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Section IV
Organ-specific cancers – liver metastases
Chapter
Colorectal masses:Ablation
16
Elena N. Petre, Stephen B. Solomon, and Constantinos T. Sofocleous
Introduction
Colorectal cancer (CRC) is the third most frequently diagnosed
cancer and the third leading cause of cancer-related death in
the USA.1 About 10–25% of patients present with synchronous
liver metastases at the time of primary diagnosis and another
20–25% develop metachronous liver metastases during the
course of the disease. Surgical resection of distant CRC metastases may result in improved long-term survival and even cure
in a subset of selected patients.2 e 5-year survival rates aer
curative resection of liver metastases range from 35% to 58%.
However, only 25% of patients with colorectal liver metastases (CLM) are candidates for liver resection, while the majority remain unresectable.5 Chemotherapy and newer therapies
can extend survival of patients with non-resectable CLM up to
24months.
6,7,8
In recent years, image-guided percutaneous ablation therapies have ourished as alternative treatment options for
selected patients with unresectable CLM. Dierent ablation
technologies include radiofrequency, microwave, laser, and
cryoablation, that use heat or freezing as a means of causing
cell damage and death of the target tumor. More recently, irreversible electroporation (IRE), a non-thermal technology, has
been applied for liver tumor ablation, includingCLM.
e goal of local tumor ablation is to eciently destroy the
malignant tumor with surrounding margins while minimizing the destruction of non-aected liver. is is an important
parameter for patients with low volume of healthy functioning parenchyma as those with underlying cirrhosis or steatohepatitis from prolonged chemotherapy exposure as well as
those who have previously undergone extensive liver resection
and present for ablation as a salvage therapy for postsurgical
recurrences.
e safety and eectiveness of local tumor ablation in
patients with CLM have been demonstrated in several uncontrolled studies. Patient survival aer percutaneous ablation
seems comparable to that of surgical series (up to 55% at
5 years) in selected patients with small-volume disease that
can be treated with sucient margins.
9,10,11
is observation
may suggest that image-guided ablation could be an equally
eective and less morbid alternative to surgery for a subset of
selected patients.
3,4
Indications
e most common indications for image-guided ablationare:
1. Limited number (arguably less than four) and small
size (arguably less than 5cm in largest diameter) of hepatic metastases in patients who cannot undergo or refuse
surgery.
2. e ideal tumor for percutaneous ablation is a solitary
lesion with largest diameter up to3cm.
A tumor size up to 5 cm may be acceptable for ablation,
although multiple overlapping ablation will be required to
achieve complete ablation with a sucient surrounding
margin (ideally a 1-cm margin all around the tumor should
be created).
3. ere is no absolute number of tumor eligibility; but most
series agree that patients with more than four simultaneous
liver metastases are not good candidates for image-guided
percutaneous ablation.
Contraindications
1. No safe access of the ablation needle to the tumor despite
protective maneuvers such as hydrodissection.
2. Uncorrectable coagulopathy.
3. A relative contraindication is the inability of a patient to
undergo deep sedation or general anesthesia.
Ablation modalities
Radiofrequency ablation
Radiofrequency ablation (RFA) is the most widely employed
and most studied tumor ablation technique. RFA delivers
high-frequency alternating electric current through a needle
electrode placed within a target lesion. is causes local ionic
oscillation and tissue heating that leads to protein denaturation
when temperature exceeds 50°C. At 70°C thermal coagulation
occurs and this thermal injury causes cell death. When temperature reaches 100°C, tissue desiccation (charring) occurs,
resulting in high tissue impedance, which limits the amount
of energy that can be delivered in the tumor, thus preventing expansion of the lethal temperature within tissue. Tissue
Interventional Oncology, Second Edition, ed. Jean-François H. Geschwind and Michael C. Soulen. Published by Cambridge University Press.
©Cambridge University Press2016
139
Section IV:Liver metastases
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AB
DE
Figure 16.1 A 59-year-old woman with a 1.8-cm solitary colorectal liver metastasis in segment 4 (arrow, A) was treated with radiofrequency ablation.
