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LIVER 377
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two-stage resection is generally recommended, typically with portal
vein embolization (PVE) between stages. An alternative to two-stage
hepatectomy is associating liver partition and portal vein ligation
(ALPPS), which may increase resection rates with comparable surgical margins, complications, and short-term morbidity.
In patients with synchronous CRLM, the primary tumor and liver
metastasis can be resected at the same time or in staged operations.
Sequencing will also include a period of systemic therapy. In general,
extensive hepatectomy in combination with complex colorectal resection, for example, those requiring extensive pelvic resection or low
rectal anastomosis, are best avoided. Several factors are considered
in sequencing these operations. If the primary tumor is symptomatic
with evidence of bleeding or obstruction, it should be addressed
first. If the primary tumor is asymptomatic, a “liver first” approach
is favored by many centers. In patients with rectal cancer, short- or
long-course radiation will also be necessary, and this must be carefully sequenced with systemic therapy and planned surgical resection.
Unlike primary liver tumors, limited extrahepatic metastasis
is not necessarily a contraindication to hepatic metastasectomy if
the extrahepatic disease can be treated completely. This reflects the
excellent response rates to systemic therapy in patients with colorectal cancer. Preoperative chemotherapy is typically administered
to assess tumor response and to address potential micrometastatic
disease not visible on imaging. A large randomized, controlled trial
of perioperative chemotherapy for CRLM demonstrated improved
progression-free survival compared with patients who underwent
resection alone. However, prolonged chemotherapy can be associated with significant liver injury. Specifically, irinotecan-based
regimens are associated with steatohepatitis, and oxaliplatin-based
regiments are associated with sinusoidal congestion. “Disappearing”
liver metastases are an additional consideration because they will
eventually recur in up to 80% of patients if not resected. Careful
coordination among members of the multidisciplinary team is necessary to determine sequencing of all therapy. In general, preoperative
systemic therapy should be limited to 4 to 6 cycles or 2 to 3 months.
In the case of unresectable disease, additional locoregional therapies
including ablation, transarterial embolization, and placement of
a hepatic artery infusion pump can be considered. Hepatic artery
infusion pumps may also be utilized to convert from unresectable to
resectable disease and as adjuvant therapy following resection.
Prognostic factors for patients who undergo curative-intent
resection include the disease-free interval between diagnosis of the
primary tumor and hepatic metastasis, size of the largest hepatic
tumor, presence of extrahepatic metastasis, mutation status (e.g.,
RAS, BRAF), and nodal status of the primary tumor. Five-year overall and disease-free survival range from 30% to 60% and 20% to 40%,
respectively.
PREOPERATIVE EVALUATION
Patients should undergo preoperative optimization and risk stratification tailored to their comorbidities and performance status. Liver
function is assessed with evaluation of total bilirubin, prothrombin
time, albumin, presence of ascites, and history of encephalopathy.
The Child-Pugh scoring system (see Table 1) is associated with
perioperative mortality rates of 5%, 30%, and 80% in patients with
class A, B, and C cirrhosis, respectively. Thrombocytopenia (platelets
<100,000 mm
of portal hypertension, which is associated with prohibitive rates of
perioperative mortality after hepatectomy.
The location of the liver lesions and their relationship to major
vascular and biliary structures are determined by high-quality,
contrast-enhanced CT scan or MRI. The volume of the FLR is
calculated to estimate the risk of posthepatectomy liver failure. In
the absence of underlying hepatic dysfunction, an FLR of 20% of
the standardized total liver volume is typically sufficient. Patients
with some degree of liver dysfunction, such as those who have
been treated with cytotoxic chemotherapy, should have an FLR of
3
), splenomegaly, and esophageal varices are indicative
at least 30%, and patients with cirrhosis need an FLR of at least
40%. Volumetry is calculated with three-dimensional CT scan or
MRI. The volume of nonfunctional liver (parenchyma that is either
nonperfused or replaced by tumor) is subtracted from the total liver
volume, which is especially important for patients with large lesions.
