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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_1260_Библиотеки_им_академика_М_И_Перельмана
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Ablation strategies for tumors of the liver and pancreas 259
Figure 18.2 Radiofrequency electrodes. (a) Expandable multitined probe. (b) Cluster of three straight electrodes spaced optimally by
a plastic guide.
Multitined electrodes allow for increased spatial distribution of heat and can create larger ablation zones. Internally cooled electrodes aim to prevent desiccation
(charring) at the electrode–tissue interface, which disrupts energy transfer to deeper tissues. Traditionally,
monopolar systems have been used, but bipolar and
multipolar systems are also now available. A bipolar
circuit is completed with a second interstitial electrode
and obviates the need for a skin surface grounding pad,
while multipolar systems allow the operator to transition
between sets of bipolar electrodes on a single needle.
These strategies can generally produce larger ablative
volumes.
There is a small risk of thermal injury at the site of
the grounding pads, which warrants careful temperature
monitoring. Strategies such as pad cooling and the use of
multiple pads to increase surface area are possible in the
setting of high pad temperatures and impedance.
Even as new technologies are developed, RFA remains
the most widely used of all ablative techniques within the
liver.
18.1.2 Microwave ablation
Microwave ablation (MWA) generates heat through
dielectric hysteresis. Polar molecules, such as water, present within the liver are subjected to a rapidly oscillating
electromagnetic field, and when they fail to align with the
field, some of the applied energy is converted to heat with
subsequent cytotoxic effects on adjacent tumor tissue. A
basic MWA set-up requires a generator (magnetron or
solid state), a coaxial cable with inner and outer conductors for power distribution, and MWA antennas for
energy transfer to tissue (Figure 18.2). In contrast to
RF electrodes, MWA antennas unload energy as a propagating field, not an electric current. Thus, they can create
large zones of active heating without the need for a
grounding pad or additional electrodes to complete a
bipolar circuit. The speci fic design of individual MWA
antennas can alter the shape and depth of ablative zones
and cooling systems can minimize collateral damage
along the insertion track of a long probe needed for
deeper lesions [4]. Cooling also helps protect skin at
the insertion site during percutaneous and laparoscopic
procedures; it can be achieved with either gas or water
cooling systems.
Microwave ablation is frequently used f or hepatic
tumor ablation in China and Japan and is gaining
interest within Europe and the United States. This
technique holds promise as an alternative to RFA,
particularly for large tumors, because it is capable of
performing multiple ablations at the same time (multiple antennas powered simultaneously by a single generator), genera tes higher temper atures and he ats tissue
more efficiently (Figure 18.3). This theoretically translates into larger ablation volumes produced more rapidly (Figure 18.4).
18.1.3 Irreversible electroporation
Irreversible electroporation (IRE) is a new nonthermal
ablation technology that uses high-voltage pulses of
electrical current to create permanent nanopores in
cells that ultimatel y result in irreversible membrane
damage and cell death by apoptosis. Voltages as high
as 1500 volts/cm are used with electr ical pulses gated to
260 Chapter 18
Figure 18.3 Microwave ablation instruments. (a) Cooled shaft AMICA probe. (b) Generator. (c) Schematic of electrode from (a), with accompanying intraprocedural imaging:
CT-guided ablation of a lung tumor (left) and ultrasound-guided ablation of liver tumor (right). Source: HS Hospital Services SpA, Rome, Italy. Reproduced with permission.
Figure 18.3 (Continued )
Ablation strategies for tumors of the liver and pancreas 261
the cardiac cycle to minimize the risk of generating an
arrhythmia. Complete muscle paralysis is required during treatment. Very early data sugges t that IRE is a more
precise and complete method of tumor ablation, with
possibilities in both the liver and pancr eas. IRE generates permanent nanopor es within cell membranes but
does not affect noncellular structures, such a s basement
membranes, lamina propria, and adventitia. It thereby
preserves vital vascular and ductal structures within the
ablation zone [5]. Furthermore, it avoids the heat or
cold sink effects of neighboring vessels with the potential to create a more complete ablation, thereby reducing the risk of local recurrence in tumors adjacent to
hepatic and pancreatic vasculature. Since tumor ablation is not induced by thermal energy, many of the
limitations of RFA and MWA are avoided. Well-demarcated margins are produced with IRE, compared to
larger gray zones with both RFA and MWA that have
some viable parenchymal and cancer cells mixed within
a generally necrotic region. Ablation times are even
shorter with IRE than MWA, with 90 pulses needed to
ablate a 3 cm tumor complete within one minute [6]. As
a result of cell death by apoptosis instead of coagulation
necrosis, the ablation zone resolves relatively quickly.