(B) Postablation contrast-enhanced computed tomography scan 4 weeks after ablation demonstrates ablation zone that geometrically encompassed the
tumor with clear margin > 5 mm in all direction. This resulted in good local tumor control, as evidenced on follow-up imaging at 1 (C), 2 (D), and 3 years (E) after
percutaneous radiofrequency ablation.
C
desiccation is one of the technical limitations of RFA; another
important limitation is the “heat-sink” eect that occurs when
ablating tumors near the blood vessels. e heat sink refers to
heat dissipation that results from tissue cooling by vascular
ow nearby. is phenomenon prevents sustained elevation of
high temperature in adjacent tissue, thus decreasing the extent
of coagulation necrosis and resulting in incomplete ablation.
RFA has been used to control CLM successfully in selected
patients with non-resectable disease.
12,13,14,15,16
ere is a growing understanding that, for small tumors that can be ablated
completely with clear margins, RFA may be able to provide
results similar to those of surgery (Figure16.1).
10,11,17,18,19
In selected resectable patients percutaneous ablation was
proposed within the concept of a “test of time.”20 Using this
approach resectable patients undergo percutaneous ablation
during the interval from the time of diagnosis of liver metastases to the time of hepatic metastasectomy. is delayed period
allows the biology of disease to express itself. Patients without local recurrence, as well as those who develop multifocal
unresectable metastases, are spared unnecessary surgery. For
patients with local recurrence or limited intrahepatic progression there would still be an opportunity to repeat ablation or
resect the metastasis. e test-of-time approach could represent the starting point to prospective randomized trials comparing percutaneous ablation to surgery, to establish the role of
this technology as a potentially curative treatment for selected
patients with small size and number of CLM that can be ablated
with clear margin.
One other practical application of the test-of-time
approach is for the treatment of recurrent CLM aer hepatic
resection (particularly new liver metastasis within 6months of
resection), in particular in those patients who are technically
re-resectable. Patients completely treated by percutaneous
image-guided ablation and those with multifocal disease progression who would not benet form repeat surgery are spared
the increased morbidity of a repeat resection that would not
improve oncologic outcomes.
Median overall survival times over 30months for thermal
ablation are superior when compared to those of unresectable historical controls treated by chemotherapy alone.
13,21,22
However, only randomized trials can establish the exact benet of tumor ablation therapies over systemic chemotherapy. To
date, there is a single randomized clinical trial comparing RFA
combined with systemic chemotherapy to systemic chemotherapy alone as rst-line therapy for CLM.23 e benet of RFA in
combination with systemic chemotherapy is reected in a statistically signicant prolongation of median progression-free
survival (PFS) to 16.8months for the combined arm compared
to 9.9months for the chemotherapy-only arm. Overall patient
survival for the combined treatment was 61.7% for the combined therapy compared to 57.6% at 30months. is modest
prolongation did not reach signicance in a study that was
not powered to address this and with follow-up time of only
30months.
e local recurrence rate aer RFA varies widely, between
2%24 and 60%,25 and remains an important limitation of
20,24,25,26,27,28
RFA.
Size of the lesion, distance from major vessels,
and ablation margins are well-known factors that have been
associated with local tumor control. Atumor size up to 3cm is
now established as the ideal candidate for RFA.
29,30,31
Due to the
“heat-sink” phenomenon, as described above, tumors adjacent
to vessels larger than 3mm in diameter are at increased risk for
ablation failure and local tumor progression.
29,31,32,33
Similarly to
the surgical margin,34 the ablation margin has been associated
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with local tumor control (Figure16.2 and Figure16.3).
Aminimal ablation margin >5mm in all directions around the
target CLM on the 4–8 weeks post-RFA computed tomography
(CT) was associated with improved local tumor control.37
Immediately aer RFA, the ablation margins are recommended
to be at least 10mm all around the target tumor, whenever safe
and feasible.
37
29,35,36,37
microvascular thrombosis, and apoptosis. Similarly to RFA,
owing blood in the large-diameter vessels nearby can carry
away the low thermal energy through convection, limiting the
extent of cryoablation.