Alternatively, the estimated liver volume can be calculated from the
patient’s body weight or body surface area (i.e., total liver volume in
3
cm
= −794.41 = 1267.28 × body surface area in m²). Patients with
insufficient FLR should undergo PVE of the branches of the segments
planned for resection to induce hypertrophy of the contralateral liver.
Volumetry is repeated about 4 weeks after PVE and in a few more
weeks if the minimal recommended FLR has not been achieved.
ALPPS, an alternative to two-stage hepatectomy, was first described
in 2011. This consists of a short interval two-stage resection with the
first stage typically involving right portal vein ligation and parenchymal transection. This induces rapid contralateral hypertrophy, with
the goal of completing the second stage during the same hospitalization in 1 or 2 weeks. This approach is only recommended in highly
experienced centers because morbidity and mortality can be high.
TECHNICAL CONSIDERATIONS
Liver resections are classified into anatomic and nonanatomic. Anatomic resections include segmentectomy, sectionectomy, hemihepatectomy, and trisectionectomy. Small peripheral lesions are usually
amenable to parenchymal-sparing nonanatomic resections. Larger or
more centrally located lesions often require anatomic resection. This
can be performed though an open or minimally invasive approach.
Positioning, Incision, and Exposure
Patients are placed in the supine position with arms extended at
90 degrees. Intravenous fluids are restricted until the parenchymal
transection is complete to decrease blood loss from hepatic veins.
Central venous cannulation is often unnecessary but should be considered in patients with extensive comorbidities, especially if major
hepatectomy is planned. If measured, a central venous pressure less
than 5 cm HO is recommended. Once the parenchymal transection
is complete, intravascular volume is restored to achieve euvolemia.
In an open technique, a right subcostal incision with an upper
midline extension provides adequate exposure for most cases.
Alternative incisions include a midline, inverted “L” (Makuuchi’s
incision) or bilateral subcostal with midline extension (Mercedes
Benz incision). If necessary, the xiphoid is removed to facilitate visualization of the suprahepatic inferior vena cava (IVC). The peritoneal
cavity is explored for extrahepatic metastasis. The round ligament is
divided and the falciform is dissected along the anterior surface of
the liver up to the hepatic venous outflow. The gastrohepatic ligament is opened to expose the caudate lobe with care not to injure an
accessory or replaced left hepatic artery. Intraoperative ultrasound is
performed to identify all lesions, including any that may have been
occult on preoperative imaging. Furthermore, ultrasound is used to
define tumor relationship with vascular and biliary structures and
define the resection plane.
Inflow and Outflow and Outflow Control
For major hepatic resections, hepatic and portal venous inflow can
be dissected and controlled in the hilum of the liver, intraparenchymally, or through small hepatotomies (Fig. 1). The latter approach
should be avoided if the tumor is within 2 cm of the hilum. Inflow
control before parenchymal resection will result in a vascular demarcation line that will guide the correct transection plane. It is our
practice to divide the inflow structures in the hepatic hilum using
a vascular stapler or sutures. After inflow has been controlled, the
hepatic venous outflow is controlled. This can also be done extrahepatically, which is our preference whenever feasible, or within the
parenchyma during the transection.
378 MANAGEMENT OF MALIGNANT LIVER TUMORS
AB
Umbilical
BA
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IV
V
3
2
4
1
VI
FIG. 1 (A) For the right portal pedicle to be accessed, hepatotomies are made in the gallbladder fossa (2) and in the caudate process (1). The pedicle is
encircled with a renal pedicle clamp, and a vessel loop is passed around it. The vessel loop is used to retract the main portal vein/left portal vein to the left
as a TA stapler is passed and fired (B) to divide the right portal pedicle. (From Fong Y, Blumgart LH. Useful stapling techniques in liver surgery. J Am Coll Surg.
1997;185:93.)
