin groups (p<0.001). The
average transverse diameter in the BETA-peritoneum, BETA-liver, RFA and BETA-skin
groups were 19.7 mm, 17.9 mm, 14.6 mm and 12.4 mm respectively (p<0.001). The axial
diameter in the BETA-peritoneum and BETA-liver groups were also larger compared to the
RFA and BETA-skin groups, although the differences did not reach statistical significance
(p=0.09).
Macroscopic and Microscopic Findings
The gas bubbling was most vigorous during BETA-peritoneum and BETA-liver compared to
BETA-skin. There was no gas bubbling during RFA as no DC energy was provided. This
indicated that the electrolytic process was most active when the anode was placed on the
peritoneum and the liver compared to the skin.
Macroscopic and microscopic examinations of the skin specimens where the anode was
placed in the BETA-skin group showed no signs of local tissue injury (Figure 9).
On the internal abdominal wall where the anode was placed on the peritoneum (BETAperitoneum), there was a circular area of erythema which persisted up to 48 hours when the
liver was harvested. The circular shape corresponded to the ECG dots used. Microscopic
examination showed focal coagulation necrosis involving the serosal lining of mesothelium
and sub-mesothelial layer of connective tissue, attended by minor haemorrhage, fibrin
deposition, a mild mixed inflammatory infiltrate (chiefly neutrophils), and early fibrovascular
granulation tissue formation (Figure 10)
There was a similar discoid area of purplish discoloration on the liver where the anode was
placed in the BETA-liver group. This discoloration however was no longer visible
macroscopically at 48 hours. Under microscopic examination the discoid area of
discoloration corresponded to an extensive, but of variable severity, area of coagulation
104
necrosis of the collagenous hepatic (Glisson’s) capsule with a mixed neutrophilic and
lymphoplasmacytic infiltrate and early fibroblastic invasion. The underlying liver
parenchyma was normal (Figure 11).
(a)
(b)
(c)
Figure 9. Morphology of the skin pre-operatively (a) compared to post-operatively (b) The brown discoloration
in the picture on the right was from iodine solution (c) Microscopic examination showing normal skin.
(a)
(b)
(c)
Figure 10. BETA-peritoneum (a) A circular area of erythema and inflammation was evident on the internal
abdominal wall immediately after procedure, and (b) 48 hours later (c) H&E (x4 magnification) showed
coagulation necrosis of the peritoneal serosa and superficial submesothelial connective tissue.
105
(a)
(b)
(c)
Figure 11. Beta-liver (a) A similar circular area of inflammation on the liver, the anode was placed on the
surface of the liver away from the RF electrode (b) 48 hours later the inflammation was no longer visible
macroscopically, but H& E examination (c) showed coagulation necrosis involving the liver capsule with
sparing of the underlying liver parenchyma.
Discussion
The ECG dots used in this study worked well as the anode of the DC circuit. It conducted
electricity well and avoided the unnecessary trauma of inserting an electrode into the animal
tissues. However it was difficult to stick the ECG dots onto the abdominal wall or the liver
because of the “wetness” of those surfaces. A pack was used to hold the ECG dots against the
peritoneal and liver surfaces. Therefore it might be impractical to be used in humans in the
clinical setting.
Rigorous gas bubbling, a sign of DC activity, could be seen during the pre-treatment phase
and was more active in the BETA-peritoneum and BETA-liver groups compared to the
BETA-skin group. This observation correlated with previous experiments showing better
electrical conductivity in the peritoneum and the liver tissues compared to the skin[260].
The results from this study showed that the more “active” the DC was, the larger the ablation
size. Better electrical conductivity led to more rigorous electrolytic reactions which meant
that there was more net movement of the water molecules from the anode to the cathode. The
relatively higher tissue hydration in the BETA-peritoneum and BETA-liver groups compared
to the BETA-skin and RFA groups meant that the ablation process could proceed for a
significantly longer period of time before “roll-off” occurred. Consequently larger ablations
106
were obtained in the BETA-peritoneum and BETA-liver groups compared to the latter (Table
5).
It was observed during the course of the animal study that the distance between the cathode
and the anode might affect the size of ablation produced. During BETA-liver the anode (ECG
dot) was placed on the surface of the liver away from the RF electrode (to which the cathode
was attached). It was noted that when the anode was placed on the opposite surface of the
liver to the RF electrode, the duration of ablation would be shorter and the ablation size
relatively smaller compared to when the anode was placed on a separate liver lobe. In
addition the axial and the average transverse diameter in BETA-liver were slightly smaller
when compared to BETA-peritoneum in this study (Table 5). Therefore putting the cathode
and the anode too closely together could negate the benefits of BETA. When the anode was
placed in close proximity to the cathode, the distance between the two electrodes might be
too small for any meaningful transport of the water molecules.
We found that the anode still produced localized tissue injury when attached to the
peritoneum or the liver using ECG dots. There was visible local tissue inflammation after the
ablation process, with evidence of coagulation necrosis under microscopic H&E examination.
The extent of the injury however was superficial and not as severe as those in previous
studies[12, 13].
Placing the anode on the peritoneum may be undesirable as it produced localised coagulation
necrosis of the superficial epithelium. The extent of injury was not as severe as the full
thickness skin necrosis as seen in previous studies[12, 13]. Nevertheless any peritoneal injury
can induce adhesions which can cause complications such as bowel obstructions. In addition,
the peritoneal surface is not accessible to place the anode during percutaneous RFA.
The liver could be an ideal place to put the anode. During conventional electrolytic therapy,
the anode will induce small vessel thrombosis with resultant wedge ischaemia/infarct in the
liver tissues distally[227]. Therefore the anode could be inserted into a proximal location
107
relative to the tumour to be ablated. This will induce thrombosis of the vessels feeding the
tumour causing ischaemia, and may have a synergistic effect with the subsequent RFA. The
distance between the electrodes must not be too close; otherwise the main benefit of the DC
to increase tissue hydration around the RF electrode is lost. A second option is to insert the
anode into a different liver lobe to where the tumour is located. This gives the distance
required for effective tissue hydration at the cathode. These two options would limit the
iatrogenic injury to the liver only. There would be coagulation necrosis at the anode, but the
amount of tissue involved would be minimal as the whole BETA process will take
significantly less time than the conventional electrolytic therapy. In addition the liver has a
large functional reserve and excellent regenerative capability.
An alternative option is to induce artificial ascites in the intra-abdominal compartment using
0.9% normal saline solution, and immerse the anode in this solution. Artificial ascites using
normal
saline
solution
has
been
employed
when
RFA
was
used
to
treat
superficial/subcapsular tumour in close proximity to surrounding organs e.g. bowels and
stomach[261, 262]. This method appeared to be well tolerated with minimal morbidity. The
artificial ascites act as an intermediary medium between the anode and the biological tissues.
The presence of sodium chloride in the solutions greatly facilitates electrical conduction. In
addition the larger surface contact area between the saline solution and the biological tissues
minimizes any adverse effects normally seen at the anode, as the toxic chemicals produced
are diluted in the saline solution.
The idea of using an electrosurgical grounding pad attached to the skin as the anode is very
attractive as it cheap and readily available. The downside of this was the fact that the ablation
sizes produced were not as large compared to when the anode was placed intra-abdominally.
The hypothesis was that the skin has a high electrical resistivity, therefore minimizing the
hydrating effect at the cathode. It is possible that the pig skin is thicker than human skin,
therefore causing higher electrical resistivity. As BETA has never been tested in humans, it is
not known what the effect of using an electrosurgical grounding pad on the human skin as the
anode would be. Therefore further research is required to investigate how to maximize the
efficacy of the DC with the anode attached to the skin using an electrosurgical grounding pad.
108
There are several possible methods to reduce the electrical resistivity of the skin. One is to
wet the skin which will greatly facilitate electrical conduction[263]. The risk with this
obviously is the possibility of causing electrical burns. Another method to improve electrical
conductivity of the skin is to scrap the superficial layers of the skin off. Previous studies have
shown that the resistivity to DC and AC resides almost exclusively in the stratum
corneum[263, 264]. The stratum corneum is only approximately 15-20 μm thick[265, 266]
and consists of anucleated cells which contain only 15% water[241]. Subsequent layers of the
epidermis contain 70% water and therefore have electrical resistivity similar to internal
organs[241]. One group of researchers found that combing the hair scraps off the superficial
layer of the scalp greatly facilitates measurement of the brainwaves activity during an
electroencephalography (EEG)[267]. Therefore simple methods, e.g. applying sticky tape to
the skin and stripping it off multiple times before putting on the anode, may improve
electrical conductivity. However further studies are required to ensure that such methods do
not cause unwanted side effects such as skin irritation, or increasing the skin’s susceptibility
towards electrochemical injury.
In conclusion, BETA produced larger tissue ablations compared to standard RFA, and hence
could be used to treat larger tumours more effectively and potentially reduce the tumour
recurrence rates. The efficacy of BETA depends on ensuring good electrical conductivity
between the cathode and the anode of the DC circuit. Research so far has shown that BETA
works best when the anode is placed deep into the skin layer as the stratum corneum consists
of a layer of anucleated cells which have high electrical resistivity. The liver could be the
ideal location to place the anode as it has excellent electrical conductivity, therefore ensuring
maximum tissue hydration around the cathode to produce the largest ablations possible.
Future studies should investigate the effect of the distance between the cathode and the anode
on the size of tissue ablation in BETA. There might be an optimum distance between the two
electrodes which will produce the largest tissue ablation.
109
Title of Thesis: Improving the Safety and Efficacy of Bimodal Electric Tissue Ablation
Student Name: Dr. Tiong, LU
CHAPTER 5:
Experiment 3
Bimodal Electric Tissue Ablation (BETA) compared to the Cool-Tip
RFA System
Tiong LU (MBBS)‡, Field JBF (PhD, AStat)†, Maddern GJ (PhD, MS, MD, FRACS)‡
‡Department of Surgery, The Queen Elizabeth Hospital, Adelaide, Australia
†University of Adelaide Faculty of Health Sciences & Basil Hetzel Institute, Adelaide,
Australia
Australian and New Zealand Journal of Surgery 2011 – accepted paper
110
Title of Thesis: Improving the Safety and Efficacy of Bimodal Electric Tissue Ablation
Student Name: Dr. Tiong, LU
Statement of Authorship
Title of Paper: Bimodal Electric Tissue Ablation (BETA) compared to the Cool-Tip RFA
System
Australian and New Zealand Journal of Surgery 2011 – accepted paper
Dr. Tiong, LU (Candidate)
Planned and performed experiment, data collection and analysis, and prepared the
manuscript.