One of the advantages of this technique is the creation of ice
balls that are visible under CT, ultrasonography, or magnetic
resonance (MR) guidance, allowing easier visual monitoring of
the ablation zone during the procedure. e appearance of the
Cryoablation
Cryoablation uses liquid nitrogen or argon administered
through a needle applicator to decrease tissue temperature to
lethal levels (–20°C to–40°C). Repetitive cooling–thawing cycles
result in disruption of the cell membranes, extra- and intracellular ice formation, protein denaturation, cellular dehydration,
ice ball on imaging correlates with the tumor ablation margins.
Tissue temperature at the periphery of the ice ball is cooled to
0°C, a non-lethal level, while 5 mm inward the temperature
reaches–20°C. erefore, the operator should aim for creation
of an ice ball that completely covers the targeted tumor with
a 5–10-mm margin beyond the edge of the tumor, in order to
ensure complete ablation.
Cryotherapy alone or in combination with hepatic resec-
1.0
tion has been used in selected patients, resulting in oncologic outcomes comparable to surgery with clear margins.
38,39
Cryoablation applied to the edge of hepatic resections (edge
0.8
Margin size 11-15 mm (n=8)
cryotherapy) is frequently used in cases with “close” margin,
aording a 5-year survival rate of 31% for advanced CRC.40
e same authors reported a 5-year survival rate of 21% for
0.6
Margin size 6-10 mm (n=15)
0.4
Margin size 1-5 mm (n=41)
LTP-free Survival Rate (%)
0.2
Margin size 0 mm (n=30)
0.0
020406
Months after RFA
Figure 16.2 Local tumor progression-free survival curve for different minimal
margin size demonstrates that ablation margin is a key factor for local control.
LTP = local tumor progression; RFA = radiofrequency ablation. (Reproduced
from Wang X, Sofocleous CT, Erinjeri JP, Petre EN, Gonen M, Do KG, et al. Margin
size is an independent predictor of local tumor progression after ablation of
colon cancer liver metastases. Cardiovasc Intervent Radiol 2013; 36 (1): 166–175.
Reprinted with permission from Springer.)
080
the group that was treated with hepatic cryotherapy alone or
in combination with liver resection, with curative intention.40
ese results are promising and suggest that, with the use of
cryotherapy, more patients with CLM can be oered treatment
resulting in similar survivals as those who undergo resection.
41
e only randomized trial42 comparing cryotherapy and
conventional surgery included 82 patients with CLM (among
the 123 patients in the study). ree-, 5-, and 10-year survival
rates for all patients were 60%, 44%, and 19% in the cryotherapy group, and 51%, 36%, and 8% in the conventional surgery
group, respectively.
42
Microwave ablation
Microwave ablation (MWA) utilizes high-frequency waves
similarly to radiofrequency but in much higher range, between
900MHz and 2.4GHz. ese high-frequency waves cause water
molecules to oscillate, creating friction, causing heat and tissue
destruction by coagulation necrosis similarly to RFA. MWA
presents at least some theoretical advantages over RFA, such
as lower susceptibility to the heat-sink phenomenon and lower
ABC
Figure 16.3 A 73-year-old woman with a 2-cm solitary colorectal liver metastasis (arrow) in the remnant left liver status post hepatic resection (A) was treated
with radiofrequency ablation. Postablation contrast-enhanced computed tomography (CT) scan 6 weeks after ablation demonstrates a suboptimal ablation margin
at 4 o’clock location (B). Follow-up CT at 7 months after ablation identifies tumor progression in a location concordant with the minimal margin (C).
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heat dissipation caused by charring, thereby achieving larger
areas of ablation in a relatively shorter period of time. For these
reasons, MWA is thought to be more ecient in the treatment
of larger lesions and for targets located near large vessels when
compared to other thermal ablation modalities.43 With regard
to overall survival, intraoperative MWA has demonstrated
similar results to surgery in retrospective series.
44,45
To date
there is a single randomized trial comparing MWA to hepatic
resection in patients with CLM.46 e mean survival time was
suitable to MR image guidance and MR thermometry monitoring. e theoretical advantages of LITT compared to other
modalities such as RFA are the fact that it is not aected by the
heat-sink phenomenon, has the potential of achieving larger
ablation volumes, and has the ability to monitor the thermal
ablation zone in real time with MR imaging. With a median
overall survival up to 29months and a 5-year survival rate of
8–10% in patients with unresectable CLM, currently LITT performance is not superior to that of RFA.
