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LIVER 387
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FIG. 3 Chemotherapy-associated liver injury. (A)Intraoperative gross photograph of a fatty liver. Note the hepatomegaly, yellow appearance, and rounded
edges.(B)Intraoperative photograph of a liver with sinusoidal obstructive syndrome. Note the patchy blue mottled appearance. (From Srinevas K. Reddy S,
Geller D. Hepatic steatosis, steatohepatitis, and chemotherapy-related liver injury. In: Blumgart’s Surgery of the Liver, Biliary Tract and Pancreas, Philadelphia: Elsevier;
2007)..
status and patient outcomes is likely influenced by a myriad of clinical and biological factors.
Parenchymal-Sparing Techniques
A parenchymal-sparing approach is increasingly advocated in the
surgical management of CRLM. The goals of parenchymal-sparing
hepatectomy (PSH) are to achieve the oncologic principles of
margin-negative resection while preserving maximal uninvolved
liver parenchyma. PSH not only leads to improved perioperative
outcomes and reduced incidence of PHLF, but the preservation of
normal liver is also associated with improved odds of salvageability
in the case of liver recurrence. Although some anatomic resections, such as segmentectomy or sectionectomy, can be considered
parenchymal-sparing approaches, PSHs are more commonly nonanatomic resections, occasionally termed wedge resections. An example of a PSH might be several nonanatomic resections of superficial
tumors in the right liver instead of a formal right hepatectomy.
Minimally Invasive Approaches
While minimally invasive approaches to liver surgery have had
slower widespread adoption than in other areas of surgery, minimally
invasive liver resection (MILR) is now considered an acceptable
approach to the management of CRLM by experienced surgeons.
Numerous retrospective and institutional studies have demonstrated
its safety and appropriate oncologic outcomes. More recently, the
OSLO-COMET trial randomized patients with resectable CRLM to
either open or laparoscopic PSH. In this study, patients who underwent MILR experienced improved perioperative outcomes with no
differences in margin status or long-term outcomes. Increasingly,
robotic surgery is employed to extend the benefits of MILR to
patients with CRLM, and robotic approaches appear to result in
similar short- and long-term outcomes compared with laparoscopic
liver surgery. Several society guidelines have recommended MILR
as the standard of care for metastases in favorable locations (e.g.,
left lateral sectionectomy, nonanatomic resections in anterosuperior
segments), and MILR is increasingly used at experienced centers for
major hepatectomy.
LOCOREGIONAL THERAPIES
Ablation
For oligometastatic disease that is not amenable to resection,
thermal ablation is an alternative locoregional therapy for select
patients (Fig. 6). For small tumors, thermal ablation is a potentially
curative-intent treatment with only marginally increased local recurrence rates compared with resection when performed by experienced
providers. Intraoperative ablation can also be used at the time of
surgical resection to address multifocal or bilateral disease in a
parenchymal-sparing approach, especially for central tumors that
would otherwise have required a hemihepatectomy. Cryoablation
and radiofrequency ablation (RFA) are less commonly used now in
place of microwave ablation (MWA), which offers advantages in thermal spread and efficiency of use. Ideal metastases are <3 cm that are
separate from major blood vessels and other vital structures. Ablation
can generally be performed open, laparoscopic, or percutaneous.
Hepatic Artery Infusion Therapy
The primary rationale for hepatic artery infusion (HAI) therapy is
that liver metastases derive their blood supply predominantly from
the hepatic artery, while normal hepatocytes are primarily supplied
by portal venous blood. HAI therapy involves delivering chemotherapy directly to the liver via a catheter surgically placed into the
gastroduodenal artery and connected to a subcutaneous port that
can be accessed percutaneously. HAI therapy is generally well tolerated, although hepatic artery thrombosis, biliary toxicity, incomplete
perfusion of the liver, and toxicity from inadvertent perfusion to the
stomach or duodenum can occur. In general, the primary tumor
should be resected and there should be minimal or no extrahepatic
disease. Floxuridine (FUDR) is the most commonly utilized drug for
HAI therapy and is especially ideal given its short half-life and high
hepatic extraction.
There are two current indications for HAI therapy: unresectable
CRLM and adjuvant therapy following resection of CRLM. For
patients with initially unresectable CRLM, the use of HAI therapy,
with or without simultaneous systemic chemotherapy, has been
shown to increase response rates compared with systemic therapy
alone in some studies. A limitation of the current evidence is that
most trials of HAI therapy were not compared with patients receiving contemporary multiagent chemotherapy with biologic agents.
Although further randomized controlled trials are needed, HAI
therapy can be considered for patients with isolated unresectable
CRLM to increase the odds of successfully downstaging to surgical
resection. Similarly, a few randomized controlled trials, primary
performed at a single high-volume institution, have suggested
improved outcomes with adjuvant HAI therapy typically combined
with systemic therapy versus systemic chemotherapy alone following
resection of CRLM. Given the single institution nature of this evidence, the potential toxicity associated with HAI therapy, challenges
388 MANAGEMENT OF COLORECTAL LIVER METASTASES
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A
FIG. 4 Functional division of the liver into
eight segments as described by Coinaud:(A)
as observed in the anatomical position in the
patient;(B) as observed ex vivo. (From Vincent
S. Yip V, Fenwick S. Hepatic, biliary and pancreatic
anatomy. In: Hepatobiliary and Pancreatic Surgery:
A Companion to Specialist Surgical Practice, 2 ,
17–40.)
with maintaining a pump program, and the improved effectiveness
of modern chemotherapy, adjuvant HAI therapy has not gained
universal acceptance.