5
tape
6
I
FIG. 2 (A) For division of the liver parenchyma, two stay sutures are placed for traction. The parenchyma is sequentially crush-clamped with a Kelly clamp;
this demonstrates various size pedicles and veins. Those <5 mm are sealed and divided with the LigaSure device. (B) If the structure is >5 mm, the endovascular stapler, clips, and ties are used. (From Patrlj L, Tuorto S, Fong Y. Combined blunt-clamp dissection and LigaSure ligation for hepatic parenchyma dissection: postco-
agulation technique. J Am Coll Surg. 2010;210:39.)
We also generally apply umbilical tape with a Rummel tourniquet
to the porta hepatitis, which can be tightened in the event a Pringle’s
maneuver is needed to control bleeding from the contralateral inflow
structures.
and hepatic veins that can be controlled with a combination of
energy devices (Fig. 2), clips, ties, and firings of a vascular stapler.
An alternative method is the two-surgeon technique, in which one
surgeon dissects with the Cavitron Ultrasonic Surgical Aspirator
(CUSA) and the other surgeon divides the vasculature and provides
Parenchymal Transection
Multiple tools and techniques are available for parenchymal transection. There are no compelling data to support one method over
another and thus is left to the discretion, expertise, and comfort
of the surgeon. A simple and frequently employed technique is
the crush-clamp method in which the liver parenchyma is gently
“crushed” with a Kelly clamp exposing branches of portal pedicles
exposure. Regardless of technique, small vessels less than 3 mm can
be divided with electrocautery, medium vessels are controlled with
titanium clips, and larger vessels greater than 5 mm are divided
with suture or a vascular stapler. Caution should be given to overuse of linear staplers in the absence of meticulous parenchymal
dissection as this technique can lead to inadvertent biliary or
vascular injury, especially in the setting of significant bleeding and
poor exposure.
LIVER 379
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A
FIG. 3 (A) Division of the inferior vena cava ligament. (B) This ligament may contain liver parenchyma and/or a short hepatic vein and is therefore most
safely transected with a stapler. (C) Transection will allow exposure and control of the right hepatic vein. (From Blumgart LH, editor. Surgery of the liver, biliary
tract, and pancreas. 4th ed. Philadelphia: Elsevier; 2007:1354.)
HEPATECTOMY
Right Hepatic Lobectomy
If a right hepatectomy is planned, further dissection of the falciform
ligament is carried up to expose the hepatic venous outflow, particularly the right hepatic vein. The right coronary and triangular
ligaments are divided, exposing the bare area of the liver. The right
liver is mobilized and rotated to the patient’s left. The short hepatic
veins draining directly into the retrohepatic IVC are controlled with
a combination of clips, ties, and firings of a vascular stapler for any
larger branches. The retrocaval ligament (Makuuchi’s ligament) is
identified and transected with a vascular stapler (Fig. 3). Further
dissection between the liver and the IVC will isolate the right hepatic
vein, which is encircled with a vessel loop.
Attention is turned to the hilum, where the right hepatic artery
and right portal vein are dissected and divided. A clear line of
demarcation should be visible. The right hepatic vein, which was
previously controlled with a vessel loop, is divided with a vascular
stapler (Fig. 4). The transection plane follows the area of vascular
demarcation. The right hepatic duct can be divided with a stapler or
between ties.
For large right-sided tumors, an anterior approach can be used
in which the parenchyma is divided before liver mobilization. Inflow
control is obtained, and the parenchyma is transected until the anterior surface of the IVC is exposed. The right hepatic vein and short
hepatic veins are identified and ligated. The hanging maneuver, elevation of the liver by an umbilical tape passed between the anterior
surface of the IVC and the liver, can facilitate an anterior approach.
The space between the right and middle hepatic veins is dissected,
and a long clamp is gently passed along the anterior surface of the
vena cava to emerge between the right and middle hepatic veins.
An umbilical tape is then passed behind the liver and used to gently
elevate the liver, serving as a guide to the transection plane.
Right Trisectionectomy
This includes extension of the right parenchymal transection to
include segment IV. The initial hepatic mobilization is as described
FIG. 4 Division of the right hepatic vein. With the liver retracted to the
left, the right hepatic vein may be rapidly and safely divided using an Endo
GIA stapler (Covidien) with a vascular load. (From Blumgart LH, editor.
