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Radiofrequency Ablation in Lung Cancer: Promising Results in Safety and Efficacy

Radiofrequency Ablation in Lung Cancer: Promising Results in Safety and Efficacy

ABSTRACT: Only about 15% of patients diagnosed with lung carcinoma each year are surgical candidates, either due to advanced disease or comorbidities. The past decade has seen the emergence of minimally invasive therapies using thermal energy sources: radiofrequency, cryoablation, focused ultrasound, laser, and microwave; radiofrequency ablation (RFA) is the best developed of these. Radiofrequency ablation is safe and technically highly successful in terms of initial ablation. Long-term local control or complete necrosis rates drop considerably when tumors are larger than 3 cm, although repeat ablations can be performed. Patients with lung metastases tend to fare better with RF lung ablation than those with primary lung carcinoma in terms of local control, but it is unclear if this is related to smaller tumor size at time of treatment, lesion size uniformity, and sphericity with lung metastases, or to differences in patterns of pathologic spread of disease. The effects of RFA on quality of life, particularly dyspnea and pain, as well as long-term outcome studies are generally lacking. Even so, the results regarding RF lung ablation are comparable to other therapies currently available, particularly for the conventionally unresectable or high-risk lung cancer population. With refinements in technology, patient selection, clinical applications, and methods of follow-up, RFA will continue to flourish as a potentially viable stand-alone or complementary therapy for both primary and secondary lung malignancies in standard and high-risk populations.

After 52 pack-years of smoking,
Don had little to celebrate
on his 70th birthday
when he was diagnosed with stage IB
non-small-cell lung carcinoma. To
make matters worse, he was told that,
despite his early-stage cancer, he was
not a suitable candidate for surgical
resection due to his extensive lung
disease. Bereft of his most promising
option, Don was left without much
hope. Although not a candidate for
surgery, Don did indeed have other
options, many of which would not have
been available to him had he been diagnosed
a decade earlier. Don did eventually
undergo radiofrequency ablation (RFA) of his lung cancer and has just
celebrated his 75th birthday.

Lung carcinoma remains the leading
cause of cancer death in the United
States. Over the past decade, lung
cancer death rates have more than quadrupled,
from 5.4 to 29.4 per
100,000.[1] The American Cancer
Society estimates that in 2005 the
number of lung cancer deaths will
rise to 163,510-90,490 men and 73,020 women-accounting for 28%
of all cancer-related deaths. The number
of newly diagnosed lung cancers
will rise to 172,570, or 93,010 new
cases in men and 79,560 in women.[
2] Nearly 60% of those diagnosed
with lung cancer die within 1 year of
their diagnosis and nearly 75% within
2 years.[2]

Despite recent advances in therapy,
the relative 5-year survival rate for all stages of lung cancer has improved
only slightly to 15%.[2] For
early-stage lung carcinoma, surgical
resection confers the best survival option,
with 5-year survival rates approaching
80% for stage I disease and
40% for stage II disease.[3]

Only about 15% of patients diagnosed
with lung carcinoma each year
are surgical candidates.[4] Most patients
present with advanced or widespread
disease at the time of diagnosis
and, therefore, are not considered candidates
for surgery. Some patients
have technically resectable disease but
cannot undergo surgery because of
comorbid cardiopulmonary disease.
This population represents a suitable
target for novel, minimally invasive
lung-sparing therapies providing local
control.

Local therapy may also be appropriate
in limited metastatic disease.
The lung is the second most frequent
site of metastatic disease. Surgical resection,
or metastasectomy, appears
to confer some survival benefits in
carefully selected patients.[5] Although
it is somewhat uncertain
whether this benefit results from total-
body tumor burden cytoreduction
or a less aggressive natural course of
disease in this patient subpopulation,
pulmonary metastasectomy is increasingly
accepted as treatment in selected
patients, with a 10-year survival
rate of approximately 25%.[5] At least
90% of the 10-year survivors remain
free of disease.[6] Yet the size and
number of metastatic nodules frequently
preclude attempts at surgical
resection. Since the majority of patients
develop disease recurrence following
metastasectomy, and repeated
resections can remove significant
amounts of functioning lung, this patient
population also represents a suitable
target for minimally invasive
lung-sparing therapies.