Other hepatic-artery based therapeutic strategies, including yttrium-90 transarterial radioembolization (
transarterial chemoembolization (TACE) have also been studied,
particularly in the management of unresectable CRLM. An important
study is the SIRFLOX trial that randomized 549 patients with unresectable CRLM to first-line chemotherapy with or without
Although there was no difference in OS, the TARE group experienced increased adverse events. Although TARE should not be used
as a first-line treatment, it is still occasionally considered in patients
B
90
Y TARE) and
90
Y TARE.
chemotherapy. TACE and drug-eluting bead (DEB)-TACE are not
commonly used in the current management of unresectable CRLM.
SPECIFIC CLINICAL SCENARIOS
Initially Unresectable Disease
A substantial proportion of patients with metastatic CRC will present
with unresectable bilateral or locally advanced CRLM. Given the
effectiveness of systemic chemotherapy, neoadjuvant chemotherapy has the potential to downsize unresectable CRLM and convert
initially inoperable lesions to resectable disease in up to 40% of
patients. FOLFOX or FOLFIRI with or without a biologic agent are
1.0
Months
Proportion surviving
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LIVER 389
.8
.6
.4
.2
.0
1 20 40 60 80
Positive
5–9 mm
≥10 mm
1–4 mm
100 120 140 160
suggested for induction therapy, though higher response rates and
thus resectability rates may be observed with triplet regimens such as
FOLFOXIRI. As discussed, HAI therapy can also be used for patients
with initially unresectable CRLM. When used in a first-line setting in
combination with systemic chemotherapy, conversion to resectability
may occur in as high as 70% of patients. Response to conversion
therapy should be assessed every 2 months with cross-sectional
imaging, and liver resection should be considered when metastases
become resectable.
Bilateral Metastatic Disease
Although bilateral metastases present increased complexity, several
strategies exist to extend the benefits of surgery to patients with
advanced CRLM (Fig. 7). The preferred surgical approach depends
on the burden and location of the bilateral disease. For example,
a single-stage approach with multiple PSHs can be utilized for
small and peripherally located tumors. PSH can be combined with
ablation for more central tumors to avoid the need for major hepatectomy. When a right or extended right hepatectomy is required,
careful assessment of the anticipated left FLR after resection of the
left-sided metastases is necessary. Those patients with inadequate
FLR may be considered for two-stage hepatectomy (TSH). In the
first stage, the FLR is cleared of metastatic disease. Portal vein
embolization (PVE) is then performed followed by a second-stage
hepatectomy of the remaining metastases once there has been adequate hypertrophy of the contralateral liver. An alternative to TSH is
associated liver partition and portal vein ligation for staged hepatectomy (ALPPS). During the first operation, a right portal vein ligation is first combined with parenchymal transection and clearance
of the FLR of metastases. A second operation to remove the affected
liver is then performed 1 to 2weeks later during the same hospital
admission once adequate hypertrophy is confirmed. Management
of advanced bilateral CRLM requires multidisciplinary expertise to
achieve optimal perioperative and oncologic outcomes.
FIG. 5 Survival after hepatic resection of colorectal liver
metastases, stratified by margin status. Median survival was
49.6 months in patients with positive margins and was not yet
reached in patients with negative margins (P= .005). No significant difference in survival was seen in patients with a negative
surgical margin, regardless of the width of the margin (allP> .5).
(From Pawlik TM, Scoggins CR, Zorzi D, et al. Effect of surgical margin
status on survival and site of recurrence after hepatic resection for
colorectal metastases. Ann Surg. 2005;241(5):715–722.)
FIG. 6 Long-term appearance of microwave-ablated lesions in the liver.
(A) Classical portal venous phase appearance of metastatic colorectal
cancer lesions(arrows); dark lesions with hyperemic rim. (B) Unperfused
ablated areas 3 years later.
Synchronous Colorectal Metastases
For patients with synchronous CRLM, the timing of hepatic resection
remains controversial. The classic approach involves first resecting
the primary tumor, administering chemotherapy, and then managing the liver disease. In the liver-first approach, the liver disease is
resected following neoadjuvant chemotherapy; once recovered, additional chemotherapy or radiation therapy is given as needed and then
eventually resection of the asymptomatic primary is performed. This
approach is particularly advantageous for advanced CRLM and when
preoperative radiation is required for rectal cancers. Increasingly,
390 MANAGEMENT OF COLORECTAL LIVER METASTASES
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Bilateral Colorectal Liver Metastases
Right Peripheral
Right Peripheral
Left Peripheral
PSH
FIG. 7 A systematic algorithm for assessing the distribution and extent of bilateralcolorectal liver metastasesthat informs operative treatment strategy.
Each scenario is modeled with the right liver inblue(representing ≈65% of total liver volume and the left liver inredrepresenting ≈35% of total liver
volume). Tumors are represented asclosed circles, parenchymal sparing resections asopen circles, and ablations asopen stars.PVO, Portal vein occlusion; RH,
righthepatectomy. (From Cloyd JM, Aloia TA. Hammer versus Swiss Army knife: Developing a strategy for the management of bilobar colorectal liver metastases. Surgery.