Surgery of the liver, biliary tract, and pancreas. 4th ed. Philadelphia: Elsevier;
2007:364.)
for a right hepatectomy. The transection plane is along the falciform
ligament, from the groove separating the middle and left hepatic
veins cranially to the right side of the umbilical fissure caudally,
directed toward the medial aspect of the right hilar plate while
avoiding the confluence of the left and right hepatic ducts. Inflow
to segment IV is controlled during the transection, as is the middle
hepatic vein as the surgeon follows the transection caudally.
380 HEPATIC MALIGNANCY: RESECTION VERSUS TRANSPLANTATION
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Left Hepatic Lobectomy
For a left hepatectomy, the triangular ligament is divided, exposing
the IVC and left hepatic vein. The round ligament is elevated and the
parenchymal bridge between segments II and IVB is divided, exposing the left hilum at the base of the umbilical fissure. The left hepatic
artery, portal vein, and hepatic duct are ligated individually. The left
lateral segment is rotated to the patient’s right and the gastrohepatic
ligament is divided. Exposure of the left hepatic vein is facilitated
by dividing the ligamentum venosum at its insertion. The common
trunk of the middle and left hepatic veins is encircled. Depending on
the location of the pathology and the anatomy of the venous outflow,
the middle and left hepatic vein may be divided together as a common trunk or the middle hepatic vein may be spared. The outflow
can usually be divided extrahepatically with a vascular stapler before
proceeding with the parenchymal transection. If this is not feasible,
the left hepatic vein can be divided intraparenchymally. The liver
parenchyma is transected along the line of vascular demarcation. If
oncologically feasible, the transection plane should run horizontally,
approximately 1 cm above the hilum, from the area of transection of
the left hilar plate to the left side of the gallbladder fossa, thus avoiding transection of an aberrant right anterior or posterior duct, and
then turning vertical, parallel to Cantle’s line.
Left Trisectionectomy
When indicated, the right anterior section (segments V and VIII)
may be transected along with the left hemiliver. The initial steps are
the same as for a left hepatectomy. The main challenge is to define
the transection plane, which is horizontal, extending from the right
of the gallbladder fossa and anterior to the right hepatic vein toward
the base of segment IV without injuring the inflow to the posterior
sector. The right anterior pedicle is identified and ligated as the
parenchymal transection approaches the hilum.
S u g g e S t e d R e a d i n g S
Jarnagin WR. Hepatic resection: general considerations. In: Jarnagin WR, ed.
Surgery of the Liver, Biliary Tract, and Pancreas: Elsevier; 2017:1520–1521.
Kemeny N, Niedzwiecki D, Hollis D, 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.
Memeo R, de Blasi V, Adam R, etal. Parenchymal-sparing hepatectomies
(PSH) for bilobar colorectal liver metastases are associated with lower
morbidity and similar oncological results: a propensity score matching
analysis. HPB. 2016;18:781–790.
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 randomized, controlled phase 3 trial. Lancet Oncol. 2013;14:1208–1215.
Primrose J, Fox R, Palmer D, etal. Capecitabine compared with observation
in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol. 2019;20(5):663–673.
Sandstrom P, Rosok C, Sparrelid E, et al. ALPPS improves resectabil-
ity compared with conventional two-stage hepatectomy in patients
with advanced colorectal liver metastasis. Results from a Scandinavian
Multicenter Randomized Controlled Trial (LIGRO Trial). Ann Surg.
2018;267(5):833–840.