I hereby certify that the statement of contribution is accurate.
Dr. Field, JBF
Performed power calculation for sample size and statistical analysis on the experimental data
obtained
I hereby certify that the statement of contribution is accurate and I give permission for the
inclusion of the paper in the thesis
111
Title of Thesis: Improving the Safety and Efficacy of Bimodal Electric Tissue Ablation
Student Name: Dr. Tiong, LU
Prof. Maddern, GJ
Supervised the development of work, helped in data interpretation, manuscript evaluation and
acted as the corresponding author.
I hereby certify that the statement of contribution is accurate and I give permission for the
inclusion of the paper in the thesis
112
Experiment 3: Bimodal Electric Tissue Ablation Compared to
Standard Radiofrequency Ablation Using the Cool-Tip RF
System
Introduction
RFA is currently one of the most popular ablative therapies used for the treatment of unresectable liver malignancies, including HCC and secondary liver metastases[1, 85, 268]. The
most important aim of RFA is to achieve complete ablation of a tumour. However the
fundamental problem with the existing RFA technology is the limited ablation size that is
achievable, leading to incomplete tumour ablation. Currently some RFA equipment is
capable of creating a lesion up to 5 cm in size during a single application[269-271]. This is
only adequate for treating a tumour 3 cm in size, with a 1 cm ablative margin to ensure
complete eradication of any cancerous cells. In reality the ability to achieve complete ablation
including a safety margin of 1 cm is usually more complicated. Numerous factors such as
tumour size >3 cm, irregularly shaped tumours, tumours adjacent to vital structures e.g.
bowel or gallbladder, and the “heat sink” effect from major vessels can all affect the complete
ablation rates[149, 155]. For these reasons, RFA is associated with higher rates of local
disease recurrence compared to other curative treatment such as resection or liver
transplantation for HCC[153, 217, 218].
One of the latest developments in the field of RFA is BETA[11-14]. BETA incorporates the
process of electrolysis (which uses direct current) into RFA to increase the size of tissue
ablation. The cathode of a DC circuit is attached to the RF electrode so that both the RF and
DC energy can be administered at the same time. The electrochemical reactions at the
cathode (which is attached to the RF electrode) attract water molecules to the tissues
surrounding it[7, 239]. The increased tissue hydration was postulated to delay the process of
desiccation during RFA, which prolongs the duration of ablation therefore producing larger
ablations compared to standard RFA[11, 14].
113
Previous research on BETA used a 5-15 minutes pre-treatment phase where 9V of DC was
used to increase tissue hydration before the RF generator was started[12-14]. Thereafter both
electrical circuits were allowed to run at the same time until “roll-off” occurred. Dobbins et al
used the RF 3000 generator (Boston Scientific) with multi-tined LeVeen needle electrodes,
and produced significantly larger ablations compared to standard RFA[14].
The RF 3000 generator (Boston Scientific) is an impedance based machine. This means that
an ablation process typically continues until “roll-off” occurs; defined as when the tissue
electrical impedance increases dramatically which precludes any further electrical
conduction. The RF generator then automatically stops any further power output. Therefore
BETA can improve the efficacy of the RF 3000 system (Boston Scientific) by delaying tissue
desiccation and prolonging the ablation process resulting in larger ablations.
Another popular RF system in the market is the Cool-Tip RF system (Covidien) which uses
internally-cooled electrodes (ICE) for ablation. This system circulates chilled saline to the tip
of the electrode needle, which lowers the temperature of the tissue immediately adjacent to it.
In addition, the generator has an “impedance mode” which makes it capable of continuously
monitoring the tissue impedance during an ablation. When it senses that the tissue impedance
has increased by ≥15 Ohms from baseline level, the power output will be ceased temporarily.
These intermittent pauses allow gases adjacent to the electrode to dissipate while the internal
cooling with chilled-saline minimizes tissue charring, hence improving the delivery of energy
to surrounding tissues[36]. Data from the manufacturer’s website claims that an ICE with a 3
cm exposed tip can produce a lesion 3.6 x 3.1 x 3.7 cm in diameter in ex-vivo bovine livers
after 12 minutes of ablation. The endpoint of an ablation process using the Cool-Tip RF
system is based on time (12 minutes), rather than upon “roll-off”. Therefore whether the
principle of BETA can be applied to the Cool-Tip RF system (Covidien) to improve its
efficacy is unknown and has never been tested before.
Besides this, all previous research using in-vivo animal models had run the DC circuit before
(for 5-15 minutes) and during RFA[11-14]. It was not known whether applying the DC only
during the pre-treatment phase, followed by just the RFA (named ECT/RFA in this thesis),
could produce similar results compared to BETA. This information has important practical
114
and financial implications. If the 2 methods have similar efficacy, it is possible to use the
existing equipment (ECT and RFA are widely used all over the world) and start treating
patients more effectively without the need to spend large sums of money or time to develop a
new BETA machine.
Therefore, the purpose of this experiment is two-fold:
1.
To investigate whether the principle of BETA can be applied to the Cool-Tip RF
system (Covidien) to produce larger ablations compared to standard RFA.
2.
To compare the size of ablations produced in ECT/RFA (defined as 10 minutes of
pre-treatment with 9V DC followed by RFA only) to standard RFA and BETA.
Methods
This study was performed in the animal laboratory at The Queen Elizabeth Hospital
(Adelaide) using domestic female white pigs each weighing approximately 40-50 kg. All
animals were admitted to the experimental facility a minimum of two days before the
experiment for acclimatization. The animals were housed in individual pens maintained at
23±1ºC at ambient humidity. Lighting was artificial with a 12-hours on/off cycle. The air
exchange rate and airflow speed complied with the Australian code of practice for the care
and use of experimental animals. The pigs were fed and watered ad libitum.
Pre-operatively, the pigs were fasted for 12 hours. Each pig was sedated with an intramuscular injection of ketamine (0.5 mg/ kg). General anaesthetic was induced and maintained
using 1.5% isoflurane mixed with oxygen. An endotracheal tube was placed to maintain the
airway and a temperature probe was placed inside the endotracheal tube to monitor the core
temperature of the animal. The pig was placed on a warming pad in the base of its cradle to
assist in temperature homeostasis. A pulse oximeter was placed on the pigs tongue to monitor
oxygen saturations. Throughout the procedure temperature, oxygen saturations, end-tidal
carbon dioxide levels, heart rate and cardiac rhythm was monitored.
115
The abdomen was cleaned with iodine solution and square-draped with sterile towels. A right
subcostal incision was made to expose the liver. The falciform ligament was divided and the
liver mobilized infero-medially. The porcine liver exhibits deep fissures that divide it into left
lateral and medial and right lateral and medial lobes. Additionally, the short quadrate lobe
and the caudate process were present centrally[255].
All experimental procedures were carried out in the liver tissues thick enough to
accommodate the whole ablation. The surrounding organs were protected and packed away
with moist gauze packs. Three types of ablation setup were tested:
1. Standard RFA
2. BETA – 9V of DC for 10 minutes, then the RF generator was switched on and both
circuits operated simultaneously
3. ECT/RFA – 9V of DC for 10 minutes, then followed by RFA only
A Cool-Tip RF Ablation System (Covidien) capable of producing 200 watts of energy at 480
kHz was used in this study. The parameters displayed on the panel of the generator included
tissue temperature and impedance, electrical current, power output and time. The generator
comes with a peristaltic pump that circulates chilled saline through the needle electrodes. The
Cool-Tip RF Ablation System (Covidien) has an automatic feedback algorithm which
continuously monitors tissue impedance and adjust power output to maximize energy
delivery. When tissue impedance rises more than 15 Ohm above baseline during an ablation,
the process automatically pauses for 20 seconds before the generator delivers any more
energy[36]. The intermittent pauses when tissue impedance increased allowed gases adjacent
to the electrode to dissipate while the internal cooling with chilled-saline minimizes tissue
charring, hence improving the delivery of energy to surrounding tissues. The grounding pad
for the RFA generator was attached to the inner hind-leg of the animal.
116
Two 20 cm internally cooled electrodes (ICEs) with 3 cm exposed tips were used in this
study. Each of the electrodes had insulated electrical wire tubing, as well as two extra plastic
tubing to circulate chilled saline throughout the needle electrode.
A generic AC/DC adaptor was used to provide the DC. In BETA and ECT/RFA the cathode
of the AC/DC adaptor was connected to the RF electrode wiring using a 100 mH inductor.
This inductor allowed the flow of the DC into the radiofrequency circuit, but prevented the
leakage of alternating current from the RF 3000 generator into the DC circuit. Therefore the
needle electrode of the Cool-Tip RF system (Covidien) and the cathode of the DC circuit
were one and the same. The anode of the DC circuit was attached to aluminium rods inserted
into the subcutaneous tissue. A new aluminium rod was used and inserted at a different
location during each BETA and ECT/RFA procedure.
For standard RFA, only the Cool-Tip RF system (Covidien) was used. The water pump was
started first to circulate the chilled saline (<10ºC) throughout the needle electrode. Once the
temperature of the electrode tips dropped <10ºC, they were inserted into the liver and the
ablation process started as per the manufacturer’s protocol. The generator was switched to the
impedance mode and the timer set to 6 minutes. The power output was set to 100 watts each
time.
In BETA and ECT/RFA, 9 volts of DC was provided to the liver tissue for 10 minutes before
the Cool-Tip RF system (Covidien) was switched on. This 10 minutes of 9V DC was called
the “pre-treatment” phase. After this period of pre-treatment, the RFA generator was started
and both circuits allowed to run concurrently in BETA. IN ECT/RFA however, the DC
circuit was switched off after the 10 minutes pre-treatment phase, and only the RF generator
was used as described above.