2017;162(1):12–17.)
primary CRCs and liver metastases are resected in a combined or
simultaneous approach. Although the combination of major liver
resections and complex colorectal resections should be avoided, in
general, the combined approach, when feasible, tends to be associated with a shorter total length of hospital stay and less morbidity but
with comparable oncologic outcomes.
CONCLUSION
The management of CRLM continues to evolve but largely depends
on experienced multidisciplinary teams working collaboratively at
high-volume centers. The cornerstone of potentially curative therapy remains surgical resection, and advances in perioperative and
surgical technique have expanded the number of patients eligible for
surgery. In addition, improvements in systemic therapies as well as
locoregional treatments have not only improved outcomes for patients
with advanced disease but also led to improved conversion rates that
result in resection for those with initially inoperable disease. Given
the importance of locoregional control in the overall management of
patients with metastatic CRC, expanding the role of surgery for CRLM
should lead to improved outcomes for patients with advanced CRC.
S u g g e S t e d R e a d i n g S
Adams RB, Aloia TA, Loyer E, etal. Selection for hepatic resection of col-
orectal liver metastases: expert consensus statement. HPB (Oxford).
2013;15(2):91–103.
Allen PJ, Stojadinovic A, Ben-Porat L, etal. The management of variant arte-
rial anatomy during hepatic arterial infusion pump placement. Ann Surg
Oncol. 2002;9:875–880.
Cloyd JM, Aloia TA. Hammer versus Swiss Army knife: Developing a strat-
egy for the management of bilobar colorectal liver metastases. Surgery.
2017;162:12–17.
Cloyd JM, Mizuno T, Kawaguchi Y, etal. Comprehensive Complication Index
Validates Improved Outcomes Over Time Despite Increased Complexity
in 3707 Consecutive Hepatectomies. Ann Surg. 2020;271(4):724–731.
Ducreux M, Ychou M, Laplanche A, et al. Hepatic arterial oxaliplatin
infusion plus intravenous chemotherapy in colorectal cancer with
Right Peripheral
Left Central
Single Stage
Hepatectomy
Right Central
Left Peripheral
Two Stage
Hepatectomy +/- PVO
inoperable hepatic metastases: a trial of the gastrointestinal group of the
Federation Nationale des Centres de Lutte Contre le Cancer. J Clin Oncol.
2005;23:4881–4887.
Fong Y, Fortner J, Sun RL, etal. Clinical score for predicting recurrence after
hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg. 1999;230(3):309–318.
Fretland Å A, Dagenborg VJ, Bjørnelv GMW, et al. Laparoscopic Versus
Open Resection for Colorectal Liver Metastases: The OSLO-COMET
Randomized Controlled Trial. Ann Surg. 2018;267:199–207.
Ghiasloo M, Pavlenko D, Verhaeghe M, etal. Surgical treatment of stage IV
colorectal cancer with synchronous liver metastases: A systematic review
and network meta-analysis. Eur J Surg Oncol. 2020;46:1203–1213.
Kemeny NE, Gonen M. Hepatic arterial infusion after liver resection. N Engl
J Med. 2005;352:734–735.
Kemeny NE, Niedzwiecki D, Hollis DR, etal. Hepatic arterial infusion versus
systemic therapy for hepatic metastases from colorectal cancer: a randomized trial of efficacy, quality of life, and molecular markers (CALGB
9481). J Clin Oncol. 2006;24:1395–1403.
Mise Y, Aloia TA, Brudvik KW, Schwarz L, Vauthey JN, Conrad C.
Parenchymal-sparing Hepatectomy in Colorectal Liver Metastasis
Improves Salvageability and Survival. Ann Surg. 2016;263:146–152.
Mitry E, Fields AL, Bleiberg H, etal. Adjuvant chemotherapy after potentially
curative resection of metastases from colorectal cancer: a pooled analysis
of two randomized trials. J Clin Oncol. 2008;26(30):4906–4911.
Nordlinger B, Sorbye H, Glimelius B, etal. Perioperative FOLFOX4 chemo-
therapy and surgery versus surgery alone for resectable liver metastases
from colorectal cancer (EORTC 40983): long-term results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2013;14(12):1208–1215.
Pawlik TM, Scoggins CR, Zorzi D, etal. Effect of surgical margin status on
survival and site of recurrence after hepatic resection for colorectal metastases. Ann Surg. 2005;241:715–722, discussion 22–4.
Primrose J, Falk S, Finch-Jones M, etal. Systemic chemotherapy with or with-
out cetuximab in patients with resectable colorectal liver metastasis: the
New EPOC randomised controlled trial. Lancet Oncol. 2014;15(6):601–611.
Stangl R, Altendorf-Hofmann A, Charnley RM, etal. Factors influencing the nat-
ural history of colorectal liver metastases. Lancet. 1994;343(8910):1405–1410.
Wasan HS, Gibbs P, Sharma NK, etal. First-line selective internal radiother-
apy plus chemotherapy versus chemotherapy alone in patients with liver
metastases from colorectal cancer (FOXFIRE, SIRFLOX, and FOXFIREGlobal): a combined analysis of three multicentre, randomised, phase 3
trials. Lancet Oncol. 2017;18:1159–1171.