This cutting-edge technology has only recently been
applied in patients and reported in small-scale studies [7,8]. Limitations include the necessity of extremely
precise applicator positioning, which adds time to an
otherwise short ablative approach. All patients must
receive muscle relaxants for these cases as the IRE pulses
can trigger muscle twitches. Cardiac arrhythmias are also
a concern owing to alterations in ion transport initiated by
electrical current. This procedure should not be performed in close proximity to the heart or in the absence
of an experienced anesthesiologist. The safety and efficacy of IRE are yet to be confirmed in larger studies, and
this approach is still in its infancy.
18.1.4 Cryoablation
Though once in widespread use, most surgeons no longer
perform cryotherapy because it is associated with significant start-up costs and high morbidity compared with
other options. Bleeding is among the most notable complications, but patients are also at risk of “cracking” the
iceball formed during ablation, fracture of the liver surface, and myoglobinuria, with the potential for acute
renal failure. Unlike other modalities, cryotherapy generally requires laparotomy.
262 Chapter 18
Figure 18.4 Table of ablation zones. Approximate ablation zone sizes generated by MWA based on power setting and duration.
Source: HS Hospital Services SpA, Rome, Italy. Reproduced with permission.
18.1.5 Chemical ablation
Prior to the development of RFA, ethanol injection was
the most commonly employed means of ablation for liver
tumors. It was primarily used for HCC within a cirrhotic
liver because these tumors tend to be softer compared
with metastatic disease and the cirrhotic parenchyma
provided a barrier to ethanol diffusion outside the tumor.
The superiority of RFA over ethanol injection has subsequently been demonstrated by multiple randomized trials, as well as two large meta-analyses [9–13]. Patients
treated with RFA have improved local recurrence rates,
cancer-free survival at three years, and overall survival [7]. Ethanol ablation seems to have similar efficacy
when compared with RFA for small solitary HCCs
2 cm [14,15]. However, its utility is limited by patient
discomfort and the need for multiple visits for recurring
injections.
In countries with resources sufficient to support the
expenses of RFA, perhaps the only role for ethanol
ablation is in small tumors that are not amenable to
thermal ablation because of their proximity to major
vasculature, the hepatic hilum, or the gallbladder. It is
generally agreed that in skilled hands, RFA can be safely
performed on tumors of the dome adjacent to the diaphragm. Ethanol ablation may also be a reasonable alternative in resource-poor settings owing to its lower cost,
minimal complications, and need for relatively simple
equipment.
Acetic acid injection is another option for chemical
ablation, which appears to have comparable efficacy
and fewer adverse effects [16].
18.2 Ablation of hepatocellular
carcinoma
Hepatocellular carcinoma is distinguished from other
liver cancers by the increased prevalence of a cirrhotic
Ablation strategies for tumors of the liver and pancreas 263
liver parenchyma. While patients with a normal surrounding liver can tolerate resection of 70 – 80% of their
liver volume, cirrhotics can only tolerate resections in
the 40–50% range. Even if the size of the functional
liver remnant (FLR) is sufficient, there is a dramatic
increase in perioperative mortality as cirrhosis progresses. An inadequate FLR or advanced cirrhosis, as
well as invasion of major hepatic vasculature and
extrahepatic disease, may deem a patient unresectable.
In contrast to resection, RFA is improved by a cirrhotic
liver because of the “oven effect,” whereby the surrounding cirrhotic liver traps heat withi n the tumor and
promotes more effective ablation.