Since the early 1990s, an increasing
number of minimally invasive techniques have been introduced into
clinical practice in the treatment of
primary and secondary pulmonary
malignancy. Image-guided interventional
and video-assisted thoracoscopic
approaches have become attractive
alternatives to open thoracic surgical
resection. The past decade has seen
the emergence of minimally invasive
therapies using thermal energy sources:
radiofrequency, cryoablation, focused
ultrasound, laser, and
microwave. Radiofrequency ablation
is the best developed, secondary to the
advent of bipolar and multielectrode
and internal tip-cooling RF electrodes
as well as advances in computed-tomography
(CT) technology.

Radiofrequency ablation is a controlled
electrosurgical technique that
implements high-frequency alternating
current to generate localized electromagnetic
fields, heating targeted
tissues to desiccation, or thermal coagulation.
Naturally, cells of targeted
tissue die when exposed to high thermal
doses. For a variety of reasons,
including less efficient heat dissipation,
the cells of neoplastic tissues are
more sensitive to heat effects than are
cells of healthy tissues.[7] Thus, RFinduced
hyperthermia exploits this
difference in heat sensitivity by creating
localized temperature increases in
neoplastic tissues to greater than 57C
to 60C, while restricting temperatures
in healthy tissues to normal ranges.[
8] Several authors have advocated
that lung tumors are well suited to
RFA because of the so-called "oven
effect," whereby the air (high resistance)
surrounding an intraparenchymal
tumor (low resistance) affords an
insulating effect and traps heat within
the targeted tumor.[9]

Well established in the treatment
of various cardiac and neurologic dysfunctions,
RFA has faced a major barrier
to further application: the small
lesion size created by earlier generation
devices and delivery methods.
The advent of bipolar and multielectrode
and tip-cooled RF electrodes, enabling
the creation of larger areas of
controlled and reproducible necrosis in
animal and human models in vitro and
in vivo,[10] has expanded potential clinical
applications to include tumor therapy-
notably in the treatment of primary and secondary brain and hepatic
malignancies.[11,12]

The feasibility and safety of percutaneous
interstitial thermal ablation
of pulmonary tissue have also been
investigated. Using a percutaneous
CT-guided transthoracic technique,
Goldberg et al showed that RFA was
not only performed safely in the pulmonary
tissue of rabbits but that tissue
response to thermal injury was controlled,
predictable, and easily monitored.[
9] Subsequent investigation has
been directed to the ablation of abnormal
tissue within the pulmonary parenchyma,
specifically malignancy.

Since 1996, several authors have
used CT-guided RF application to successfully
treat induced sarcomas within
the lungs of rabbit, canine, and
ovine models, characterizing tissue
changes following lung ablation with
at least 95% necrosis to complete eradication
of treated tumor nodules at
histopathologic analysis and demonstrating
the influence of surrounding
tissue on ablation outcome.[13-17]
Complications recorded during these
studies include pneumothorax, pulmonary
hemorrhage, and tumor relapse.

Patient Selection

No solid or strict criteria currently
exist regarding patient appropriateness
for undergoing RFA. For primary lung
carcinoma, much of the current literature
focuses on the unresectable or
high-risk group.[18-26] These patients
have early-stage lung carcinomas that
could qualify for surgical resection
but are medically inoperable because
of comorbid cardiopulmonary disease,
particularly severe chronic obstructive
pulmonary disease or inability to
withstand lung loss. Other relevant
populations have limited local recurrence
following primary treatment,
have refused surgical intervention,
seek palliation such as pain control,
or desire cytoreduction to render more
feasible complementary therapy such
as radiation using a smaller field.

In any scenario, all imaging-CT,
PET, and/or PET/CT-should demonstrate
localized disease without hilar
or mediastinal nodal and
extrathoracic involvement. Radio-graphic staging is limited in its description
of the full extent of disease,
particularly in groups in whom mediastinoscopy
and lymph node sampling
cannot be performed due to the high
risk of general anesthesia. Even in the
best-case scenario, disease is likely to
be understaged by imaging alone.[27]

Solid or strict criteria are also lacking
for tumor characteristics favorable
for RFA, although trends are
beginning to emerge. "Ideal" lesion
features include solitary status. But
multiple lesions are considered if they
are fewer than five in number, completely
intraparenchymal, smaller than
5 cm (more appropriately 3 cm), confined
within a single ablation zone,
spherical vs irregular, and noncontiguous
with the hila and its large airways
and pulmonary arteries and veins, or
the mediastinum or vital structures within
such as the trachea, esophagus, heart,
aorta, and great arteries.

Akeboshi et al achieved lower rates
of complete necrosis in those targeted
lesions greater than 3 cm,[22] and Lee
et al found that lower rates of control
correlated with decreased mean survival
rates: 8.7 vs 19.7 months for the
complete necrosis group.[21] As with
hepatic tumor ablation, tumors close to
large arteries and veins are often incompletely
ablated, owing to the heatsink
effect.[28,29] Tumors close to the
hilum likely already have regional nodal
involvement.