53,54,55
27months in the MWA group versus 25months in the surgery
group. e mean disease-free interval was 11.3months in the
MWA group versus 13.3months in the surgery group. ese
dierences were not statistically signicant. Procedure-related
complication rates were similar between the groups, except for
blood transfusion requirement, which was signicantly more
frequent in the surgery group.
46
Irreversible electroporation
IRE is a non-thermal ablation modality. Electroporation
involves permeabilization of the lipid cellular membrane via
application of ultrashort pulses of high-voltage direct electric
current to create permanent openings (nanopores). Formation
of permanent nanopores alters cellular components and causes
lysis, loss of homeostasis, and cellular death. e extracellular
matrix remains unperturbed, thus tissue architecture is preserved. In this manner, IRE avoids injury to the bile ducts and
vessels within the organ, while still ablating tumors.47 One of
the key limitations of this technology at its current form is that
it requires a minimum of two electrodes, placed parallel and
spaced 1–1.5cm apart in order to create any ablation zone. is
requirement can be challenging when placing the electrodes
through the intercostal spaces in order to treat liver tumors.
e safety and ecacy of IRE for treating liver tumors has
been shown in preclinical studies,
ing perivascular and peribiliary tumors in humans.
47,48
and recently when treat-
49,50
Clinical
series that included patients with CLM have demonstrated
a primary ecacy of 67–100% for tumors adjacent to major
vascular/biliary structures.
49,50,51,52
that could not be safely
treated with thermal ablation. e risk of recurrence seems
to be higher for tumors >3cm in size.
50,51,52
Current evidence,
although encouraging, is still limited, with no randomized controlled trials. Moreover, most of the series included dierent
organs and dierent pathologies, making it impossible to draw
any generalized conclusion. Further study and understanding
of the electric properties of dierent tissues are necessary in
order to optimize the technique.
Laser-induced interstitial thermotherapy
Laser-induced interstitial thermotherapy (LITT) is another
minimally invasive thermal ablation technique. Laser energy
is delivered via a quartz beroptic with diuse light emission
and converted into heat in the target tissue. Tissue temperature increases to 60°C, the lethal level that results in protein
denaturation, coagulation, and cell death. e optic bers and
light are not aected by the magnetic eld of MR imaging,
nor is the MR signal disturbed by them, making this modality
Discussion
e exact role of ablation in the management of CLM is evolving and may vary based on institutional and local preferences.56
ere is, however, an overall recognition that this modality
may oer good local control and for small tumors that can be
ablated completely with clear margins it may be able to provide results similar to those of surgery. In a systematic review
of 75 series (36 RFA, 26 cryoablation, and 13 MWA), the 1-, 3-,
and 5-year survival rates for patients treated with one of the
three modalities varied between 40–93%, 7–60%, and 7–68%,
respectively. Median survival ranged from 4 to 43months and
local recurrence rate ranged from 2% to 39%.57 Overall survival
rates appear to be similar between the dierent ablative modalities, although randomized trials have yet to be performed.
In general it appears that smaller number of tumors,
smaller size of treated tumors, absence of extrahepatic disease, no involvement of the lymph nodes at initial excision,
and longer time between initial diagnosis to the development
of liver metastasis correlate with best outcomes.
modication of the previously described surgical clinical risk
score (CRS)
3,60
was designed for patients undergoing salvage
ablation to treat posthepatectomy recurrences.58 Tumor size
over 3cm, lymph nodal inltration at the time of resection, a
disease-free interval from primary diagnosis to liver metastasis
under 12months, and more than one lesion were considered
risk factors. Patients accumulating more than two of these factors were considered at high risk and had worse outcomes than
those with 0–2 factors (2-year survival of 74% for CRS of 0–2 vs.
42% for CRS of 3–4, P=0.03) (Figure16.4). Similarly, the local
tumor PFS was better for the low-risk patients (66% for CRS of
0–2 vs. 22% for CRS of 3–4 at 1year; P<0.01) (Figure16.5).