Right Central
Right Central
Left Central Limited
RH + Ablation
Right Central
Left Central Multiple
HAI Therapy
Ablation of Colorectal
https://t.me/med1917
Carcinoma Liver
Metastases
Naomi M. Sell, MD, MHS, Zhi Ven Fong, MD, PhD,
and Kenneth K. Tanabe, MD
INTRODUCTION
The liver is the most common site of metastases for patients with
colorectal cancer. Approximately one-third of patients have liver
metastases at the time of diagnosis, with others developing metastases over the course of their treatment. The ease of spread to the liver
is facilitated by drainage of the portal venous system with a direct
path from the colon to the liver. Surgical resection is the treatment
of choice when feasible. The addition of neoadjuvant chemotherapy
that may shrink hepatic metastases now enables more patients to
undergo surgical resection. However, there are still many patients
with colorectal cancer liver metastases (CLM) who are deemed
unresectable. Reasons for unresectability include tumor location,
inadequate remnant liver volume, and comorbid conditions that may
preclude an operation.
Ablative treatment modalities were developed to provide treatment options for patients with unresectable CLM. Since the 1980s,
multiple ablation techniques have been developed, beginning with
cryotherapy and now including radiofrequency ablation (RFA),
microwave ablation (MWA), irreversible electroporation (IRE), and
laser thermal ablation (LTA).
ABLATION MODALITIES
Cryotherapy
Cryotherapy was one of the first methods of ablative therapy for
treatment of liver tumors. It was first introduced in the 1950s to treat
hepatocellular carcinoma (HCC). By the 1980s, it was also used for
CLM. Early cryotherapy systems instilled liquid nitrogen for direct
contact with the tumor at temperatures as low as −190°C. Freezing
followed by thawing results in cell death. Eventually, liquid nitrogen
systems were replaced with argon and helium gas systems to achieve
hypothermia. Insulated probes are placed into the liver tumor and
argon gas is passed under high pressure to freeze, followed by helium
gas to thaw. Repeated freeze-thaw cycles cause protein denaturation,
cellular dehydration, and ultimately tumor cell death. Bleeding is a
known complication of cryotherapy. The interface between the ice ball
and unfrozen liver can “crack” and result in bleeding from the liver
parenchyma. An additional complication is “cryoshock,” which is a
cytokine-mediated complication. The mechanism of this complication
is poorly understood and can occur when the lesion completely thaws
before refreezing (double-freeze cycle). Cryoshock affects 1% of cryotherapy patients and results in a severe coagulopathy with the potential for disseminated intravascular coagulation and multiorgan failure.
Radiofrequency Ablation
RFA has become the most widely used liver ablative treatment
modality. It can be performed via laparotomy, laparoscopically, or
percutaneously via image guidance in which ultrasound (US) or
computed tomography (CT) is used to place electrodes directly
into the CLM lesion (Fig. 1). A radiofrequency generator conducts
high-frequency alternating currents of 5000 to 9000 MHz between
the intratumoral electrode and the grounding pad on the patient.
LIVER 391
FIG. 1 Radiofrequency electrode designs. An expandable multilined probe
with its array deployed.
This creates friction from agitation of ions within the tissue, resulting
in the generation of heat that leads to coagulative necrosis of the tissue surrounding the electrode. Thermistors within the electrodes on
the RFA needle allow close temperature regulation. Cell death occurs
at 60°C. Care must be taken to not allow tissue temperatures to rise
excessively. At very high temperatures, the effectiveness of ablation is
decreased due to increased electrical impedance from the formation
of char in the tissue and on the electrode. This increases the risk of
incomplete tumor ablation. In total, approximately 30 minutes are
required to perform a 3 to 5 cm ablation.
The efficacy of RFA decreases as tumor size increases. Some of
the energy transmission is reliant on conduction. Consequently,
tumor cells located further from the probe heat less efficiently. Retrospective studies have shown higher local recurrence rates when RFA
is performed on tumors larger than 3.5 cm in size. RFA is also less
effective for metastases that are located in close proximity to vascular
structures. The continuous blood flow within the vessels maintains
physiologic temperatures (37°C) for tumor cells along the blood
vessel walls. Large blood vessels act as “heat sinks” that dissipate heat
away from the tumor, which prevents necessary tumor heating and
tumor destruction.
To date, no prospective randomized clinical trials comparing RFA
with any other treatment modality have been performed in patients
with CLM. There have been numerous nonrandomized trials that
compare RFA with resection, chemotherapy, or other ablative modalities, yet the heterogeneity and bias inherent in retrospective study
design limits meaningful comparison and interpretation. Overall, RFA
has been shown to be inferior to resection when analyzing both local
recurrence and overall survival (OS). However, these studies were not
randomized trials. Some patients treated with RFA in these comparative reports were not surgical candidates, indicating worse disease
progression or underlying tumor biology. Five-year OS after RFA has
been estimated to be 18% to 22%. The best outcomes are observed
after ablation of solitary liver lesions that are smaller than 3 cm.
Serious complications are uncommon following RFA. A study of
3554 RFA-treated lesions in 2320 patients by Livraghi and colleagues
found the incidence of major complications to occur in 2.2% of
patients. Major complications included intrahepatic abscess, hemorrhage, neoplastic seeding, and intestinal perforation. The most
common adverse event is postablation syndrome that occurs in
approximately one-third of patients. The symptoms are flulike and
often include malaise, myalgias, low-grade fever, nausea, and vomiting. It is self-limiting and typically lasts for only a few days.