18.2.1 Small unresectable HCCs
Radiofrequency ablation alone is potentially curative for
small, limited HCCs and should be considered first-line
treatment when a patient with reasonably preserved liver
function (Childs A or B) and good functional reserve
presents with an unresectable tumor and is not a candidate for transplantation. Specifically, patients with up to
three tumors 3 cm each who are otherwise unresectable
should be treated with RFA unless tumor is not safely
accessible or other contraindications are present [17,18].
Efficacy should be assessed one month following tumor
ablation with contrast-enhanced computed tomography
(CT) or magnetic resonance imaging (MRI). Loss of contrast enhancement within the tumor indicates successful
ablation.
18.2.2 Small resectable HCCs
Though more controversial, there may be a role for RFA
in patients with limited resectable disease. Three randomized trials and a meta-analysis compare RFA with hepatic
resection for the treatment of small resectable HCCs. The
largest trial randomized patients who fell within the
Milan criteria (single tumor <5 cm; three or fewer tumors,
each 3 cm) to undergo resection or RFA, and resected
patients enjoyed a clear advantage in survival, diseasefree survival, and local recurrence rates [19]. The two
remaining randomized trials [20,21] and the meta-analysis [22] suggested no difference between RFA and surgical resection, particularly for small tumors 3 cm.
Despite these provocative findings, most experienced
centers continue to favor surgical resection whenever
feasible. In cases of small tumors where tumor, liver, or
patient-related factors tip the balance towards RFA, it is a
reasonable treatment option. In some cases, RFA may be
preceded by transarterial chemo embolization as the combination has been demonstrated to increase ablation sizes
and potentially decrease recurrence (see later in this
chapter).
18.2.3 Ablation of bulky unresectable
disease
As technology advances, there may be an expanding role
for tumor ablation, both alone and in combination with
other locoregional and surgical therapies, in the management of larger or multifocal tumors that would otherwise
be considered nonoperable. Traditionally, management
of intermediate to large tumors has relied most heavily on
transarterial approaches.
18.2.4 Multipolar RFA
The efficacy of monopolar RF techniques falls off after
tumors exceed 3 cm in diameter. Complete ablation often
requires multiple repositionings of monopolar devices,
which may increase procedure times and complications
and decrease efficacy, even in experienced hands. In
addition, ultrasound becomes a less reliable guidance
modality as the ablative process continues and progressive tissue water vaporization causes transient hyperechogenicity in the heated tissue because of the
formation of microbubbles. This makes accurate placement of additional probes difficult.
Most multipolar RFA systems consist of three bipolar
electrodes, which are positioned no more than 3 cm apart
and can generate 15 sequentially activated RF combinations. Ablation zones of 6 cm can be reliably produced
with the need for probe repositioning. After the first
round of ablation, one or two probes can be repositioned
to expand the ablative margin as necessary. Clusters of
four probes are also available. These techniques have
shown promise in animal models and small patient
series [23] but implementation has been limited because
of complex equipment and high costs.
A separable clustered electrode known as the Octopus
(Taewoong Medical, Goyang, Republic of Korea) used in
conjunction with a multichannel generator was recently
compared with traditional RFA clusters (three electrodes
on a single fixed body with a fixed 5 mm interelectrode
distance) in a porcine model using an open approach [24].
Unlike other systems, Octopus electrodes can be used
either simultaneously in monopolar mode or in the
switching monopolar mode and may be a reasonable
option for tumors >5 mm in the future.