Complete ablation (A0 ablation) is the desired endpoint
of any ablation modality, similar to achieving R0 tumor-free
margin at resection. Methods to ensure this endpoint is accomplished are continuously being investigated. Unlike the resected
specimen, the evaluation of the ablation zone and ablation
margin is very challenging when determined by imaging alone.
In addition to contrast-enhanced CT,61 contrast-enhanced
ultrasound,62 MR imaging63 and, more recently, positron emission tomography CT64 have been used to assess tumor margin
and ablation completeness (Figure16.6). ere is discordance
between complete ablation based on imaging and microscopic
residual disease that may remain occult at the ablation site.65
is is supported by studies that analyzed the tissue extracted
from the electrode aer liver RFA
66,67,68
identication of residual prolic12 or viable tumor cells69 with
58,59
Arelevant
and correlated the
142
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1.0
All patients
1.0
CRS 0-2
CRS 3-4
0.8
0.6
0.4
0.2
0.0
0102030405
Months
060
Figure 16.4 Overall survival curves by clinical risk score (CRS) demonstrate
significantly lower survival time for patients who present more than two
risk factors. (Reproduced from Sofocleous CT, Petre EN, Gonen M, Brown
KT, Solomon SB, Covey AM, et al. CT-guided radiofrequency ablation as
a salvage treatment of colorectal cancer hepatic metastases developing
after hepatectomy. J Vasc Interv Radiol 2011; 22 (6): 755–761. Reprinted with
permission from Elsevier.)
0.8
0.6
0.4
0.2
0.0
010203040
Months
Figure 16.5 Local tumor progression-free survival curves by clinical risk
score demonstrate significantly lower local tumor progression-free survival
time for patients who present more than two risk factors. (Reproduced from
Sofocleous CT, Petre EN, Gonen M, Brown KT, Solomon SB, Covey AM, et al.
CT-guided radiofrequency ablation as a salvage treatment of colorectal cancer
hepatic metastases developing after hepatectomy. J Vasc Interv Radiol 2011; 22
(6): 755–761. Reprinted with permission from Elsevier.)
A
BC
D E
Figure 16.6 A 53-year-old man with solitary colorectal liver metastases (CLM) underwent percutaneous microwave ablation using the split-dose positron
emission tomography (PET) technique for guidance and treatment completeness assessment. An initial 4 mCi of fluorodeoxyglucose (FDG) was administered
before the ablation procedure and permitted the visualization and targeting of the FDG-avid CLM (A). At completion of ablation, an additional 8 mCi of FDG was
administered to assess ablation adequacy. The photopenic ablation defect equals effective ablation (B). Follow-up imaging with computed tomography (CT)
and fused PET/CT demonstrated good ablation result at 7 weeks (C) and further decrease of the ablation zone and no metabolic activity at 6 months (D) and
13 months (E).
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Section IV:Liver metastases
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local tumor progression
ese results support the incorporation of tissue sampling of
the ablation zone. Ideally, these tissue examinations should be
performed immediately aer ablation to detect cell death or
residual tumor cells and allow appropriate therapeutic modications in the same session or adjuvant therapies aer the
ablation, similarly to the management of resected CLM with or
without clear margins.
Current indication for therapeutic use of image-guided
ablation is in the setting of unresectable CLM. e National
Comprehensive Cancer Network (NCCN) guidelines list local
ablation therapies, alone or in conjunction with surgical resection, for the treatment of CLM when all disease foci appear
treatable, with a level 2A evidence (the recommendation is
based on lower-level evidence and there is uniform NCCN consensus).71 Development of guidelines for more uniform clinical
indications and tools for the evaluation of the clinical outcomes
remains a priority for the establishment of image-guided percutaneous ablation as a standard in the management of CLM.72
e creation and validation of a clinical risk score to predict
survival, improved imaging criteria to assess response to treatment, and incorporation of clinical and imaging biomarkers
to predict oncologic outcomes are important areas of current
investigations in the eld that will help to establish the role of
image-guided ablation in the treatment ofCLM.