The ICEs have sensors at their tips which were capable of measuring tissue temperature and
impedance. Therefore measurements of these 2 parameters were performed at 3 time-points
during each procedure:
1.
Baseline – before the start of any procedure.
117
2.
Pre-treatment phase – after the delivery of DC energy, but before RFA. The RF and
DC generators and the peristaltic pump were switched off temporarily to ensure accurate
tissue temperature and impedance measurement.
3.
End – after 6 minutes of RFA the maximum tissue temperature and impedance were
recorded.
Once all ablations were completed, the animals were euthanized using intravenous injections
of sodium pentobarbitone. The livers were then harvested and the sizes of the ablations were
measured in three dimensions. The axial diameter (parallel to the electrode insertion track)
and two transverse diameters (perpendicular to each other) were measured between the white
zones of the ablation.
Animal research ethics approval was obtained from the Institute of Medical and Veterinary
Science (IMVS) and the University of Adelaide animal ethics committees. The study
conformed with the Code of Practice for the Care and Use of Animals for Scientific Purposes
2004 and the South Australian Prevention of Cruelty to Animals Act 1985.
Results
A total of 12 pigs were used in this study. Twelve ablations (RFA=4, BETA=4, ECT/RFA=4)
in three pigs were performed in a pilot study to determine the optimum ablation settings to
use for this experiment. RFA was initially conducted according to the manufacturer’s
protocol which sets the generator to deliver 100W of power for 12 minutes in the impedance
mode. However this setting was “too powerful” to use in our in-vivo liver model using 50kg
pigs. It was observed that some of the ablations would extend to both the anterior and
posterior surface of the liver, therefore making comparison of ablation sizes between the
groups impossible. As our animal laboratory had limited capacity to accommodate pigs
>50kg, we chose to modify the ablation protocol by reducing the duration of ablations to 6
minutes. Therefore the ablation setting used in this study was 100W of RF energy for 6
minutes in the impedance mode. Forty-four ablations (RFA=14, BETA=16, ECT/RFA=14) in
118
9 pigs were performed using this modified RFA protocol. None of the pigs died prematurely.
The experimental parameters measured are displayed in Table 6.
BETA
ECT/RFA
RFA
p-value
Transverse A
23.1 (a)
20.1 (b)
17.4 (c)
<0.001
Transverse B
21.1 (a)
18.9 (b)
16.6 (c)
<0.001
37.3
36.3
35.4
0.78
75.6 (a)
74.4 (a)
84.7 (b)
0.004
68.2
67.4
-
0.30
62.4 (a)
63.1 (a)
74.2 (b)
0.001
Baseline
38.5
38.5
38.4
0.12
Pre-treatment
38.9
39.1
-
0.23
End
68.9
64.9
59.5
0.08
Diameter (mm)
Axial
Impedance (Ω)
Baseline
Pre-treatment
End
Temperature (ºC)
Table 6. The data was analysed using analysis of variance for unbalanced data in Genstat 13 th edition (VSN
International, UK) to remove the effects of pigs and replicates within pigs from the treatment comparisons. The
table shows means for each treatment with the significance level for the treatment comparison from the analysis
of variance. Where the significance level is less than 0.05, significance of means is indicated: means followed
by the same alphabetical letter are not significantly different at p=0.05.
The ablations achieved using BETA were significantly larger compared to ECT/RFA and
RFA. The mean transverse diameter A was 23.1 vs. 20.1 vs. 17.4 mm (p<0.001), whereas the
mean transverse diameter B was 21.1 vs. 18.9 vs. 16.6 mm (p<0.001) respectively. The mean
119
axial diameter was also larger in the BETA group compared to ECT/RFA and RFA, although
the differences were not statistically significant (37.3 vs. 36.3 vs. 35.4 mm, p=0.78).
The baseline mean liver tissue impedance was significantly higher in the RFA group
compared to BETA and ECT/RFA (84.7 vs. 75.6 vs. 74.4 Ohm, p<0.004). A similar
observation was made at the end of the ablation process (74.2 vs. 62.4 and 63.1 Ohm,
p<0.001). After 9V of DC was provided for 10 minutes in the BETA and ECT/RFA groups,
the mean liver tissue impedance was reduced to an average of 68.2 and 67.4 Ohm
respectively. There was no significant difference in the reduction of tissue impedance
between the 2 groups after the pre-treatment phase.
There were no significant differences in baseline tissue temperature between the three groups.
The tissue temperature essentially remained the same after 10 minutes of pre-treatment with
9V DC. The end tissue temperature was higher in the BETA and ECT/RFA groups compared
to the RFA group, although the differences were not statistically significant. The average end
tissue temperature in all three groups was ≥60ºC, which would be enough to cause
instantaneous cellular necrosis.
On one occasion involving standard RFA in Pig 5, a loud “popping” sound was heard during
the ablation (Figure 12). It was later discovered that the inferior surface of the liver had
“fractured” and bled quite profusely. The tear in the liver tissue, which measured 1 cm in
length, was likely caused by a high intra-tumoral pressure created by the ablation process. It
was hypothesized that the ablated liver tissue was more fragile and brittle, and could not
withstand the pressure built-up leading to the haemorrhagic fracture. Fortunately on this
occasion the procedure was the final ablation in the animal, and it was euthanized as per
protocol.
120
Figure 12. Fractured liver tissue after standard RFA associated with the “popping sound” phenomenon.
Fig. 13 BETA lesion
121
Fig 14. ECT/RFA lesion
Fig 15. RFA lesion
122
Discussion
The principle of BETA involves the use of electrolysis to improve the efficacy of RFA to
produce larger ablations. The electrochemical reactions from the DC attract water molecules
to the cathode, which is attached to the RF electrode. The increased tissue hydration will
delay tissue desiccation during RFA, therefore allowing the ablation process to continue for
longer periods of time to produce larger ablations.
In a way this process is not dissimilar to the mechanism of perfused electrodes currently used
in some RFA generators. These perfused electrodes infuse sterile saline into the tissue
interstitium before and during an ablation[74, 271, 272]. The saline infusion increases the
tissue hydration and the ionic concentration around the tissue to be ablated, and this improves
the electrical conductivity[273]. This allows the thermal energy to be distributed more
uniformly throughout the whole volume of tumour tissue to be ablated [274, 275]. Increased
tissue hydration reduces the risk of tissue desiccation adjacent to the electrode and allowed
the ablative process to continue for a longer duration of time [274, 275]. All these effects
worked together to produce larger ablations. In addition, when saline is infused into the
interstitial tissue, it acts as an extension of the metal electrode forming a “virtual” or “liquid”
electrode which has a larger surface area than the metal electrode. Previous research has
shown that the diameter of ablation was proportional to the surface area of the electrode,
hence this “liquid electrode” may produce larger ablations[74]. This perfused electrode
system is not without flaws in its concept. Infusion of saline at a high rate has been shown to
spread irregularly into the tissue and to leak along the electrode track, causing iatrogenic
thermal injury to distant structures [36, 39, 252]. Several authors have raised the possibility
that the saline contaminated with tumour cells may leak along the electrode track and cause
tumour seeding[37, 74]. Another concern is that saline infusion may cause an increase in
intra-tumoral pressure, therefore forcing tumour cells into the circulation causing distant
tumour seeding[37, 74]. The difference between the perfused electrode system and BETA
however, is that water molecules are “sucked” to the tissues surrounding the RF electrode,
instead of being infused into the interstitium. Therefore the risk of tumour seeding due to
high intra-tumoral pressure, or iatrogenic viscera/vessels/ducts injury from the hot saline is
not present in BETA.
123
The main finding of this study was that the principles of BETA could be incorporated into the
Cool-Tip RF system (Covidien) using the ICEs to increase the size of tissue ablations. The
results demonstrated the mean transverse diameter A & B produced in BETA (23.1 and 21.1
mm) were significantly larger than those in RFA (17.4 and 16.6 mm) (p<0.001). The axial
diameter was also larger in BETA compared to RFA, although the difference was not
significant (37.3mm vs. 35.4mm, p=0.78).
BETA was also proven to be more effective than ECT/RFA (where DC was only provided
for 10 minutes in the pre-treatment phase). This suggested that the beneficial effect of the DC
continued even during the RFA process. This study showed that the mean transverse diameter
A (23.1 mm vs. 20.1 mm) & B (21.1 mm vs. 18.9 mm) in BETA were significantly larger
than ECT/RFA (p<0.001). The mean axial diameter was also larger in BETA although it was
not statistically significant (37.3 mm vs. 36.3 mm, p=0.78). ECT/RFA, however, produced
significantly larger ablations compared to standard RFA. In summary, ECT/RFA increased
the size of ablation by approximately 2.5 mm compared to standard RFA, while BETA
increased it by 5 mm.
The duration of the RFA (12 minutes as per the manufacturer’s recommendation) had to be
modified to 6 minutes because the porcine livers in this study were not large enough to
accommodate the full ablations. This change applied to all three study groups and should not
biased the results in any way.
It was noted that BETA and ECT/RFA produced significantly larger ablations compared to
RFA using the Cool-Tip RF System (Covidien) despite the same duration of ablations in all
three groups. It was discovered that during each of the 6 minutes ablation, the RFA group
would “roll-off” an average of four times compared to two times in BETA and ECT/RFA.
Therefore despite the same duration of ablations in each group, the flow of energy was
actually significantly more during BETA and ECT/RFA which could explain the larger
ablations in the latter groups. Another possibility is that the increased tissue hydration around
the RF electrode allowed a more uniform and improved delivery of energy to the liver, thus
producing larger ablations.
124
The reason for the differences in the baseline tissue impedance measured between the RFA
and the other treatment groups was not clear. The order of the experiment (RFA, BETA,
ECT/RFA) performed in each pig was random to minimize any bias. It was unlikely to be due
to interference from the DC energy, as the tissue impedance was always measured with the
DC generator switched off.