Hepatic Malignancy:
Resection Versus
Transplantation
Sharon R. Weeks, MD, and Shane E. Ottmann, MD
INTRODUCTION
Hepatocellular carcinoma (HCC) is the most common primary
malignant tumor in the liver and the fifth most common cause of
malignancy worldwide. It develops most commonly in the setting of
hepatic injury or chronic liver disease. Prevalence of HCC is higher
in populations and geographic regions with higher rates of hepatitis
infection; the highest HCC rates are seen in Asia and sub-Saharan
Africa. Worldwide, the most common risk factor for HCC is hepatitis
B virus infection or carrier status, whereas in the United States, hepatitis C is the most critical risk factor. Although the rates of many cancers in the United States have been decreasing over the last decade,
the incidence of HCC and resultant mortality have been on the rise.
HCC remains the third most common indication for transplant in the
United States, comprising 14% of liver transplants performed in 2019.
The prognosis for HCC is poor if left untreated, with a 5-year
overall survival of less than 10% and a median survival less than
6 months. For patients with a resectable tumor without underlying liver disease, resection is the treatment of choice. However, as
the majority of patients with HCC have concomitant chronic liver
disease, resection options can be limited due to concern for postoperative liver failure from inadequate remnant volume. Although
transplantation for well-selected HCC patients has excellent outcomes and should be the treatment of choice in patients with decompensated cirrhosis, the limited donor pool prevents widespread
application of this treatment modality for all patients. The patient
with a resectable HCC in the setting of well-compensated cirrhosis
presents a treatment dilemma: who should be resected and who
would be better served with transplant? The answer for any given
patient depends on local resources, including the availability of
transplant, severity of underlying liver disease, and the technical
resectability of the tumor, while weighing the risks associated with
remnant liver recurrence and dropout on the transplant waitlist
from tumor progression. Finally, while surgical intervention is the
mainstay of treatment for HCC, many patients present at advanced
stages that are not amenable to resection or do not meet criteria for
transplant. For these patients, multiple locoregional therapies have
been developed in the last few decades, including ablation, embolization, and radiation therapy; these interventions can be used as
monotherapy or as a bridge to surgical therapy.
PATIENT EVALUATION
Risk factors for development of HCC include hepatitis B and C, alcohol consumption, genetic hemochromatosis, nonalcoholic fatty liver
disease (NAFLD), primary biliary cirrhosis, alpha-1 antitrypsin deficiency, and other causes of cirrhosis. Patients with HCC are typically
asymptomatic until advanced stages of the disease. When patients
do have symptoms, they are typically due to mass effect of the tumor
and may include abdominal pain, early satiety, weight loss, or a palpable mass. As cirrhosis is present in more than 90% of patients with
HCC, cirrhotic symptomatology may be present, including weakness, fatigue, jaundice, pruritis, and hepatic encephalopathy. Patients
may also manifest features of liver decompensation such as ascites
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or variceal bleeding. Finally, liver decompensating events may result
from tumor extension into the hepatic or portal veins.
Ideally, patients at high risk for HCC are followed via a surveillance protocol with ultrasound and alpha fetoprotein (AFP). The
National Comprehensive Cancer Network (NCCN) recommends
surveillance ultrasound every 6 months in all patients with chronic
hepatitis B (including those without cirrhosis) as well as patients with
cirrhosis due to any cause. Cross-sectional imaging with multiphasic
CT or MRI is a more sensitive but less cost-effective approach to
HCC screening; these modalities may be used as alternatives to ultrasound if visualization is poor. Unfortunately, adherence to these recommendations is low and patients often present at advanced stages of
disease. Whether identified on surveillance, incidental, or for cause
imaging, the diagnosis of HCC can typically be made radiographically without need for liver biopsy. Abdominal multiphasic CT or
MRI with contrast should be performed to confirm the diagnosis and
the extent of tumor burden. All patients with diagnosis of HCC warrant oncologic staging; NCCN guidelines recommend evaluation for
distant metastases with chest CT and complete imaging of the abdomen and pelvis if not previously performed. The most common sites
of metastasis are lungs, bone, and lymph nodes; less common sites
include adrenal and peritoneal metastases. Consequently, selective
use of bone scan in patients with skeletal symptoms may be considered. Laboratory evaluation should include hepatitis panel, bilirubin, transaminases, alkaline phosphatase, coagulation factors, basic
chemistry and blood counts, and AFP if not previously performed.