264 Chapter 18
18.2.5 Microwave ablation
As discussed above, microwave ablation holds promise for
large tumors. It penetrates charred or desiccated tissue,
and multiple antennas may be employed simultaneously
to generate larger ablative volumes as well as greater
temperatures compared with RFA. In preclinical models,
ablation zones up to 6.5 cm are reliably and rapidly
created using three 17 gauge antennas simultaneously
powered by a single generator [25]. Furthermore, mounting evidence shows that MWA is less susceptible to the
heat sink effect of neighboring hepatic vasculature, which
is known to increase local recurrence rates in tumors
treated with RFA. Preclinical evidence suggests that
MWA is effective for tumors adjacent to vessels measuring up to 10 mm [26,27], while RFA is limited by hepatic
vessels greater than 3 mm [28]. Furthermore, MWA
times, often in the 2–10 minute range, are much shorter
than those needed for RFA [29]. This certainly has implications for efficiently treating larger and multiple unresectable tumors. Though the modality seems promising,
particularly for the ablation of large and multiple tumors,
more convincing long-term clinical evidence will be
forthcoming as MWA gains greater acceptance among
hepatobiliary surgeons.
18.2.6 Pre-RFA transarterial embolization
In patients with Childs A or B cirrhosis and large or
multifocal tumors who are not candidates for surgical
resection or transplantation, combined ablation and
transarterial methods may also be considered. Transarterial chemoembolization (TACE) has become the default
therapy for patients with intermediate size (>4–5 cm) or
multifocal HCC. It combines the cytotoxic effects of targeted chemotherapy administration to the hepatic arterial circulation supplying the tumor and induces ischemic
necrosis by arterial embolization. When combined with
RFA, TACE diminishes the heat sink effect of the surrounding vasculature and allows for ablation of larger
areas [30]. In addition, the effect of chemotherapeutic
agents on the cancer cell microenvironment may attenuate its susceptibility to hyperthermia and promote additional coagulative necrosis [31]. TACE may also disrupt
intratumoral septa that, when present, limit the efficacy
of RFA. Although combination therapy with TACE and
RFA is the most well studied, other transarterial and
ablative combinations can also be considered on a caseby-case basis. Mounting data in the form of meta-analyses [32] and randomized trials support combination
therapy as a regional approach [33], especially for intermediate-stage tumors [34,35]. The morbidity associated
with a combined approach must be carefully weighed by
the multidisciplinary treatment team.
18.2.7 Tumor ablation as a bridge to
transplant
The scarcity of transplantable livers has prompted most
centers to consider locoregional or surgical therapies as a
bridge to liver transplant for patients expected to have
prolonged wait times, generally greater than six
months [36]. Bridging treatments are pursued with the
hope of containing tumor progression and decreasing the
risk of “drop-off” from waiting lists. High-quality data in
the form of prospective randomized trials are lacking, but
pretransplant RFA is widely accepted as a safe approach
that may allow patients to be maintained on waitlists for
longer periods [37,38].
18.3 Ablation of liver metastases
As with HCC, resection is the treatment of choice for
isolated liver metastases whenever feasible. Although
superimposed cirrhosis is rarely present, the majority
of patients with liver metastases are still not candidates for resection owing to tumor size, location,
mutifocality, or the presence of significant co-morbidities. In contrast to patients with HCC, patients with
metastatic liver tumors are almost never candidates
for transplantation, which increases the relevance of
RFA (or resection plus RFA) for bilobar disease. In the
absence of extrahepatic metastases, some of these
patients are c andidates for tumor ablation as a potentially curative therapy.
18.3.1 Colorectal cancer
Compared with other malignancies, isolated hepatic
metastases are relatively common in patients with colorectal cancer and the survival benefits associated with
surgical resection are well documented. Ablation for
colorectal metastases is generally reserved for patients
who are poor surgical candidates. Currently, no randomized trials have addressed whether tumor ablation affords
similar overall survival, progression-free survival, or local
recurrences rates, though the majority of retrospective
data suggest that resection is superior [39,40]. Based on
the available data, it would be inappropriate to pursue
Ablation strategies for tumors of the liver and pancreas 265
ablation over resection in patients who are operative
candidates outside a clinical trial [41].
18.3.2 Breast cancer
As many as one in five deaths from breast cancer result
from liver failure in the setting of metastatic disease [42].
In the vast majority of these patients, metastatic disease is
not limited to the liver and systemic therapy is the firstline treatment. Patients with isolated liver metastases that
are stable or decrease while on appropriate chemotherapeutic regimens may obtain some benefit when
treated with RFA. The use of RFA in breast cancer patients
with isolated hepatic metastases is limited to relatively
small case series, and though reasonable in select patients,
its role remains unclear.