The electrochemical reactions from the DC increased the tissue hydration around the RF
electrode. Besides delaying tissue desiccation and prolonging the ablation process, the
increased hydration also lowered tissue electrical impedance. The Cool-Tip ICE has a sensor
at the tip of the needle was used to measure the electrical impedance in the tissue before and
after the 10 minutes of pre-treatment with 9V DC. The data showed that the mean baseline
electrical impedance was reduced by approximately seven Ohm in both the BETA and the
ECT/RFA groups.
The tissue impedance in all three study groups dropped significantly after ablation, which is
contrary to what was expected. The tissue impedance was expected to be significantly higher
as they became desiccated which then prevented further conduction of electrical energy,
therefore resulting in roll-off of the ablation. One possible explanation is that there could be
blood seeping into the needle track, which would result in the low impedance reading. The
impedance of the ablated tissues, on the other hand, was likely to be much higher than the
baseline values.
This study also showed that the beneficial effect of the DC is not due to additional thermal
energy. The tissue temperatures before and after the 10 minutes of 9V DC were essentially
unchanged. The tissue temperatures measured using the ICEs showed that they were all
≥60ºC at the end of ablation, enough to cause instantaneous cellular necrosis.
125
The data from the current and previous research have shown that BETA can be readily
incorporated into existing RF systems such as the RF 3000 RFA System (Boston Scientific)
and the Cool-Tip RF System (Covidien). RFA and electrochemical therapy is widely used
around the world for the treatment of un-resectable liver cancers. Therefore it would not be
difficult to assimilate these two technologies to create BETA without spending enormous
amounts of time or money.
In addition, both procedures were proven to be safe with minimal morbidity and mortality
risks. The safety features of BETA have also been elucidated in animal research. Data from
Dobbins et al showed that apart from a transient rise in serum liver enzymes and
inflammatory markers, there were no long term adverse effects when BETA was tested in
pigs[12]. As the safety and efficacy of BETA has been confirmed in animal experiments, it
might be time to take a step further and bring this technology into human study.
During the course of this experiment in the 5th pig, an unexpected complication of RFA was
encountered. A loud “popping” sound was heard during the ablation process, followed by the
discovery of a “fractured” liver surface with profuse bleeding. This “popping sound” has
been described in the literature and was attributed to the high intra-tumoral pressure created
by the ablation process. In one report the incidence of the “popping sound” phenomenon was
as high as 58%[276]. In the cardiovascular literature, this phenomenon has been associated
with major complications such as ventricular wall rupture[277]. However there is no report
yet of a liver fracture or a bleeding complication as a result of this “popping”. Clinicians need
to be aware of this potentially disastrous complication especially when RFA is used
percutaneously in a day procedure setting. Under such circumstances it would be easy to miss
a liver fracture, leading to a major haemorrhagic complication.
In conclusion, this study has shown that BETA increases the size of ablation by
approximately 5 mm using the Cool-Tip RF System (Covidien) with the ICEs. The benefit of
the DC extended into the RFA phase, and therefore it should be continued for the whole
treatment duration. Providing the DC only during the pre-treatment phase (9V DC for 10
minutes in this study) also produced significantly larger ablations compared to standard RFA,
126
although the benefit is less compared to BETA. The principle of BETA works by attracting
the water molecules to the tissues surrounding the cathode, which is attached to the RF
electrode. The increased tissue hydration improves energy distribution, delays tissue
desiccation and allows the ablation process to continue for longer periods of time and
therefore produce larger ablations.
127
6. Area for Future Research
Future studies should investigate what is the optimum duration and voltage of the ECT to use
to achieve the maximum liver hydration, therefore producing the largest ablations possible.
The ECT settings used in the previous and current research (9 volts for 10 or 15 minutes)
were arbitrarily chosen, and may not be the best. The duration of the ECT must not be too
long, or it will make BETA impractical to use in the current busy hospital settings.
Another area of research is whether the principle of BETA could be incorporated into other
thermal ablative therapy such as MCT or LITT. These ablative technologies also have the
problem of premature tissue desiccation which BETA may help to overcome.
Lastly it will be very useful to have a custom-built BETA machine, which combines both the
DC and the RF circuit into one. Currently the electrical insulators of the RF electrodes have
to be removed to attach the DC circuit to them. An inductor was used to allow the DC to flow
into the RF circuit, but not vice versa. This method is crude and not suitable for clinical
human trials as the exposed electrical wirings pose an occupational health and safety risks. A
custom-built BETA machine would overcome this problem and facilitate a step further
towards human trials.
128
7. Conclusion
With better knowledge and equipment, the clinical outcomes after RFA for liver tumours are
improving. Systematic reviews of the literature showed that RFA for un-resectable liver
tumours could achieve good outcomes. Some centres around the world have started to use
RFA to treat resectable liver tumours in a carefully selected group of patients. Early data
from these studies showed that the results were favourable.
The critical factor in RFA is its ability to completely ablate a tumour. Current RFA
equipment is only capable of ablating a 3 cm tumour with a 1 cm ablative margin. Tumours
larger than 3 cm, or multi-focal tumours, are risk factors for incomplete ablation leading to
higher local disease recurrence rates and reduced survivals.
BETA is a new local ablative therapy that has been shown in previous experiments to
produce significantly larger ablations compared to standard RFA. The research projects
described here added further knowledge in this field
The first experiment demonstrated that the ability of BETA to produce larger ablations was
due to the increased tissue hydration from the electrolytic process. The polarity of BETA was
reversed, and the anode was attached to the RF electrode instead of the cathode. This new
arrangement, called reversed polarity bimodal electric ablation (RP-BEA), was shown to
produce shorter duration of ablation and smaller ablation size compared to standard RFA and
BETA. The anode desiccated the tissues adjacent to the electrode, therefore leading to earlier
roll-off and smaller ablations.
The second experiment showed that the efficacy of BETA was significantly better when the
anode of the DC circuit was placed below the skin layer. In the experiment the size of BETA
ablations was compared to standard RFA with the anode placed at different locations (skin,
peritoneum, and liver). The results showed that ablation size was largest when the anode was
placed on the peritoneum and the liver. The liver could be the ideal location to place the
129
anode as it has excellent electrical conductivity, therefore ensuring maximum tissue hydration
around the cathode to produce the largest ablations possible. In addition the liver has a huge
functional reserve and excellent regenerative capability to tolerate the local tissue injury
associated with the electrolytic reactions at the anode.
The third experiment showed that the principle of BETA could be incorporated into the CoolTip RF System (Covidien), which is another popular RF system on the market. BETA could
produce significantly larger ablations compared to standard RFA using the internally-cooled
electrodes. Therefore BETA can be readily translated into the clinical setting using existing
equipment as both RFA and ECT are widely used around the world. In addition it was also
shown that the benefit of the DC extended into the RFA phase, and therefore it should be
continued for the whole treatment duration. Providing the DC only during the pre-treatment
phase (ECT/RFA - 9V DC for 10 minutes in this study) also produced significantly larger
ablations compared to standard RFA, although the benefit is less compared to BETA.
In summary BETA is a new innovation in the field of local ablative therapy which has shown
promising results. Research in animal liver models demonstrated that BETA could be readily
incorporated into existing RF generators on the market to produce significantly larger
ablations compared to standard RFA. This can improve the efficacy of RFA in treating larger
liver tumours, minimizing local disease recurrence rates and increasing survival. Data from
previous and the current study suggested that it might be time to extend research in this area
into human clinical trials.
130
Appendix 1: Survival Rates – RCTs comparing RFA vs. PEI for Un-Resectable HCC
Study
Treatmen
t
Patients
(tumours
)
Media
n size
(mean)
in mm
Media
n
followup
(mean)
in
months
Lencioni
RFA
52 (71)
(28)
(22.9)
(2003)[107
]
Tumour
s
Median
surviva
l rate at
1 year
(%)
100
HCC
PEI
50 (73)
(28)
(22.4 )
96
Median
survival
rate at 3
years
(%)
2yr=98
%
2yr=88
%
Median
survival
rate at 5
years
(%)
Median
survival
(months
)
n/a
n/a
Disease
free
survival
(months)
1yr^=86%
,
2yr^=64%
n/a
n/a
1yr=77%,
2yr=43%
1yr=78%^
,
RFA
52
(29)
(24.5)
Lin
74^
n/a
n/a
3yr=37%^
≤4cm
PEI
High dose
PEI
2yr=59%^
,
HCC
(2004)[108
]
90^
52
(28)
(23.8)
85
50
n/a
n/a
53
(28)
(24.1)
88
55
n/a
n/a
62
(25)
(28)
93^
74^
n/a
n/a
1yr=61%,
2yr=42%,
3yr=17%
1yr=63%,
2yr=45%,
3yr=20%
1yr=74%^
,
RFA
2yr=60%^
,
Lin
HCC ≤30
(2005)[109
]
3yr=43%^
PEI
62
(23)
(27)
mm
1yr=70%,
88
81
n/a
n/a
2yr-41%,
3yr=21%
1yr=71%,
PAI
63
(23)
(27)
90
53
n/a
n/a
2yr=43%,
3yr=23%
≤2cm
RFA
118
>2cm
37.2
n/a
n/a
n/a
n/a
92
4yr=74%
n/a
n/a
4yr=57%
n/a
n/a
62
38
n/a
n/a
n/a
59
n/a
n/a
n/a
n/a
57
n/a
n/a
n/a
^
(62%)
Shiina
(2005)[110
]
(38%)
PEI
114
≤2cm
HCC
(50%),
≤3cm
>2cm
34.8
(50%)
Non-naïve
345
(26)
27.6
RFA
70
(24.2)
26.1
Child-
PEI
69
(22.5)
25.3
HCC ≤30
RFA
Brunello
(2008)[113
]
Pugh
A/B, ≤3
mm
131
The tables were presented according to the year of article publication, and the name of the first author in
alphabetical order. The percentage numbers of survival and disease recurrence rates were rounded to the nearest
figure.