392 ABLATION OF COLORECTAL CARCINOMA LIVER METASTASES
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FIG. 2 Microwave ablation electrode, with intraprocedural imaging of a CT-guided ablation of a lung tumor (left) and US-guided ablation of a liver tumor
(right). (Images courtesy H.S. Hospital Services S.p.A, Rome, Italy.)
Microwave Ablation
MWA is the other commonly utilized ablative therapy. Like RFA,
it relies on heating of the tumor and coagulative necrosis. It uses
high-frequency (900–2500 MHz) oscillating electromagnetic field
“microwaves” delivered through antenna probes (Fig. 2). The microwaves cause agitation of water molecules within the tissue that generates friction and ultimately heat. Lesions with higher concentrations
of water are more susceptible to heating by MWA.
MWA has been demonstrated to have some advantages over RFA.
(1) MWA can reach higher temperatures faster than RFA. (2) With
MWA, multiple ablations can be performed simultaneously. This
allows for treatment of multiple tumors simultaneously and larger
ablation zones. (3) Because heating of the tumor is less reliant on
conduction, MWA is less affected by the “heat sink” phenomenon
than RFA, making it more suitable for metastases located near vessels. (4) MWA results in less tissue charring than RFA, resulting in
decreased impedance and more effective ablation of larger lesions.
(5) MWA takes less time than RFA. MWA ablation times average
between 2 to 5 minutes, while RFA takes approximately 30 minutes.
Like RFA, MWA can be performed by open, laparoscopic, or percutaneous access. Open and laparoscopic ablations are typically used
in patients who have tumors in locations that are not accessible percutaneously, or when combined with resection. Percutaneous ablations are ideal in patients who are not surgical candidates. Similar to
RFA, MWA can be performed under either US or CT guidance. General anesthesia is typically used for patient comfort and to decrease
motion during the procedure. Recently, dual application probes have
been created (Amica) that have the capability of delivering both RFA
and MWA ablative techniques through the same hardware (Fig. 3).
Complication rates are comparable to RFA. Mortality rate is
approximately 0.5% while ablation related complication rates range
from 2% to 5%. The most common complications reported are skin
burn, liver abscess, bile leak, hemorrhage, portal vein thrombosis,
FIG. 3 Dual ablation system by Amica. This apparatus can deliver both
RFA and MWA utilizing the same probe. The device contains a built-in
thermocouple that allows for temperature monitoring and has an internal
water-cooling property that serves to avoid probe overheating.
and pleural effusion. In evaluating multiple retrospective studies of
MWA, the local recurrence rates range between 5% to 20% at 3 years
and 3-year OS from 50% to 85%. No randomized controlled trials
have been performed comparing the two approaches in CLM, but
on meta-analysis, the disease-free survival (DFS) and OS rates are
comparable between MWA and RFA (Table 1).
Irreversible Electroporation
IRE is a nonthermal ablation technique that uses high-voltage
electrical shocks rather than heat to induce cell death. IRE is delivered by the placement of multiple electrodes near the tumor that each
LIVER 393
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TABLE 1 Outcomes of Local Ablative Techniques on Colorectal Liver Metastases
Follow-up
Study n
CRYOTHERAPY
Littrup 2016 77 20 — — 80 20 21 — — —
Wallace 1999 20 14 — — 84 — — — 4 0
RADIOFREQUENCY ABLATION
Aliyev 2013 44 31 69 10 90 47 18 5 — 0
Boostrom 2011 12 — 74 36 83 46 37 — — —
Chiou 2005 63 22 — — — — 14 11 5 0
Gu 2008 37 — — — — — — — 3 0
He 2016 21 — 76 5 86 14 — 0 0 0
Knudson 2009 24 — — 32 — 49 — — 0 0
Ko 2014 36 27 — — 90 34 — 5 5 0
Otto 2010 17 — 52 18 100 38 — — — 0
Snoeren 2015 28 27 40 — 95 — 32 — — 0
Vietti-Violi 2018 52 — — — — — 21 25 — 0
Wang 2018 60 20 — — — — 10 — — —
Yang 2017 46 44 46 18 96 43 — — — —
MICROWAVE ABLATION
Franzese 2018 61 24 — — — — 24 — 0 0
Seki 1999 15 — — — — — — 7 0 0
Shady 2014 26 8 — — — — 8 7 13 0
Shibata 2000 14 — — — 71 — — 14 0 0
Song 2017 28 55 95 38 88 52 — 7 0 0
Yang 2017 71 39 80 39 80 58 1 11 — 0
(mo) 1y DFS (%) 5y DFS (%) 1y OS (%) 5y OS (%) LTP (%) AE (%) SAE (%) Mortality (%)
AE, adverse events; DFS, disease-free survival; LTP, local tumor progression; n, number of subjects; OS, overall survival; SAE, severe adverse events.
Data from Di Martino M, Rompianesi G, Mora-Guzmán I, etal. Systematic review and meta-analysis of local ablative therapies for resectable colorectal liver
metastases. Eur J Surg Oncol. 2020;46(5):772–781.
delivers 2 to 3 kV pulses that each last only 70 to 100 microseconds.
These voltages create pores in cell membranes in the surrounding
tissue. This damage is irreversible and results in tumor cell apoptosis. Compared with thermal ablation techniques, IRE efficacy is
not adversely impacted by the heat sink effect, and there is minimal
destruction of the extracellular matrix in surrounding tissue. Bile
ducts and blood vessels maintain their integrity because of the
extracellular matrix. This makes IRE a suitable option for metastases
situated in close proximity to large blood vessels or bile ducts.