18.3.3 Neuroendocrine tumors
As with other metastatic hepatic tumors, hepatic resection is the treatment of choice for patients with neuroendocrine tumors who are optimal surgical candidates.
Many patients with metastatic neuroendocrine disease
will go on to live for several years and control of hormone
hypersecretion is of tremendous value. Accordingly,
ablation of hepatic metastases can be helpful even in
the presence of small-volume extrahepatic disease.
Symptomatic control from excess hormone release can
immediately and dramatically improve quality of life.
18.4 Postablation follow-up
All ablation strategies require postprocedural imaging
to assess the comp letenes s of ablation and for thermal
modalities, to ensure an adequate 5–10 mm circumferential margin (Figur e 18.5). Successful ablation is indicated by the absence of contrast enhancement and,
over time, the formation of a contracted and fibrotic
scar. Even in the setting of an entirely necrotic ablation
zone with adequate margins, patients are at risk for
local recurrence, as well as new primary HCC or metastatic tumors. While a positron emission tomography
(PET) scan may be helpful to detect local recurrence, it is
subject to false-positive interpretation as a result of fluorodeoxyglucose (FDG) uptake in inflammatory cells. As
with postresection surveillance, current NationalComprehensive Cancer Network (NCCN) guidelines recommend
Figure 18.5 (a) Successful RFA of a colorectal carcinoma liver metastases with CT imaging prior to ablation, one month following
ablation, and 18 months following ablation. (b) Incomplete ablation leads to local recurrence. Figure shows preablation CT,
postoperative CT revealing contour of ablation affected by blood vessels, and ultimately tumor recurrence resulting from
incomplete ablation.
266 Chapter 18
imaging every 3–6 months for the first two years following
ablation and then annually [43].
18.5 Treatment approach:
percutaneous, laparoscopic
or open?
Most ablation modalities can be performed with open,
laparoscopic, or percutaneous approaches. Each approach
comes with specific risks and benefits and it is crucial that
the choice be tailored to the individual patient. In this
section we focus on advances in the laparoscopicapproach
after discussing a few key general points.
18.5.1 Percutaneous tumor ablation
The percutaneous approach (Figure 18.6a) is beneficial in
that it is the least invasive and can often be completed
on an outpatient basis without the need for general
anesthesia. I t is the preferred option for patients with
Figure 18.6 Microwave ablation. (a) Set-up for CT-guided percutaneous MWA of HCC in a poor surgical candidate. (b) MWA of
hepatic tumor via a laparoscopic approach with accompanying ultrasound-guided imaging. Intraoperative ultrasound demonstrates
hypoechogenic tumor with typical intraprocedural hyperechoic ablation artifacts. Source: Dr R. Santambrogio, San Paolo Hospital,
University of Milan, Italy. Reproduced with permission.
Ablation strategies for tumors of the liver and pancreas 267
Figure 18.7 Hydrodissection to protect neighboring structures from thermal injury during percutaneous ablation. (a) HCC in the
dome of the liver in close proximity to the diaphragm and heart. (b) Saline percutaneously injected into potential space between
liver and hemidiaphragm to create an insulating barrier, effectively protecting the heart from thermal injury.
small tumors located in easily accessible regions. Guidance of elec trodes with CT or MRI is general ly better
than with intraoperative ultrasound. Percutaneous
ablation of tumors in the dome of the liver should be
attempted with great caution on account of the r isk of
diaphragmatic injury (Figure 18.7a). The same is true
for tumors along the inferior edge of the liver adjacent
to the stomach, duodenum, or colon. These structures
can be protected from thermal injury by hydrodissection, a technique that involves instillation of saline
to separate the structure from the ablation zone
(Figure 18.7b).