^statistically significant differences compared to other groups
132
Appendix 2: Recurrence Rates – RCTs comparing RFA vs. PEI for Un-Resectable HCC
Study
Treatment
RFA
Patients
(tumours)
52 (71)
Median
size
(mean) in
mm
(28)
Median
follow-up
(mean) in
months
(22.9)
Lencioni (2003)
PEI
RFA
PEI
High dose PEI
Lin (2005)
[109]
Recurrence
site
Recurrence
rate (%)
Ablation site
5^
Intra-hepatic
24
Extra-hepatic
0
Ablation site
26
Intra-hepatic
22
Extra-hepatic
0
Ablation site
14^
Intra-hepatic
31
Extra-hepatic
0
Ablation site
35
Intra-hepatic
37
Extra-hepatic
0
Ablation site
24
Intra-hepatic
32
Extra-hepatic
0
Ablation site
13^
Intra-hepatic
30
Ablation site
35
Intra-hepatic
35
Ablation site
29
Intra-hepatic
36
Ablation site
2^
Intra-hepatic
63
Extra-hepatic
2
Ablation site
11
Intra-hepatic
64
Extra-hepatic
4
Intra-hepatic
46
Intra-hepatic
51
HCC
[107]
Lin (2004)[108]
Tumours
50 (73)
52
52
53
(28)
(29)
(28)
(28)
(22.4 )
(24.5)
(23.8)
HCC ≤4cm
(24.1)
RFA
62
(25)
(28)
PEI
62
(23)
(27)
PAI
63
(23)
(27)
HCC ≤30 mm
≤2cm
RFA
118
(38%),
>2cm
37.2
(62%)
Shiina (2005)
HCC ≤3cm
[110]
≤2cm
PEI
114
(50%),
>2cm
34.8
(50%)
Brunello
RFA
(2008)[113]
PEI
70
(24.2)
26.1
Child-Pugh
A/B, ≤3 HCC
69
(22.5)
25.3
≤30 mm
133
The tables were presented according to the year of article publication, and the name of the first author in
alphabetical order. The percentage numbers of survival and disease recurrence rates were rounded to the nearest
figure.
^statistically significant differences compared to other groups
134
Appendix 3: Survival Rates – RCTs comparing RFA vs. RFA + TACE for UnResectable HCC
Study
Cheng
(2008)[114]
Treatment
Patients
(tumours)
Median
size
(mean)
in mm
Median
followup
(mean)
in
months
TACE
95
(49.2)
(25.4)
RFA
100
(49.8)
(24.6)
96
(49.6)
RFA
12
52
TACE
11
64
24
66
31
65
18
(37)
RFA +
TACE
Yang
RFA +
(2008)[138]
TACE
Median
survival
rate at
1 year
(%)
Median
survival
rate at
3 years
(%)
Median
survival
rate at
5 years
(%)
Median
survival
(months)
Disease
free
survival
(months)
74
32
13
24
n/a
67
32
8
22
n/a
(35.8)
83^
55^
31^
37^
n/a
n/a
58
n/a
n/a
19
n/a
53
n/a
n/a
15
n/a
68
n/a
n/a
22
n/a
81
n/a
n/a
28^
n/a
89
80
n/a
n/a
n/a
100
93
n/a
n/a
n/a
Tumours
≤3 HCC
≤7.5cm
HCC
RFA +
TACE +
Lentinan
Morimoto
(2010)[116]
RFA
RFA +
TACE
19
(36)
(32)
(30)
Single
HCC 3.15cm
The tables were presented according to the year of article publication, and the name of the first author in alphabetical order. The percentage
numbers of survival and disease recurrence rates were rounded to the nearest figure.
^statistically significant differences compared to other groups
135
Appendix 4: Recurrence Rates – RCTs comparing RFA vs. RFA + TACE for UnResectable HCC
Study
Treatment
TACE
Cheng (2008)
[114]
RFA
TACE + RFA
Yang
(2008)[138]
Patients
(tumours)
95
100
96
Median
size
(mean) in
mm
(49.2)
(49.8)
(49.6)
RFA
12
52
TACE
11
64
Median
follow-up
(mean) in
months
(25.4)
(24.6)
RFA + TACE
+ Lentinan
24
66
31
65
≤3 HCC
≤7.5cm
(35.8)
Recurrence
site
Recurrence
rate (%)
Ablation site
15
Intra-hepatic
53
Extra-hepatic
13
Ablation site
16
Intra-hepatic
54
Extra-hepatic
11
Ablation site
4^
Intra-hepatic
48
Extra-hepatic
7
Ablation site +
Intra-hepatic
Ablation site +
n/a
RFA + TACE
Tumours
HCC
Intra-hepatic
Ablation site +
Intra-hepatic
Ablation site +
Intra-hepatic
35^
46^
29
18
Morimoto
RFA
18
(37)
(32)
Single HCC
Ablation site
39^
(2010)[116]
RFA + TACE
19
(36)
(30)
3.1-5cm
Ablation site
6
The tables were presented according to the year of article publication, and the name of the first author in alphabetical order. The percentage
numbers of survival and disease recurrence rates were rounded to the nearest figure.
^statistically significant differences compared to other groups
136
Appendix 5: Survival Rates after RFA for Un-Resectable HCC
Study
Treatment
Patients
(tumour
s)
Media
n size
(mean)
in mm
Media
n
followup
(mean
) in
month
s
Tumours
Media
n
surviv
al rate
at 1
year
(%)
Median
surviva
l rate at
3 years
(%)
Median
survival
rate at 5
years (%)
Median
survival
(month
s)
1yr=79%
>30
RFA
79
mm
(15.6)
78^
33^
n/a
n/a
79
mm
(28.9)
(73%)
RFA
99
(31)
^,
3yr=50%
^
>30
Resection
Cho (2005)
HCC
(72%)
Vivarelli
(2004) [134]
Disease
free
survival
(months)
(23)
Resectable
HCC
Child-Pugh
A, ≤3 HCC
1yr=60%,
83
65
n/a
n/a
96
80
n/a
n/a
n/a
98
77
n/a
n/a
n/a
3yr=20%
[121]
Surgery
61
(34)
(21.9)
Hong
RFA
55
(24)
22.7
Single
100
73
n/a
n/a
n/a
(2005) [123]
Resection
93
(25)
25.5
HCC ≤4cm
98
84
n/a
n/a
n/a
Lu
RFA
53 (72)
(26)
(24.8)
72
38
4yr=24%
27
17
(2005)[141]
MCT
49 (98)
(25)
(25.1)
82
51
4yr=37%
33
16
33
40
22
97
77
56
n/a
25.1
Resection
40
46
23
81
70
58
n/a
53.1
Ogihara
RFA
40
46
16
Single
78
58
39
51
n/a
2005 [133]
Resection
47
74
16
HCC
75
65
31
47
n/a
Xu 2005
RFA
84
(26)
19.7
(24.1)
n/a
n/a
n/a
23
6
35
9
n/a
n/a
10
n/a
n/a
10
Maluccio
(2005)[132]
[142]
Chok
(2006)[139]
RFA +
TACE
MCT
RFA
51
30
19
TACE
40
33
23
RFA –
Shibata*
53
cooled-tip
≤50 mm
≤5 HCC
≤8cm
Single
HCC <7cm
≤5 HCC
≤8cm
<4 HCC ≤5
cm
82
80
2yr=72
%
2yr=58
%
1yr=47%,
38 (41)
(17.5)
(21)
2006 [111]
≤3 HCC
100
94
n/a
n/a
3yr=34%
≤30mm
RFA –
36 (42)
(19.7)
(28)
2yr=34%,
94
77
n/a
n/a
1yr=44%,
2yr=22%,
137
expandable
3yr=22%
55
1 HCC
Ferrari*
RFA
40 (50)
(26.7)
n/a
(2007)[112]
≤4cm, or
92
61
months=4
41 (45)
(28.9)
n/a
89
57
23
n/a
15.5
n/a
n/a
n/a
37^
n/a
n/a
n/a
n/a
45^
n/a
n/a
n/a
n/a
13
n/a
n/a
n/a
n/a
n/a
6
n/a
(19)
91
71
n/a
n/a
≤5cm
Resection
52
(71%),
>5 cm
Resectable
n/a
(29%)
RFA +
TACE
44
≤5cm
(100%)
Helmberger
≤5cm
(2007) [130]
(68%),
TACE
107
>5 cm
≤3cm
17.8
1
≤3 HCC
Laser
n/a
HCC,
Child-Pugh
score 5-6
n/a
n/a
(32%)
Unresectab
le HCC
≤5cm
Tamoxifen
21
(52%),
>5 cm
(48%)
Percutaneo
us RFA
Surgical
Khan (2007)
RFA
[101]
Percutaneo
us RFA
Surgical
(2007)[94]
Lin 2007
[249]
Lupo (2007)
[125]
63
25
(19)
(22)
(36)
(18)
mm
81^
HCC >30
mm
(18)
84
15
58.8
43
18
61.2
RF 2000
25 (34)
(25)
21
87
RF 3000
25 (35)
(26)
22
88
RITA
25 (31)
(26)
22
Cool-Tip
25 (33)
(27)
22
RFA
60
(36.5)
(27)
RFA
RFA +
Interferon
Resection
42
(40)
RFA
171
21
(31.3)
Child-Pugh
A, ≤3 HCC
≤3cm
≤3 HCC
≤40 mm
Single
HCC 35cm
Child-Pugh
57
n/a
42^
n/a
n/a
n/a
1yr=52%,
3yr=33%
1yr=52%,
3yr=22%
1yr=29%,
3yr=0%
1yr=54%,
92
68
n/a
n/a
n/a
n/a
66^
n/a
n/a
n/a
n/a
83
n/a
n/a
n/a
n/a
1yr=77%,
2yr=55%
n/a
n/a
1yr=80%,
2yr=56%
n/a
n/a
1yr=79%,
2yr=55%
89
90
2yr=73
%
2yr=75
%
2yr=76
%
2yr=78
n/a
n/a
%
3yr=19%
1yr=79%,
2yr=54%
96
53
32
n/a
n/a
91
57
43
n/a
n/a
n/a
n/a
77
n/a
23^
n/a
n/a
70
n/a
25
A, 1 HCC
Resection
53
25
36.7
<5cm, or
≤3 HCC
<3cm
138
89
(39)
Takahashi
(2007)[127]
(19)
HCC ≤30
48
RFA
Kudo
92
≤30
mm
(46.3%
), 31RFA
67
50 mm
(32.8%
(32.2)
90
58
36
n/a
n/a
(35.5)
95^
76^
49^
n/a
n/a
(23)
83
42
20
28^
16
84
64
48
57
36
n/a
88
59
n/a
n/a
91
59
n/a
3yr=59%,
5yr=25%
3yr=64%,
5yr=22%
89
60
38
n/a
n/a
90
77
68
n/a
n/a
), 5170 mm
Zhang*
(28.9%