Technique and Delivery

Radiofrequency ablation systems
approved by the US Food and Drug
Administration for coagulation necrosis
of soft-tissue tumors have three
components: an RF generator, an active
electrode, and dispersive electrodes.
Radiofrequency energy is
introduced into the tissue via the active
electrode. As this alternating current
moves from the active to the
dispersive electrode (ie, electrosurgical
return pad) and then back to the active
electrode, the ions within the tissue oscillate
in an attempt to follow the change
in the direction of the alternating current.
This movement results in frictional
heating of the tissue, and as the
temperature within the tissue rises beyond
60C, cells begin to die. This phenomenon creates the region of necrosis
surrounding the electrode.[30]

Radiofrequency ablation has mostly
been performed as an outpatient
procedure, usually under conscious
sedation. Operators have at times favored
deep conscious sedation and
even general anesthesia, however,[26]
particularly in patients with targeted
lesions on the pleura and/or chest wall,
and especially in those seeking palliation
for pain. As with most interventional
procedures, intravenous access
is established and blood pressure, heart
rate and rhythm, and oxygen saturation
are continuously monitored. Because
all delivered electrical current
must be grounded, RF devices require
application of two or four grounding
pads to the chest wall or thighs, and
proper contact of the electrode gel
sometimes necessitates the shaving of
body hair. Some authors have advocated
prophylactic antibiotics, particularly
in the ablation of masses greater
than 5 cm, due to the ensuing large
volume of necrosis.[22] All intended
tumors targeted for RFA should have
histopathologic confirmation.

Conventional CT with incremental
scanning or CT fluoroscopy is used
to localize the target tumor. Following
standard sterile preparation and
draping, 1% lidocaine hydrochloride
is administered as local anesthesia intradermally
and into the deeper subcutaneous
and muscular tissue tract.
At this juncture, at least two approaches
have been used. Some authors favor
placement of a localization needle,
such as a 20- or 22-gauge Chiba or
spinal needle, with subsequent placement
of the RF electrode via tandem
needle technique, and others favor direct
placement of the RF electrode.
The former approach is more practical
under conventional scanning.[20]

Available Systems

Currently, four generator and electrode
systems from four different manufacturers
are available:

  • Boston Scientific (formerly Radiotherapeutics)
    RF-3000 generator
    and LeVeen and Concerto multitined
    expandable needle electrodes
  • RITA (RF interstitial tissue ablation)
    system with 1500X electrosurgical generator and StarBurst SDE,
    Semi-Flex, XL, and XLi multitined
    expandable electrodes
  • Valleylab (formerly Radionics)
    Cool-tip RF Ablation System with internally
    cooled single and clustered
    needle electrodes, the three-needle array
    spaced 0.5 cm apart
  • Berchtold Elektrotom 106 HiTT
    with open-perfused electrodes.

In order to optimally deliver a consistent,
homogenous, and reproducible
area of thermal ablation, Boston
Scientific and RITA employ multitined
expandable electrode design
configurations, while Valleylab opts
for single- or clustered-needle electrodes
that rely on internal cooling to
decrease surrounding tissue impedance,
allowing for maximum energy
deposition. Similarly, Berchtold uses
single- or dual-needle electrodes to
deliver RF energy. Although both the
Boston Scientific LeVeen and RITA
StarBurst XL and XLi expandable array
electrodes feature tines that are incrementally
deployed to the ablation
size required, the LeVeen electrode
employs 10 tines in a more horizontal,
or "daisy," configuration, while the
StarBurst uses a more vertical, or
"Christmas tree," configuration.

Each manufacturer offers a wide
range of electrodes and accessories,
such as thinner gauge electrodes with
smaller ablation zones achieved with
or without tine deployment, larger
gauge electrodes with the ability to
infuse saline to create a larger ablation
zone, and various tine deployment
configurations. With the RITA
SDE, the tines deploy from the side
of the electrode 1 cm from its tip,
while the Boston Scientific Concerto
uses both end and side tine deployment
to create a bipolar device. Side
deployment helps deal with difficult
tine placement in mobile or extremely
dense lesions, termed "push back,"
whereby the active tines are exposed
proximal to the tumor[31] or in close
proximity to critical structures.