The differential diagnosis for a presumed HCC on imaging
includes cholangiocarcinoma, metastases, and benign liver masses,
but typically imaging is diagnostic, particularly in high-risk patients.
Patients at high risk for HCC are also at risk for intrahepatic cholangiocarcinoma and combined HCC-cholangiocarcinoma; these
diagnoses should be considered in patients without sufficiently diagnostic imaging characteristics and in those with elevated CA 19-9 or
carcinoembryonic antigen (CEA). In these patients or in other cases
of diagnostic dilemma, such as patients with concern for metastasis
or those with a low risk history, biopsy is warranted to confirm the
diagnosis and guide treatment decisions.
Once diagnosis is confirmed, further treatment is guided by
underlying liver function, resectability of tumor, and availability of
treatment modalities, including transplantation.
ASSESSMENT OF LIVER FUNCTION
Of primary concern for choosing a treatment course is determination of the patient’s underlying liver function. Multiple schemas have
been developed for this purpose, the most well-known of which are
the Child-Pugh classification (shown in Table 1) and the Model for
End-Stage Liver Disease (MELD) score. Both predict mortality in
cirrhotic patients, including postoperative mortality. Child class C
cirrhotic patients, with up to 80% risk of mortality after surgery, are
not generally considered candidates for nontransplant surgery. The
TABLE 1 Child-Pugh Classification
1 point 2 points 3 points
Albumin (g/dL) >3.5 2.8–3.5 <2.8
Bilirubin (mg/dL) <2 2–3 >3
INR <1.7 1.7–2.3 >2.3
Ascites None Slight Moderate
Encephalopathy None 1–2 3–4
Child-Pugh classification is calculated by summing the points per
parameter. Class A = 5–6; Class B = 7–9; Class C = 10–15.
MELD score, most recently modified to include sodium, includes
bilirubin, international normalized ratio, and creatinine, and is used
for prioritization of patients on the liver transplant waitlist. It has
also been shown to predict 30-day mortality after surgery, with a 1%
increase in mortality per MELD point in patients with MELD scores
less than 20 and an additional 2% increase per MELD point greater
than 20.
In recent years, other scoring systems have been evaluated as
predictors of mortality in cirrhotic patients. The Mayo postoperative
mortality risk calculator attempts to provide more specific results for
a patient given their comorbidities; it calculates probability of mortality using age, American Society of Anesthesiologists(ASA) score,
bilirubin, creatinine, International Normalized Ratio (INR), and the
etiology of cirrhosis. This calculator provides predicted mortality at
7, 30, and 90 days postoperatively as well as at 1 and 5 years. Recently,
use of the hepatic venous pressure gradient (HVPG) has been used
to predict 1-year mortality in cirrhotic patients undergoing elective
surgery. HVPG values higher than 16 mm Hg have been shown to be
independently associated with higher mortality, and values greater
than 20 mm Hg were associated with a very high risk of death, up
to 44%. Notably, HVPG values <10 mm Hg have been shown to be
protective against postoperative decompensating liver events.
In evaluating the specific question of the risk of postresection
liver failure in patients with HCC, the albumin-bilirubin (ALBI)
grade was found to effectively predict outcomes and importantly
does not rely on the subjective scoring of the Child-Pugh classification. The ALBI grade performed as well as the Child-Pugh classification in predicting mortality in cirrhotic patients with HCC.
Three grades, corresponding to three separate prognostic groups,
were identified: ALBI grade I (score ≤−2.60), grade II (score >−2.60
to ≤−1.39), and grade III (>−1.39). The three grades also predicted
1-year survival after hepatic resection, with rates of 100%, 81.9%, and
62.9%, respectively.