1 HCC
)
≤7cm, or
(2007) [103]
≤3 HCC
≤30
≤3cm
mm
(44%),
31-50
RFA + PEI
66
mm
(37.9%,
51-70
(18.1%
)
≤30
mm
RFA
109
(30%),
31-60
mm
Guglielmi
(70%)
≤3 HCC
(2008) [100]
≤30
≤6cm
mm
Resection
91
(34%),
31-60
(32)
mm
(66%)
Hiraoka
(2008) [122]
Lam (2008)
[131]
RFA
Resection
RFA
Resection
105
59
n/a
n/a
n/a
n/a
30
24
240
n/a
35
45 (54)
(21.4)
(29.8)
273
(357)
Child-Pugh
A/B, 1
HCC <3cm
HCC
≤4 HCC
≤8cm
RFA –
internally
Seror
cooled
(2008)[148]
RFA _
saline
90
2yr=87
%
n/a
n/a
n/a
n/a
n/a
n/a
≤3 HCC
≤3cm
44 (54)
(21.1)
(17.7)
87
83%
n/a
n/a
59^
n/a
n/a
n/a
72^
n/a
perfused
Yamagiwa
(2008)[135]
Resection
101
RFA +
115
n/a
33.6
24.3
Resectable
HCC
Child-Pugh
5yr=32^
%
5yr=14^
139
TACE
PEI +
TACE
TACE
RFA +
Yamakado
TACE
A/B, ≤5
%
HCC ≤5
43
42.8
n/a
n/a
41^
n/a
5yr=4%
86
20.3
n/a
n/a
15^
n/a
5yr=5%
(37)
98
94
75
cm
1yr=92%,
104
(25)
n/a
5yr=27%
HCC
(2008) [136]
Surgery
62
(27)
(38)
3yr=64%,
1yr=89%,
97
93
81
n/a
3yr=69%,
5yr=26%
1yr=83%,
3yr=42%
RFA
209
18^
Kobayashi
Child-Pugh
39.6
(2009)[124]
99
87
5yr=75%,
7yr=65%
n/a
A cirrhosis
^,
≤3 HCC
7yr=6%^
≤3cm
Resection
199
^,
5yr=17%
20
1yr=83%,
97
90
5yr=79%,
7yr=62%
n/a
3yr=51%,
5yr=37%,
7yr=23%
Ohmoto
RFA
(2009)[143]
MCT
49 (56)
(17)
(40)
Santambrog
Lap RFA
74
(26.6)
(38.2)
Resection
78
(29.1)
(36.2)
io
(2009)[126]
Ueno
34 (37)
(16)
(26.2)
RFA
155
20
(36.8)
Resection
123
27
(35)
RFA
37
(38)
TACE
35
(36)
31
(35)
(2009)[128]
Yang
(2009)[138]
RFA +
TACE
22
HCC ≤2cm
Single
Child-Pugh
A HCC
<5cm
1 HCC
<5cm, or
≤3 HCC
<3cm
Recurrent
HCC after
resection
100^
70^
4yr=70%^
n/a
n/a
89
49
4yr=39%
n/a
n/a
88
66
41
n/a
n/a
93
85
54
n/a
n/a
1yr=78%
^,
3yr=36%
^,
5yr=20%
^,
1yr=80%,
3yr=47%,
5yr=38%,
98
92
63
n/a
99
92
80
n/a
74
51
28
37
n/a
66
39
20
31
n/a
89
65
44
52
n/a
n/a
83
50
n/a
n/a
n/a
78
58
n/a
n/a
89^
64^
42^
n/a
1yr=76%
^,
3yr=47%
^,
HCC
within
RFA
63
20.9
23
Milan
criteria, age
≥75
Hiraoka
(2010) [278]
HCC
within
RFA
143
20.7
30.5
Milan
criteria, age
<75
Peng
(2010)[279]
140
RFA
120
≤5cm
(73%),
(34.8)
1 HCC
≤7cm, or
>5cm
≤3 HCC
(27%)
≤3cm
5yr=30%
^
≤5cm
RFA +
TACE
120
(71%),
>5cm
(36.5)
(29%)
93
75
50
n/a
1yr=90%,
3yr=63%,
5yr=42%
The tables were presented according to the year of article publication, and the name of the first author in alphabetical order. The percentage
numbers of survival and disease recurrence rates were rounded to the nearest figure.
^statistically significant differences compared to other groups
*Randomized Controlled Trial
141
Appendix 6: Recurrences Rates after RFA for Un-Resectable HCC
Study
Vivarelli (2004)
[134]
Treatment
Patients
(tumours)
Median size
(mean) in mm
Median
followup
(mean)
in
months
RFA
79
>30mm (72%)
15.6
RFA
Cho (2005)
[121]
99
(31)
(23)
Tumours
HCC
Child-Pugh A,
≤3 HCC ≤50
Surgery
61
(34)
(21.9)
RFA
55
(24)
22.7
Hong (2005)
mm
Single HCC
≤40 mm
[123]
Resection
93
(25)
25.5
RFA
53 (72)
(26)
(24.8)
Lu (2005)[141]
≤5 HCC ≤8cm
MCT
49 (98)
(25)
(25.1)
Recurrence
site
Recurrence rate
(%)
Ablation site
15
Intra-hepatic
33
Ablation site
18
Intra-hepatic
28
Ablation site
10
Intra-hepatic
33
Ablation site
7^
Intra-hepatic
51
Ablation site
0
Intra-hepatic
45
Ablation site
21
Intra-hepatic
69
Ablation site
12
Intra-hepatic
76
Ablation site
RFA + TACE
33
40
Maluccio
Resection
[133]
Ferrari*
RFA
40
40
46
46
Single HCC
74
16
RFA
40 (50)
(26.7)
n/a
Extra-hepatic
13
Ablation site
10
Intra-hepatic
25
Ablation site
2
Intra-hepatic
28
Ablation Site
15
Intra-hepatic
4
Ablation Site
23
≤3cm
Laser
142
35
1 HCC ≤4cm,
or ≤3 HCC
(2007)[112]
21
Resection
hepatic
16
47
Extra-hepatic
site + Intra-
23
Resection
42
hepatic
1 HCC <7cm
(2005)[132]
Ogihara 2005
+ Intra-
22
41 (45)
(28.9)
n/a
Percutaneous
RFA
92
(19)
(19)
Intra-hepatic
9
Ablation site
13
Intra-hepatic
26
Extra-hepatic
3
Ablation site
10
Intra-hepatic
38
Khan (2007)
Extra-hepatic
11
[101]
Ablation site
8
HCC ≤30 mm
Surgical RFA
Percutaneous
RFA
63
25
(22)
(36)
(19)
(18)
HCC >30 mm
Surgical RFA
RFA
Kudo (2007)[94]
48
(39)
(18)
84
15
58.8
43
18
61.2
RF 2000
25 (34)
(25)
21
RF 3000
25 (35)
(26)
22
RFA +
Interferon
Lin 2007 [249]
RITA
Murakami
(2007)[140]
25 (31)
(26)
Cool-Tip
25 (33)
(27)
RFA
105 (109)
(16)
Ablation site
13
Intra-hepatic
35
Extra-hepatic
6
4
Intra-hepatic
71^
≤3 HCC ≤3cm
Ablation site
3
Intra-hepatic
56
Ablation Site
12
Intra-hepatic
24
Ablation Site
8
≤3 HCC ≤40
Intra-hepatic
32
mm
Ablation Site
8
1 HCC ≤5cm,
Intra-hepatic
32
Ablation Site
8
Intra-hepatic
28
Ablation Site
or ≤3HCC
TACE
133 (173)
(17)
≤3cm
Ablation Site
RFA
171
21
Child-Pugh A,
Ablation site
Resection
53
25
36.7
1 HCC <5cm,
or ≤3 HCC
≤30 mm (46%),
RFA
67
31-50 mm
(33%), 51-70
(32.2)
mm (21%)
1 HCC ≤7cm,
Zhang* (2007)
Resection
site
1yr=24%^,
2yr=40%^
1yr=37%,
2yr=51%
17^
0
Ablation site
21^
Intra-hepatic
39
Extra-hepatic
9
Ablation site
6
Intra-hepatic
33
Extra-hepatic
12
Ablation site
13
Intra-hepatic
59
Extra-hepatic
12
or ≤3 HCC
[103]
≤3cm
≤30 mm (44%),
RFA + PEI
66
31-50 mm
(38%), 51-70
(35.5)
mm (18%)
[131]
12
Ablation site
<3cm
Lam (2008)
52
Child-Pugh A,
22
22.4
Takahashi
(2007)[127]
22
Intra-hepatic
Extra-hepatic
RFA
273 (357)
30
24
HCC
143
Ablation site
RFA –
internally
Seror
(2008)[148]
45 (54)
(21.4)
(29.8)
≤3 HCC ≤3cm
RFA _ saline
perfused
RFA + TACE
44 (54)
(21.1)
Kobayashi
(2009)[124]
Surgery
RFA
Resection
Ablation site
(17.7)
Intra-hepatic
104
(25)
(37)
Yamakado
(2008) [136]
Intra-hepatic
cooled
62
209
199
(27)
HCC
(38)
18^
20
Child-Pugh A
39.6
cirrhosis ≤3
HCC ≤3cm
1yr=9%, 2yr=11%
1yr=19%,
2yr=31%^
1yr=11%,
2yr=15%
1yr=37%,
2yr=64%
Ablation site
3
Intra-hepatic
33
Ablation site
0
Intra-hepatic
37
Intra-hepatic
18
Ablation site
9^
Ablation site
1
1yr=9%^,
Ablation site
RFA
34 (37)
(16)
1yr=28%,
Intra-hepatic
Ohmoto
(17)
3yr=65%,
1yr=13%,
Ablation site
49 (56)
2yr=52%,
4yr=65%
HCC ≤2cm
MCT
3yr=9%^,
4yr=9^%
(26.2)
(2009)[143]
2yr=9%^,
2yr=16%,
3yr=19%,
4yr=19%
(40)
1yr=35%,
Intra-hepatic
2yr=62%,
3yr=72%,
4yr=78%
Santambrogio
(2009)[126]
Lap RFA
Resection
74
78
(26.6)
(29.1)
(38.2)
(36.2)
Single ChildPugh A HCC
<5cm
Ablation site
24^
Intra-hepatic
68^
Ablation site
6
Intra-hepatic
51
Ablation site
RFA
155
20
(36.8)
Ueno
(2009)[128]
Resection
123
27
(35)
+ Intra1 HCC <5cm,
or ≤3 HCC
<3cm
61
hepatic
Ablation site
+ Intra-
42
hepatic
Yang
(2009)[138]
RFA
37
(38)
TACE
35
(36)
RFA + TACE
31
(35)
RFA
120
Peng(2010)[279]
RFA + TACE
144
120
≤5cm (73%),
>5cm (27%)
≤5cm (71%),
>5cm (29%)
22
(34.8)
(36.5)
Recurrent
HCC after
resection
Intra-hepatic
43
Intra-hepatic
57
Intra-hepatic
Ablation site
51^
4
1 HCC ≤7cm,
Intra-hepatic
46^
or ≤3 HCC
Extra-hepatic
3
≤3cm
Ablation site
3
Intra-hepatic
28
Extra-hepatic
8
The tables were presented according to the year of article publication, and the name of the first author in alphabetical order. The percentage
numbers of survival and disease recurrence rates were rounded to the nearest figure.