IRE is a relatively newer technique, approved by the US Food
and Drug Administration (FDA) in 2006, and it has not yet been
widely adopted. The equipment is more expensive than RFA and
MWA systems, and there is a learning curve with positioning the
cholangiocarcinoma). The first report of IRE results in patients with
CLM was published in 2014. A total of 11 patients with 22 lesions
less than 5 cm were treated. From this group, 55% of lesions were
completely ablated and there was local tumor recurrence in 6 of
the 11 patients by 9 months. Often the patients included in these
studies were poor candidates for other ablative techniques due to
tumor location. In a larger, mixed patient series of 58 patients with
75 lesions, there was a 6- and 12-month local DFS of 87% and 70%,
respectively.
Across the limited number of studies, IRE has been reported
to have a complication rate of 10% to 16%. The most common
complications were portal vein thrombosis, cholangitis, and pleural
effusion. The rate of arrhythmia is approximately 5%.
ablation probes effectively. The probes cannot be repositioned in the
middle of an ablative treatment. IRE also requires general anesthesia
with paralysis because the high voltages can cause arrhythmias and
muscle spasms. To reduce the risk of arrhythmias, the IRE electrical
generator is connected to an ECG sensor and IRE pulsations are
administered in the cardiac refractory period.
A majority of studies to date are small in size and often include
Laser Thermal Ablation
LTA is a percutaneous technique that uses light energy delivered via
flexible quartz optical fibers that are inserted directly into tumors to
deliver high-energy laser radiation. The most commonly used lasers
are diode (wavelength 800–980 nm) and neodymium:yttrium alu-
patients with multiple different liver malignancies (CLM, HCC,
394 ABLATION OF COLORECTAL CARCINOMA LIVER METASTASES
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achieves optimal light penetration. This method relies on coagulative
necrosis, and the light energy can generate temperatures of up to
150°C, creating a thermal injury zone of approximately 12 to 15 mm
in diameter. Up to four optical fibers can be utilized at one time to
increase the ablation zone. LTA is most effective in lesions less than
4 cm in size.
In one of the largest series of this technique, Vogl etal. described
594 patients with CLM ≤5 cm who were treated with LTA. The 3- and
5-year survival rates were 28% to 74.2% and 10% to 37%, respectively, which is comparable to RFA and MWA. LTA use is limited
and is primarily utilized in Europe. The equipment is expensive, and
placement of the fibers is difficult in the inexperienced hand. LTA is
not as extensively studied as the other ablation modalities, and there
has been no evidence of its superiority to RFA or MWA.
PATIENT SELECTION
Patients with CLM should undergo evaluation for all sites of metastases. Necessary imaging includes a CT scan of the chest, abdomen,
and pelvis, and in some situations positron emission tomography
(PET) CT. Contrast-enhanced MRI is the most sensitive tool to
evaluate CLM.
Surgical resection of CLM remains the standard of care when feasible. However, ablative therapies offer a treatment option to patients
who are either not surgical candidates or have unresectable disease.
Given the number of treatment options available, all patients should
be evaluated by a multidisciplinary care team with specialists including but not limited to surgeons, medical oncologists, radiation oncologists, pathologists, and interventional radiologists. Before choosing
ablation as a treatment regimen, each patient should be reviewed for
the possibility of surgical resection before or after chemotherapy, or
combined resection and ablation.
(27.6% vs. 10.6%, p = 0.025). These results dispel the notion that
chemotherapy combined with ablation is a superior approach to
chemotherapy alone. However, use of ablation instead of chemotherapy to allow for a “chemotherapy holiday” has merit in selected
patients.
PATIENT EVALUATION
Baseline Hepatic Function
Before consideration for ablation, all patients need to undergo a baseline evaluation of hepatic function. Serum liver function tests (LFTs)
and carcinoembryonic antigen (CEA) levels should be checked for a
pretreatment baseline. LFTs can assess for cholestasis or liver inflammation. Evaluation of pretreatment scans should include assessment
for portal hypertension, which places patients at increased risk for
complications following ablation. The majority of CLM patients have
liver function to support liver tumor ablation.
Extrahepatic Metastases
In accordance with National Comprehensive Cancer Network
(NCCN) guidelines, patients with metastatic colon cancer should
undergo a CT and PET scan to evaluate for extrahepatic metastatic disease. Patients whose metastases are limited to the liver
remain the best candidates for ablation. Patients with extrahepatic
metastases should be considered on a case-by-case basis. Those
with concurrent pulmonary metastases require evaluation by a
thoracic surgeon for possible lung-directed treatment particularly
those with minimal lung metastasis, such as a small solitary lesion.
Patients with peritoneal or bulky nodal metastases are not suitable
candidates for ablation of liver metastases because it will not lead
to benefit.
Tumor Characteristics
Larger tumors (>5 cm) are associated with an unacceptably high risk
of recurrence when treated with ablation due to incomplete tumor
destruction. In select patients with larger tumors, surgical resection
of larger tumors may be combined with ablation of smaller tumors to
offer the best chance at long-term DFS. For example, a patient with
a large metastasis in the left lobe and two smaller metastases located
deep in the right lobe may benefit from left hepatectomy combined
with ablation of the two right lobe lesions. Although RFA is the most
commonly used ablation modality, MWA should be considered when
the tumor is larger than 3 cm or in close proximity to a large blood
vessel. For lesions adjacent to major vessels or central bile ducts, IRE
may be appropriate to minimize adjacent vessel or ductal injuries
that may lead to strictures.