The most commonly used staging classification for HCC that
incorporates both tumor characteristics as well as underlying liver
function is the Barcelona Clinic Liver Cancer (BCLC) staging system
(Fig. 1). It classifies patients based on Child-Pugh classification and
performance status, in addition to tumor size, nodal and metastatic
disease, and local invasion characteristics. It also provides recommended treatment modalities for patients based on these characteristics. Studies of its prognostication outcomes have been mixed,
with some evidence that it outperforms many models (including
the American Joint Committee on Cancer [AJCC] TNM staging
system) but underperformed in other settings. Importantly, several
studies have shown that treatment outside Barcelona guidelines can
be effective, and surgical resection has potential beyond the limited
scope detailed in BCLC guidelines.
RESECTION FOR HEPATOCELLULAR
CARCINOMA
Surgical resection remains the mainstay of treatment for HCC
patients without underlying liver disease. Additionally, in many areas
where access to transplantation is low, it remains standard therapy
for HCC patients with well-compensated cirrhosis without evidence
of portal hypertension. Well-selected patients in this group have an
overall 5-year survival as high as 60% to 70%. However, recurrence
rates in the remnant liver are quite high, with most large studies
reporting only 25% to 45% disease-free survival at 5 years. Furthermore, as many patients present with advanced disease, only 20% to
30% present as initially resectable on surgical evaluation.
Careful preoperative evaluation of these patients to determine
candidacy for resection is critical. Imaging studies can determine
resectability in regard to location, vascular involvement, and absence
of distant metastases. Volumetrics, using CT, MRI, or scintigraphy,
can be obtained to estimate the size of the remnant liver; 20% to 30%
is considered adequate for a healthy liver. Larger remnants, 30% for
the steatotic or chronic hepatitis liver and 40% for the cirrhotic liver,
382 HEPATIC MALIGNANCY: RESECTION VERSUS TRANSPLANTATION
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HCC
Stage 0 Stage D
PS 0,
Child-Pugh A
Very early
stage (0)
Single <
carcinoma in situ
2 cm,
Single
Portal pressure /
bilirubin
Increased
Normal No Yes
Single or 3 nodules
Early
stage (A)
PS 0
3 nodules
Associated
diseases
3 cm,
3 cm
Stage A–C
PS 0–2,
Child-Pugh A–B
Intermediate
stage (B)
Multinodular,
PS 0
Advanced
stage (C)
Portal invasion,
N1, M1, PS 1–2
2,
PS >
Child-Pugh C
Terminal
stage (D)
Liver
transplantation
/ LDLT)
(CLT
FIG. 1 Barcelona Clinic Liver Cancer staging system for hepatocellular carcinoma. (From Khorsandi SE, Heaton N. Contemporary strategies in the management of
hepatocellular carcinoma.HPB Surg. 2012;2012:154056.)
are recommended for the diseased liver. Preoperative assessment of
liver function is also critical to prevent postoperative liver failure and
decompensating liver events. Patients with Child class A cirrhosis,
no evidence of portal hypertension, and well-preserved synthetic
liver function can be considered as resection candidates. Patients
without evidence of portal hypertension include those with HVPG
<10, normal platelet count, normal appearing spleen, and lack of
ascites and esophageal varices. In these patients, however, the risk
of recurrence in the liver remnant and time at risk (with respect
to patient age and other comorbidities) must be considered. Risk
factors independently associated with tumor recurrence include
tumor size greater than 5 cm and vascular invasion. Most studies
have failed to identify a significant benefit to recommend anatomic
over nonanatomic resection in preventing recurrence or mortality.
Some have advocated for anatomic resection based on the theoretical risk of intrahepatic metastases via portal vein tributaries, but
this recommendation has not yet been supported by evidence of
improved outcomes. Regardless of planned approach, intraoperative
ultrasound should be used liberally to best define the tumor burden
intraoperatively and ensure an oncologically sound resection margin. It is the most sensitive imaging modality for identifying intrahepatic metastases and tumor margins, and it may clarify or expand on
findings from preoperative imaging.