^statistically significant differences compared to other groups
*Randomized Controlled Trial
145
Appendix 7: Survival Rates after RFA for Resectable HCC
Study
Treatmen
t
Patients
(tumours
)
Media
n size
(mean)
in mm
Media
n
followup
(mean)
in
months
Montorsi
RFA
58
n/a
(25.7)
(2005)
[146]
Resection
40
n/a
(22.4)
Tumour
s
Median
survival
rate at 1
year
(%)
Median
survival
rate at 3
years
(%)
Median
survival
rate at 5
years
(%)
Median
survival
(months
)
Disease
Free
Survival
(months)
Single
85
61
4yr=45%
n/a
n/a
84
73
4yr=61%
n/a
n/a
HCC
<50 mm
Not
HCC
Abu-Hilal
RFA
34
30
30
≤5cm
(2008)
meeting
[144]
Milan
Resection
34
38
43
criteria
83
2yr=62
%
57
achieved
at time
10^
of report
91
2yr=81
%
56
74
35
≤3 cm
90 (90) –
RFA
Chen*
(37 pt),
19 had
3.1-5
resection
cm (34
Child-
pt)
Pugh A
(2006)
(27.9)
94
69
4yr=66%
n/a
n/a
93
73
4yr=64%
n/a
n/a
77
49
40
n/a
n/a
79
45
28
n/a
n/a
5yr=60
7yr=55
10yr=34
%
%
%
76.1
48;
5yr=36%,
7yr=29%,
10yr=18
%
single
[117]
Resection
90 (90) +
≤3 cm
ethanol
(42 pt),
injection
3.1-5
in 2
cmm
patients
(48 pt)
cirrhosis
<5cm
(29.2)
≤3 cm
RFA
66 (88)
Liang
(2008)
[145]
Resection
44 (55)
(44 pt),
>3 cm
21
≤3
(22 pt)
recurrent
≤3 cm
HCC <
(26 pt),
>3 cm
33
5cm
(18 pt
Single
Peng
(2010)[137
]
ChildRFA
224
25
(44.1)
Pugh A
HCC
≤5cm
146
The tables were presented according to the year of article publication, and the name of the first author in alphabetical order. The percentage
numbers of survival and disease recurrence rates were rounded to the nearest figure.
^Statistically significant differences compared to other groups
147
Appendix 8: Recurrences Rates after RFA for Resectable HCC
Study
Montorsi (2005)
[146]
Abu-Hilal
(2008) [144]
Treatment
Patients
(tumours)
Median
size
(mean) in
mm
Median
follow-up
(mean) in
months
Lap RFA
58
n/a
(25.7)
Resection
RFA
40
34
n/a
30
(22.4)
30
Recurrence
site
Recurrence
rate (%)
Ablation site
19^
Single HCC
Intra-hepatic
35
<5 cm
Resection site
0
Tumours
HCC ≤5cm
meeting Milan
Resection
34
38
RFA
66 (88)
pt), >3 cm
43
criteria
≤3 cm (44
Liang (2008)
[145]
Resection
44 (55)
21
Peng
224
Intra-hepatic
30
Resection site
4
Intra-hepatic
57
Ablation site
8
Intra-hepatic
65
≤3 recurrent
Extra-hepatic
5
≤3 cm (26
HCC < 5cm
Resection site
7
Intra-hepatic
75
pt), >3 cm
33
Extra-hepatic
5
Ablation site
13
Pugh A HCC
Intra-hepatic
49
≤5cm
Extra-hepatic
1
Single ChildRFA
30
30^
(22 pt)
(18 pt)
(2010)[137]
Intra-hepatic
Ablation site
25
(44.1)
The tables were presented according to the year of article publication, and the name of the first author in alphabetical order. The percentage
numbers of survival and disease recurrence rates were rounded to the nearest figure.
^Statistically significant differences compared to other groups
*Randomized Controlled Trial
148
Appendix 9: Survival after RFA for Un-Resectable Liver Metastases
Number
Study
Treatment
Median
of
Media
follow-
Patients
n size
up
(tumour
(mm)
(month
s)
s)
Types of
liver
metastas
es
Media
Media
Media
n
n
n
surviv
surviv
surviv
al rate
al rate
al rate
at 1
at 3
at 5
year
years
years
(%)
(%)
(%)
Overall
Median
median
disease
surviva
free
l
survival
(month
(months
s)
)
Solbiati
(2001)[153]
Percutaneo
us RFA
Ianitti (2002)[102]
Pawlik (2003)[158]
Abdalla
(2004)[159]
Percutaneo
us RFA
117 (n/a)
52
26
52
(mean)
CLM
93
46
n/a
36
12
20
CLM
87
50
n/a
n/a
n/a
n/a
n/a
n/a
45.5
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Mets
RFA +
172
resection
(737)
RFA
57 (110)
25
21
CLM
n/a
37
101
25
21
CLM
n/a
43
Resection
190
25
21
CLM
n/a
73^
Chemo
70
25
21
CLM
n/a
14
CLM
91
40
17
32
n/a
n/a
n/a
n/a
33
n/a
RFA +
resection
18
Percutaneo
[179]
us RFA
Berber (2005)[195]
Lap RFA
53 (192)
Berber (2005)[196]
Lap RFA
135
Percutaneo
134
41
us RFA
(333)
(mean)
167 (n/a)
21.3
(124
CLM)
Gillams (2004)
Chen (2005) [155]
n/a
4yr:
22%
4yr:
36%
58^
4yr:
8%
39
17
(mean)
(mean)
31
24
“Unusual
(mean)
(mean)
” Mets
n/a
CLM
n/a
n/a
n/a
28.9
6
n/a
Mets
75.3
25.1
n/a
n/a
n/a
41
(mean)
1yr=92
%,
Elias (2005)[207]
RFA +
Resection
63 (351)
13
(15)
27.6
CLM
92
47
n/a
36
2yr=55
%,
3yr=27
%
149
Navarra (2005)
[180]
RFA (+
resection in
(2006)[181]
n/a
18.1
12 pt)
First gen
Ahmad
57 (297)
probe
Newer gen
probe
21
31
37.4
(mean)
34.7
(mean)
Mets (38
CLM)
72.5
52.5
n/a
n/a
n/a
26.2
CLM
n/a
n/a
n/a
n/a
16^
26.2
CLM
n/a
n/a
n/a
n/a
8
CLM
n/a
n/a
n/a
29.7
n/a
RFA (+
Amersi (2006)
resection in
[182]
majority of
74
35.6
33.2
(mean)
(mean)
(39)
14
Mets
80
31
n/a
n/a
n/a
35
21.2
Mets
89
38
n/a
27
n/a
CLM
96
68
n/a
n/a
n/a
pt)
Chen (2006)[199]
Hildebrand
(2006)[183]
Jakobs (2006)[184]
Machi (2006) [205]
RFA
RFA
Percutaneo
us RFA
127
(195)
81
68 (183)
RFA +
100
chemo
(507)
22.8
21.4
(mean)
(mean)
30
24.5
CLM
90
42
30.5
28
n/a
29
25
CLM
n/a
n/a
n/a
27.8
15
23
32.4
(mean)
(mean)
91
2yr=77
48
46.8
9
RFA (+
van Duijhoven
(2006) [185]
Mazzaglia(2007)[1
98]
Siperstein (2007)
[206]
resection in
29 pt)
87 (199)
Lap RFA
63 (384)
Lap RFA
(after failed
234
chemo)
39
(mean)
Neuroendocrine
liver mets
24
CLM
n/a
20.2
18.4
24
n/a
23.6
CLM
96
64
44
52
n/a
n/a
n/a
30
24-34^
9^
n/a
n/a
40
57
30
n/a
n/a
n/a
25
13
RFA (+
Sorensen (2007)
[186]
resection in
102
22
(332)
(mean)
Lap RFA
68
37
23 (27)
Resection
90
38
33 (41)
RFA
87
n/a
n/a
25 and
chemo in 6
pt)
Berber (2008)[197]
Blusse (2008)[187]
150
Solitary
CLM
CLM
RFA
Gleisner
RFA +
(2008)[160]
Resection
Resection
3yr=
11
25
n/a
CLM
n/a
72.7
n/a
n/a
55
25
n/a
CLM
n/a
44.9^
n/a
n/a
192
35
n/a
CLM
n/a
74.1
n/a
n/a
2yr=75
n/a
n/a
n/a
24
n/a
n/a
n/a
12
n/a
n/a
n/a
18
79
38
22
31.5
n/a
n/a
58^
26^
39^
n/a
n/a
29
5
25
n/a
n/a
60
26
n/a
n/a
n/a
70
50
n/a
n/a
68
43
27
29.9
n/a
n/a
n/a
21
27
12.2^
7.4%
3yr=
34%
3yr=
40%^
CLM
RFA
34
10
36
(n=18);
non-CLM
(n=16)
CLM
Leblanc
RFA +
(2008)[209]
Resection
28
10
25
(n=16);
non-CLM
2yr=68
(n=12)
CLM
Resection
37
21^
29
(n=26);
non-CLM
2yr=83
(n=11)
Veltri (2008)[189]
RFA
122
25
18.8
(199)
(29)
(24.2)
CLM
Number
of CLM
RFA
192
n/a
n/a
≤5, and
diameter
≤50 mm
Gillams (2009)
[156]
Number
of CLM
RFA
117
n/a
n/a
>5, and
diameter
>50 mm
RFA
25
25
(25)
Hur (2009)[200]
Meloni
(2009)[190]
42
Resection
42
RFA
52 (87)
RFA (+