Use of Systemic Therapies
Despite advances in systemic chemotherapies that have led to
response rates as high as 70%, durable complete clinical responses
are still rare with systemic chemotherapy alone. It has been postulated that aggressive cytoreduction with ablation combined with
chemotherapy may be more effective than chemotherapy alone.
This concept was examined in the Chemotherapy + Local Ablation
Versus Chemotherapy (CLOCC) trial, a study in which patients
with CLM were randomized to treatment with chemotherapy
alone, versus chemotherapy plus RFA. Eligible patients had up to 9
CLM lesions ≤4 cm and were considered unresectable. No difference in 30-month OS rate was observed between the two groups
(61.7% for combined treatment vs. 57.6% for chemotherapy alone,
p
= 0.22). However, the 3-year DFS rate for the combined treat-
ment group was higher than that of the chemotherapy-only group
CHOOSING A TREATMENT MODALITY
Tumor-Specific Considerations
In choosing which ablative treatment modality to utilize, the size,
number, and location of the CLM should be considered. An ideal
lesion for ablation is a small tumor, deep in the parenchyma, not
abutting any major blood vessels that is not amenable to resection.
Preferred lesions for ablation include those less than 4 cm in size.
As tumor size increases, so does the chance of local recurrence after
ablation. Location of the metastases is important to assess. Close
proximity to large blood vessels renders MWA a better choice than
RFA. Close proximity to a major bile duct is a relative contraindication for both RFA and MWA. When deciding on an operative
technique, whether open, laparoscopic, or percutaneous, proximity
of the lesion to surrounding organs must be taken into consideration
as well as the potential for combination with surgical resection.
Treatment Approach
There are two principal approaches to CLM ablation: percutaneous
or operative (open or laparoscopic) (Fig. 4). Percutaneous ablation
is the least invasive approach and is associated with lower morbidity
rates and cost than operative ablation. It can be performed under US,
CT, or MRI guidance. Patients generally require conscious sedation
for this procedure. This is an ideal approach when aiming to avoid
the morbidity of an operation and for patients who may require
repeat applications.
For lesions not accessible percutaneously, feasibility of accessing the tumor location by either laparoscopic or open approach
should be considered. Open and laparoscopic techniques allow
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Technical Considerations
Ablation via the laparoscopic approach can often be achieved with
two ports: an umbilical port (for the laparoscope) and a second
port for the laparoscopic US probe. The ablation probe can be
placed percutaneously and does not require an additional port. The
first step in performing operative ablation of CLM is a thorough
evaluation of the abdominal cavity to exclude extrahepatic metastases (peritoneal surfaces, diaphragm, etc.). Intraoperative liver US
should then be performed to evaluate the location of the tumor(s),
identify any additional tumors not seen on preoperative imaging,
and assess the relationship of tumors to major vascular and biliary
structures. Under intraoperative US guidance, the ablation electrode
A
is then placed into the target lesion, and the array deployed within.
A tourniquet may be placed around the porta hepatis for inflow
occlusion.
Thermal ablation is then initiated, and specifically for RFA, monitoring is performed to maintain a maximum parenchymal temperature of about 100°C to 110°C to minimize charring. Monitoring is
performed via different approaches depending on the manufacturer;
Rita Medical uses temperature control via sensor electrodes embedded in the tips of the tines, whereas Boston Scientific uses impedance
control where the ablation power is slowly ramped up until the tissue impedance reaches a preset threshold. Once the temperature or
impedance level is reached, the energy source is turned off to allow
tissue vaporization to settle, after which energy is reapplied at a lower
level or terminated completely.
B
FIG. 4 (A) Patient set up for a CT-guided percutaneous MWA of
a hepatocellular carcinoma in an Interventional Radiology suite. (B)
Laparoscopic MWA of a hepatic tumor under the guidance of intraoperative ultrasound. (Photo courtesy Dr. R. Santambrogio, HPB and Digestive Surgery,
San Paolo Hospital, University of Milan, Italy.)
for the opportunity for visual inspection of the abdomen, which
improves staging. Up to 10% to 20% of patients are found to have
radiographically occult extrahepatic metastases, which are a relative contraindication to ablation. And use of intraoperative US
can identify additional liver metastases not appreciated on CT or
MRI. Additionally, a surgical approach (open or laparoscopic) is
ideal for patients who may also require laparotomy or laparoscopy
for combined resections with ablations. The most frequent types
of combination operations are hepatectomy combined with liver
tumor ablation, and colectomy for removal of the primary colorectal
malignancy combined with liver tumor ablation. Once all the lesions
are identified and mapped out, the placement of the ablation probes
must be planned carefully to avoid major vessels and bile ducts.
Surrounding organs should be retracted out of harm’s way when necessary. Cholecystectomy should be performed if the gallbladder is
at risk of thermal injury. The probes should always be placed under
US guidance into the lesion. If multiple overlapping ablation zones
are required, the probe should be placed at the sonographically
“deepest” portion of the lesion first. Temporary hepatic blood flow
occlusion maneuvers, such as the Pringle maneuver or hepatic artery
occlusion, can minimize the “heat sink” effect during ablation and
increase the size of the ablation zones. Use of an operative approach
has been reported to have an ablation site recurrence rate of approximately 3% compared with 8% for the percutaneous approach. Operative ablation techniques are associated with a higher morbidity than
percutaneous ablation.