Boston Scientific and RITA market
coaxial systems as well. All systems
incorporate the principles of
temperature, impedance, and time and
the feedback of all three to varying
degrees to establish ablation end
points. Currently, operators determine the RF system and electrode used,
based on lesion size, geometry, location,
access route, operator familiarity,
and device availability. Algorithms
for proper and thorough ablation also
vary among the four manufacturers.
The Boston Scientific system relies
heavily on impedance, the RITA system
on real-time temperature sensing,
and the Valleylab system on time
and end temperature.

Procedural Considerations
Operators should situate the chosen
electrode so as to ensure at least
1-cm margins around the entire target
lesion,[31] with multiple and overlapping
ablations if needed (Figure
1). Ideally, for tumors measuring between
3 to 5 cm in diameter, six overlapping
ablations should be
performed-four in the axial plane
and two along the z-axis-with all
ablations coinciding at the tumor's
center.[32] It is critical to have CT
documentation, using at least 5-mm
collimation or thinner images through
target lesion and electrode and tine
positions,[33] of electrode placement
and, where appropriate, tine deployment
with each ablation.

Lencioni et al has demonstrated
that multiplanar reformations can
greatly aid and document accurate tine
placement.[34] Depending on the device
selected, end points for each ablation
are variable, as each system
operates on different principles. Each
manufacturer provides general algorithms
and guidelines, but modification
of these guidelines is allowable
as the operator gains experience and
familiarity with the device(s). The
operator determines ablation completion,
dependent on adequate margins
of coverage, patient condition, and
CT imaging end points, which include
documentation of electrode position,
tine deployment to establish adequate
margins, and the presence of groundglass
parenchymal change adjacent to
areas of ablation and surrounding the
targeted tumor in its entirety with
0.5-cm to 1-cm margins.[21,35]

Once ablation of the entire tumor
is achieved, the electrode is removed.
Tract ablation is recommended but
not necessary. A final series of images
is obtained to evaluate for any acute complications. If detected, small pneumothoraces
may be observed or aspirated,
while large pneumothoraces
may require placement of an evacuation
catheter. Each case should be
thoroughly documented, and documentation
will vary for each device
used. Data forms should specify type
of device including electrode used,
deployment size, maximum power,
average target temperature, number
of ablations, tract ablation, and the
presence and/or treatment of complications,
if any.

Immediate postprocedural care involves
noninvasive monitoring, pain
control, and assessment of potential
complications through physician and
nurse assessment and postprocedural
chest radiographs. Generally, an expiratory
chest radiograph should be
obtained within the first 2 hours of
the procedure, with a second one obtained
between 3 and 4 hours after the
procedure. Following assessment of
the second chest radiograph and examination,
the patient may be discharged
home. Depending on the
patient's clinical course and assessment,
the operator will determine
whether limited or overnight admission
for observation is required.

Complications
Both reported complications and
complication rates related to RF lung
ablation have been rather variable, but
overall rates of morbidity and mortality
are extremely low.[36] Complications
are related to electrode placement
and the delivery of RF energy. These
include prolonged pain following ablation,[
20] hemoptysis and pulmonary
hemorrhage,[37] pneumonia and abscess,[
22] pleural effusion,[36] pneumothorax
requiring observation and/or
evacuation,[36] bronchopleural fistula,
cerebral air embolism,[38,39] acute
respiratory distress syndrome and
death,[19,21,37] inability to retract electrode
tines,[40] and electrode tract[41]
and pleural[31] tumor seeding.

Specific complications related to
the delivery of RF energy include dispersive
electrode or grounding pad
skin burns and interference with coand/
or preexisting medical devices.
Lung ablation patients also exhibit a
postablation syndrome similar to that
described in patients posthepatic tumor
ablation,[42] consisting of lowgrade
fevers and malaise, with
productive cough with brown or rustcolored
expectorant and dyspnea, particularly
in the severe lung disease population.

Complications have been reported
in up to 76% of patients, most of them
minor postablation-type symptoms,
pneumothoraces, and pleural effusions.
Pneumothorax rates have
ranged from 4.2% to 53.8%, and those
requiring evacuation with pleural catheter
or thoracostomy tube from 7.2%
to 25%. The occurrence of pleural
effusions has been reported as 3.7%
to 52.4%. Other complications have
been sporadically reported with incidence
rates at 10% or less.

At least three deaths have been reported,
the first due to lethal pulmonary
hemorrhage in a patient on a
commonly used antiplatelet drug, clopidogrel (Plavix),[37] the second related
to Acute Respiratory Distress
Syndrome 4 days following the RF
procedure,[21] and the third as result
of hemoptysis 19 days following RFA
of a central tumor.[19]

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