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Chapter
Assessment, triage, and chemoembolization for colorectal liver metastases
17
Michael C. Soulen, Govindarajan Narayanan, and Ursina Teitelbaum
e prognosis of patients with colorectal carcinoma rests
largely on the presence or absence of distant metastases.
1,2,3
In 2013, there were an estimated 142,820 new cases of colon
cancer in the USA, with a prevalence of over 1.1million and
50,830 annual deaths from the disease.4 Twenty percent of
newly diagnosed patients already have metastases, and many
more develop metastatic disease over time. e liver is the rst
and most common site, with 80% of stage IV patients having
liver involvement and 40% of patients dying with the liver as
their only site of metastases.5 Among patients with extrahepatic
disease, more than half still die from liver failure.6 Resection
of liver metastases improves long-term survival;
7,8
however, for
the 75% of patients who are not resectable, palliative treatments
to delay cancer progression to fatal liver failure is the standard
ofcare.
Assessment of the patient with liver metastases
High-quality imaging also depicts classical or variant arterial
anatomy, status of the bile ducts and portal veins, and presence of ascites or extrahepatic disease. Positron emission tomography (PET)-CT shows uorodeoxyglucose (FDG)-avidity
in the majority of patients with metastatic colorectal cancer
and can be helpful in following treatment response for therapies where conventional Response Evaluation Criteria In Solid
Tumors (RECIST) imaging is less useful, such as ablation and
embolization.
Pathology reports should include KRAS and BRAF status
(wild-type vs. mutated) to determine susceptibility to epidermal growth factor receptor (EGFR) inhibitors such as panitumumab (Vectibix) and cetuximab (Erbitux). If this information
is lacking, a core biopsy should be obtained.
Laboratory studies should be reviewed to determine if hematologic, hemostatic, and organ function are adequate to tolerate
therapy. Carcinoembryonic antigen (CEA) is elevated in about
half of patients with metastatic colorectal cancer and can serve
as a corollary measure of tumor response or recurrence.
Initial assessment of the patient with colorectal liver metastases incorporates the history and physical examination, review
of laboratory studies including tumor markers, diagnostic
imaging, and pathology.9 Performance status is an important prognostic factor, since patients with declining function
(Eastern Cooperative Oncology Group (ECOG) >2) tend not
to benet from liver-directed therapies despite being otherwise
eligible to receivethem.
High-quality anatomic and functional imaging is key for
treatment planning and subsequent response assessment.
Reports of diagnostic imaging studies alone do not provide
the level of detail needed for triage and treatment planning.
e interventional oncologist should carefully review anatomic imaging (computed tomography (CT) or magnetic resonance imaging (MRI)) to assess segmental tumor burden.
e rst question to answer is if the patient is resectable, or
could be converted to resectability through multidisciplinary
interventions such as downstaging, ablation, or portal vein
embolization. Close collaboration with a surgical oncologist
can lead to potentially curative treatment plans even for multifocal disease. For unresectable disease, analysis of the size,
location, and distribution of metastases in the liver will guide
treatment planning among ablation and embolotherapies.
Triage of patients with liver metastases
While multidisciplinary tumor boards oer the optimal opportunity for integrated care plans, the high prevalence of metastatic colon cancer makes this impractical for all patients. e
interventional oncologist must be prepared to assess the role
of image-guided therapy within each patient’s unique circumstance, and provide collaborative referrals as needed. Asuggested triage plan is illustrated in Figure17.1.
Resection
With 5-year survival of 25–60%, complete extirpation of
liver metastases is a goal to be sought whenever possible.10
is requires a dierent mindset when evaluating the disease burden; instead of size and number of metastases, presence of adjacent disease-free segments with intact vascular
and biliary supply and adequate volume to provide hepatic
reserve become the critical criteria. For patients with a normal liver, a predicted remnant liver volume of 20% is sucient. For patients with underlying liver disease or history of
chemotherapy (>12 weeks), 30–40% remnant liver volume is
needed.11 Careful volumetric analysis of the baseline CT or
Interventional Oncology, Second Edition, ed. Jean-François H.Geschwind and Michael C.Soulen. Published by Cambridge University Press.
©Cambridge University Press2016
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