18.5.2 Open tumor ablation
Open tumor ablation provides the best hepatic exposure
and allows for a thorough inspection of the peritoneum
for concomitant extrahepatic metastases. It is ideally
suited for patients who require laparotomy for another
reason, such as combined hepatic resection and RFA, or
colon resection for a primary colorectal tumor. It is also
ideal for tumors in difficult locations in which care must
be taken to avoid injury to adjacent viscera or vasculature.
A surgical approach also allows for a Pringle maneuver to
temporarily interrupt hepatic inflow to decrease the
effects of heat sink when ablating large hypervascular
tumors or tumors adjacent to major vasculature. Finally,
high-resolution intraoperative ultrasound can be
conducted with relative ease and is better suited to detect
occult hepatic metastases.
18.5.3 Laparoscopic tumor ablation
Many believe that laparoscopy should be the first-line
approach for thermal ablation of potentially curable
tumors [44] (Figure 18.6b). In skilled hands, laparoscopy
combines many of the benefits of percutaneous and open
resection. The procedure is minimally invasive, yet
affords the surgeon the opportunity to assess for disseminated disease, effectively protect adjacent organs, and
take advantage of high-quality intraoperative ultrasonography. Hepatic or colon resections may also be performed
under the same anesthesia.
Experience with laparoscopic ultrasound and ultrasound-guided needle placement is crucial as precise probe
placement optimizes the chances for complete ablation
with a clear margin. This aspect of the operation is
particularly crucial when treating difficult-to-access
deep or posterior tumors or tumors adjacent to major
vasculature. Despite the aforementioned drawbacks,
intraoperative ultrasound can be used in real time and
is more readily available and cost-effective when compared with other imaging modalities, such as CT or MRI.
Advances in three-dimensional (3D) ultrasound probes
and the use of contrast-enhanced ultrasound have
improved intraoperative tumor identification and
268 Chapter 18
effective probe placement. Data suggest that contrastenhanced 3D ultrasound (CE-3DUS) rivals CT and MRI
in sensitivity and accuracy [45]. Contrast enhancement
can also help distinguish viable tumor regions when
ablating large tumors or managing a recurrence. Currently available software can accurately measure tumor
dimensions, which is useful in selecting the optimal RFA
probes for a given tumor. CE-3DUS can also measure the
extent of coagulation necrosis approximately 10 minutes
after ablation, with complete ablation marked by the
absence of tumor enhancement [46].
In an attempt to streamline optimal placement of RF
probes, a pilot study [47] reported a novel 3D laparoscopic
magnetic ultrasound image guidance technique used in a
preclinical in vitro model. Magnetic sensors were embedded
into a 3D laparoscopic ultrasound transducer and a needle.
Creation of an electromagnetic field allowed for real-time
image guidance on a stereoscopic monitor and enabled both
novices and expert hepatobiliary surgeons to accurately
target 100% (44/44) of 5 mm lesions. This compared
with hit rates of 0% and 59%, for novices and experts
respectively, using a traditional approach. Though still
under development, such technology could dramatically
improve intraoperative targeting for tumor ablation, especially for tumors in deep or complex locations.
18.6 Ablation of pancreatic tumors
The implications for tumor ablation are different in
patients with liver and pancreatic tumors. Patients with
liver cancer typically die of liver-specific complications,
while patients with pancreatic cancer die of disseminated
disease. As such, it is generally inappropriate to pursue
ablation with curative intent in patients with locally
advanced pancreatic cancer, while this may be possible
in patients with unresectable hepatic disease. These
organs are also quite distinct with respect to the safety
of ablation. It is feasible to ablate somewhat large regions
of hepatic parenchyma without compromising neighboring organs or vascular and ductal structures. This is nearly
impossible within the pancreas.
Figure 18.8 Irreversible electroporation. (a) IRE generator. (b) Intraoperative ultrasound-guided placement of IRE electrodes.
(c) Cross-sectional location of the first five IRE probes relative to tumor target area (shown in yellow). (d) Voltage and current
measurements across IRE electrode numbers 2 and 4 during treatment. (e) CT imaging prior to IRE showing tumor in uncinate
process of pancreas (transaxial top, coronal bottom). (f) CT imaging three months post IRE (transaxial top, coronal bottom).
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