Reuter (2009)[191]
chemo in 7
pt)
66
26
Single
CLM
(28)
25
(mean)
32
(mean)
Breast Ca
19.1
Liver
Mets
20
CLM
151
Resection
(+ chemo
126
in 18 pt)
53
(mean)
20
CLM
n/a
n/a
23
36.4
31.1
RFA +
Resection
Vyslouzil
(2009)[210]
23
n/a
n/a
CLM
83
30
n/a
n/a
n/a
31
n/a
n/a
CLM
87
26
n/a
n/a
n/a
136
n/a
n/a
CLM
91
58
n/a
n/a
n/a
+ chemo
RFA +
chemo
Resection
CLM-colorectal liver metastases; Mets-metastases; DFS-disease free survival
^Statistically significant differences between group(s)
152
Appendix 10: Tumour Recurrences after RFA for Un-Resectable Liver Metastases
Recurrence
Number
Included articles
Treatment
of
patients
(tumours)
Median
size
(mm)
Median
followup
(months)
Types of
liver
metastases
(ablation
site, intra-
Recurrence rate
hepatic or
(%)
extrahepatic)
Solbiati (2001) [153]
RFA
117 (179)
26
Bleicher (2003) [194]
RFA
59
25
n/a
CLM
Ablation site
39
CLM
Ablation site
18.3
Ablation site
2.3
Intra-hepatic
22
Extra-hepatic
30.2
Ablation site
10
Intra-hepatic
30
Extra-hepatic
48
Ablation site
9^
Intra-hepatic
44
Abdalla
Extra-hepatic
40
(2004) [159]
Ablation site
5
Intra-hepatic
28
Extra-hepatic
37
11
(mean)
Pawlik (2003) [158]
RFA + resection
Scaife (2003)[204]
RFA + HAI
RFA
RFA + resection
172 (737)
50
57 (110)
101
18
20
25
25
21.3
20
21
21
Mets (124
CLM)
CLM
CLM
CLM
153
Resection only
Elias (2004) [203]
Berber (2005)[196]
Intra-hepatic
11^
Extra-hepatic
41
27.6
Mets
Ablation site
14.8
Wedge resection
64 (99)
10 (14)
27.6
Mets
Resection site
10.9
40 (40)
42 (44.2)
27.6
Mets
Resection site
12.5
Ablation site
15.9
Intra-hepatic
33
Extra-hepatic
49
Ablation site
17
Ablation site
46
Intra-hepatic
53
Extra-hepatic
41
Liver Mets
Ablation site
10.5
CLM
Ablation site
13.8
Ablation site
17.4
Intra-hepatic
42.2
Extra-hepatic
46.2
Intra-hepatic
9
Extra-hepatic
5
Ablation site
38^
Intra-hepatic
62
Ablation site
9.7
Intra-hepatic
52
Ablation site
15
RFA
Lap RFA
Lap RFA
167 (n/a)
53 (192)
135
RFA
134 (333)
Chiou (2005)[192]
RFA
69 (109)
Navarra (2005) [180]
CLM
12 (15)
Chen (2005) [155]
Elias (2005)[207]
21
88 (227)
Anatomical
Berber (2005)[195]
25
2
RFA
hepatectomy
Gillams (2004) [179]
190
Ablation site
RFA +
Resection
RFA +/resection
First gen probe
63 (351)
57 (297)
21
39
(mean)
17
CLM
31
24
“Unusual”
(mean)
(mean)
Mets
412
(mean)
41
(mean)
n/a
n/a
29
22.4
(mean)
(mean)
13 (15)
n/a
37.4
(mean)
27.6
18.1
26.2
CLM
CLM
Mets (38
CLM)
CLM
Ahmad (2006)[181]
Newer gen
probe
Chen (2006)[199]
154
RFA
31
127 (195)
34.7
(mean)
(39)
26.2
14
CLM
Mets
Intra-hepatic
54
CLM
Ablation site
18
22.8
21.4
(mean)
(mean)
100 (507)
30
24.5
CLM
Ablation site
6.7
87 (199)
29
25
CLM
Ablation site
47.2
23
32.4
(mean)
(mean)
Ablation site
11
Jakobs (2006)[184]
RFA
68 (183)
Machi (2006) [205]
RFA + chemo
RFA +/-
van Duijhoven (2006)
resection
[185]
Mazzaglia
(2007)[198]
RFA
63 (384)
Neuroendocrine
liver mets
Ablation site
Siperstein (2007)
RFA (after
[206]
failed chemo)
234
39
(mean)
24
CLM
Intra-hepatic
Extra-hepatic
Lap RFA
68
37
23 (27)
Berber (2008)[197]
recurrence=6 mth
Median time to
recurrence=9 mth
Median time to
recurrence=10 mth
Ablation site
16
Intra-hepatic
57
Extra-hepatic
49
Ablation site
2
Intra-hepatic
24
Extra-hepatic
30
Ablation site
46
Solitary CLM
Resection
Blusse (2008)[187]
18; Median time to
RFA
90
87
38
n/a
33 (41)
n/a
CLM
Intra-hepatic
recurrence at
RFA +
Resection
10.3
1yr
55
25
n/a
CLM
Extra-hepatic
recurrence at
40.6
1yr
Gleisner (2008)[160]
Intra-hepatic
recurrence at
Resection
192
35
n/a
CLM
2^
1yr
Extra-hepatic
12.8^
recurrence at
155
1yr
Intra-hepatic
recurrence at
41.3
1yr
RFA
11
25
n/a
CLM
Extra-hepatic
recurrence at
21.2
1yr
CLM (n=18);
RFA
34
10
36
non-CLM
Ablation site
5.9
Intra-hepatic
41
Ablation site
3.6
Intra-hepatic
60.7
Intra-hepatic
54
Ablation site
28
Intra-hepatic
32
Extra-hepatic
12
Ablation site
10
Intra-hepatic
14
Extra-hepatic
24
Ablation site
25
Intra-hepatic
53
Extra-hepatic
54
Ablation site
17^
Intra-hepatic
33^
Extra-hepatic
35
Ablation site
2
Intra-hepatic
14
(n=16)
Leblanc (2008)[209]
RFA +
Resection
CLM (n=16);
28
10
25
non-CLM
(n=12)
CLM (n=26);
Resection
37
21^
29
non-CLM
(n=11)
RFA
25
25 (25)
Hur (2009)[200]
42
Resection
Meloni (2009)[190]
RFA
RFA (+ chemo
in 7 pt)
42
52
66
Single CLM
26 (28)
25
(mean)
32
(mean)
19.1
20
Breast Ca
Liver Mets
CLM
Reuter (2009)[191]
Resection (+
chemo in 18 pt)
156
126
53
(mean)
20
CLM
Extra-hepatic
33
^Statistically significant differences between group(s)
HAI-hepatic arterial infusion of chemotherapy
157
Appendix 11: Survival after RFA for Resectable Liver Metastases
Number
Included
articles
Treatment
of
patients
(tumours)
RFA
47 (107)
[213]
Otto
size
(mm)
Median
followup
(months)
Median
Median
Median
Types of
survival
survival
survival
liver
rate at
rate at
rate at
metastases
1 year
3 years
5 years
(%)
(%)
(%)
88
n/a
n/a
Overall
Disease
median
free
survival
survival
(months)
(months)
n/a
9
Recurrent
Elias
(2002)
Median
21
(mean)
14.4
hepatic
malignancies
(29 CLM)
RFA
28
30
814 days
CLM
n/a
67
n/a
Resection
82
50
644 days
CLM
n/a
60
44
Beyond
203
day 1352
days^
(2010)
[214]
^Statistically significant differences between group(s)
158
1694
days
416 days
Appendix 12: Tumour Recurrences after RFA for Resectable Liver Metastases
Recurrence
Included
articles
Treatment
Patients
Median
(tumours)
size (mm)
Median
follow-up
(months)
site (ablation
Types of liver
zone, intra-
Recurrence
metastases
hepatic or
rate (%)
extrahepatic)
Elias (2002)
[213]
Livraghi
(2003) [215]
Recurrent hepatic
RFA
47 (107)
21 (mean)
14.4
malignancies (29
CLM)
RFA
RFA
88 (134)
28
21 (mean)
30
33
814 days
CLM
CLM
Otto (2010)
[214]
Resection
82
50
644 days
CLM
Ablation site
31.9
Intra-hepatic
21.3
Extra-hepatic
31.9
Ablation site
40
Intra-hepatic
10
Extra-hepatic
6.8
Ablation site
32^
Intra-hepatic
50
Extra-hepatic
32
Ablation site
4
Intra-hepatic
34
Extra-hepatic
37
^Statistically significant differences between group(s)
159
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Buscarini E, Savoia A, Brambilla G, Menozzi F, Reduzzi L, Strobel D, et al. Radiofrequency
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