Clinical Follow-up of Ablated Tumors
Following CLM ablation, LFTs should be monitored as they may
acutely rise after ablation but should progressively return to baseline.
CEA should also be followed every 3 months as a rise in CEA is concerning for disease recurrence. Postablation imaging by CT or MRI
is performed to evaluate the efficacy of the procedure. In contrast to
HCC, CLM are hypovascular, which makes it challenging to differentiate residual tumor from areas of necrosis. An optimal strategy is
to compare pre- and postprocedural images with particular attention
to the size, shape, and location of the necrosis zone. Ideally, a 5- to
10-mm margin of ablation should be achieved circumferentially.
The International Working Group on Image-Guided Tumor Ablation recommends a baseline study (CT or MRI) to be performed
within 1 week and no greater than 4 weeks postablation. This helps
to expediently identify any residual disease as a result of incomplete
ablation. Subsequent surveillance imaging may then be performed
every 3 to 4 months (Fig. 5). PET scans have been demonstrated to
be sensitive for detection of recurrence in patients who are at least
3-months postablation after inflammation has subsided. NCCN
guidelines recommend follow-up imaging every 3 to 6 months for
the first 2 years after ablation, which may then be performed annually thereafter.
SUMMARY
For patients with unresectable CLM or who are not candidates for
surgical resection, liver ablation modalities provide an option to
improve both DFS and OS. Ablation also offers the potential for a
cure in some patients with limited, small CLM lesions. Additionally,
it can be used as an adjunct along with resection in the treatment of
select patients with bilobar disease. Additional research is needed
within this field, particularly comparative clinical trials, to truly
improve patient selection for these techniques and to better delineate outcomes between different modality types. Ablation technology continues to improve and hopefully will be able to offer more
patients a chance for improved outcomes.
396 MANAGEMENT OF HEPATIC ABSCESS
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FIG. 5 (A) Successful RFA of a colorectal carcinoma liver metastasis, with CT imaging demonstrating the lesion in segment VI preablation, necrosis zone
from ablation at 1 month, followed by radiographic resolution at 18 months postablation. (B) Incomplete ablation of colorectal carcinoma liver metastases,
with CT imaging showing the lesion preablation, postablation imaging demonstrating the irregularity in the contour of ablation affected by adjacent vessels,
and postoperative CT revealing local ablation-site recurrence resulting from incomplete ablation.
S u g g e S t e d R e a d i n g S
Correa-Gallego C, Fong Y, Gonen M, etal. A retrospective comparison of
microwave ablation vs. radiofrequency ablation for colorectal cancer
hepatic metastases. Ann Surg Oncol. 2014;21:4278–4283.
Di Martino M, Rompianesi G, Mora-Guzmán I, etal. Systematic review and
meta-analysis of local ablative therapies for resectable colorectal liver
metastases. Eur J Surg Oncol. 2020;46(5):772–781.
Evrard S, Poston, Kissmeyer-Nielsen P, etal. Combined ablation and resec-
tion (CARe) as an effective parenchymal sparing treatment for extensive
colorectal liver metastases. PLoS One. 2014;9:e114404.
Imai K, Allard MA, Benitez CC, etal. Long-term outcomes of radiofrequency
ablation combined with hepatectomy compared with hepatectomy along
for colorectal liver metastases. Br J Surg. 2017;104:570–579.
Management of
Hepatic Abscess
Daniel L. Eisenson, MD, and Jonathan B. Greer, MD
epatic abscess, with an incidence of 3 cases per 100,000 people
in the United States, is a rare but life-threatening disease. In the
H
first half of the twentieth century, liver abscesses were most often
seen in the setting of untreated appendicitis, when ruptured viscera
Kariappa SM, Morris DL. Cryotherapy–a mature ablation technique. HPB
(Oxford). 2006;8(3):179–181.
Leung U, Kuk D, D’Angelica MI, etal. Long-term outcomes following micro-
wave ablation for liver malignancies. Br J Surg. 2015;102:85–91.
Livraghi T, Solbiati L, Meloni MF, etal. Treatment of focal liver tumors with
percutaneous radio-frequency ablation: complications encountered in a
multicenter study. Radiology. 2003;226(2):441–451.
Martin RC, Scoggins CR, McMasters KM. Safety and efficacy of microwave
ablation of hepatic tumors: a prospective review of a 5-year experience.
Ann Surg Oncol. 2010;17:171–178.
Oshowa A, Gillams A, Harrison E, etal. Comparison of resection and radiof-
requency ablation for treatment of solitary colorectal liver metastases. Br
J Surg. 2003;90:1240–1243.
and these abscesses were associated with an up to 80% mortality rate.
Although the etiologies and management strategies have changed
considerably over the past 100 years, liver abscesses continue to be
lethal. Indeed, despite improved outcomes with better diagnostic
tools, antibiotics, and the advent of percutaneous drainage, mortality
rates remain between 4% and 10%.
Liver abscesses may be divided into three major categories
according to their causative organisms: pyogenic (bacterial) liver
abscess, amebic liver abscess, or fungal liver abscess. Of these categories, pyogenic liver abscesses (PLAs) are most commonly seen in
the United States, while amebic liver abscesses (ALAs), caused by the
parasite Entamoeba histolytica and relatively common in tropical low-
and middle-income countries, are typically only seen in the United
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