RF
/ PEI
In patients in whom the remnant liver volume is of concern,
portal vein embolization and the two-staged associating liver
partition and portal vein ligation for staged hepatectomy (ALPPS)
procedure are available modalities to facilitate resection. Preoperative portal vein embolization utilizes any of a number of embolization agents injected in percutaneous fashion via a transjugular
or transhepatic approach to obliterate the portal blood flow to the
ipsilateral side of the liver as the tumor (Fig. 2). This insult elicits
hypertrophy of the contralateral side to augment volume of the
future liver remnant and is performed 2 to 8 weeks in advance of
a planned hepatic resection. Repeat imaging before surgery can
determine effectiveness of the procedure. In a large clinical series
of 358 patients, median regeneration of the future liver remnant
was 50.3% at a median of 32 days postprocedure. Harnessing similar pathophysiology, the ALPPS procedure has been developed to
accelerate hypertrophy of the liver remnant. The first stage involves
operative portal vein ligation and in situ parenchymal transection
of the resection plane. The second stage, at postoperative week one
or two, involves completion of the resection and removal of the
specimen. Published studies report liver remnant growth of 40%
to 160% in only 6 to 9 days, a period in which significant tumor
progression is less likely than the longer regenerative time period
needed for portal vein embolization. Currently, ALPPS remains
SorafenibResection TACE
Best
supportive
care
FIG. 2 Portal vein embolization. Right portal vein embolization from the
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contralateral approach. (From Jarnagin: Blumgart’s Surgery of the Liver, Biliary
Tract and Pancreas, 6th ed. Elsevier; 2017.)
limited to high-volume centers due to concerns regarding high
rates of morbidity and mortality. However, a recent randomized
trial showed higher resection rates for the ALPPS group compared
with patients undergoing two-stage hepatectomy with portal vein
embolization. Additionally, the vast majority of patients who fail
to reach a sufficient future liver remnant with embolization were
able to be rescued with ALPPS. With these improved outcomes
and increasing experience with the procedure, ALPPS may play a
larger role as a treatment modality in the future for patients with an
insufficient future liver remnant.
LIVER TRANSPLANTATION IN
HEPATOCELLULAR CARCINOMA
Excellent data exist to support transplantation of patients with cirrhosis and HCC tumors with early stage HCC; 5-year survival rates
after transplant exceed 70%. The Milan criteria were developed in
1996 and remain the most commonly used and accepted criteria for
listing of liver transplant candidates with HCC. Patients meet Milan
criteria if they have a single nodule ≤5 cm or up to three nodules,
each ≤3 cm; additionally, they must be free of macroscopic vascular
invasion or distant disease. Overall survival after transplantation
within Milan criteria is over 75% at 5 years. In the decades following
Milan, the criteria received criticism for being unnecessarily narrow
and excluding patients who would benefit from transplant. Multiple other extended criteria were proposed, with the University of
California San Francisco (UCSF) criteria being the most commonly
utilized. Patients qualify by UCSF parameters if they have a single
nodule ≤6.5 cm or up to three nodules, each ≤4.5 cm, with a total
tumor diameter ≤8 cm. Five-year overall survival using these criteria
is 70% to 80%; conversely, transplantation outside these criteria was
quite poor with less than 50% 1-year survival.
In patients with cirrhosis, multiple studies have shown clear
benefits in disease-free and overall survival in those undergoing
transplantation compared with resection. In a retrospective study
of 1765 patients with HCC and concomitant cirrhosis who met
Milan criteria, patients undergoing transplantation had significantly
improved survival at 5 (74% vs. 53%) and 10 years (54% vs. 22%), as
well as increased disease-free survival (72% vs 30% at 5 years; 53%
vs 12% at 10 years) compared with transplant eligible patients who
underwent liver resection. However, in the same large series, only
about 10% of patients presenting with HCC and cirrhosis were eligible for transplant based on Milan criteria.
LIVER 383
Given the threat to life from malignancy not captured by the
degree of liver dysfunction, HCC patients in the United States who
fall within the Milan criteria are given exception points on the liver
transplant waitlist after a 6-month waiting period that correlates with
the region’s mean MELD at transplant. Thus, while transplantation
is the most oncologically sound treatment for patients with HCC,
drastically reducing the risk of recurrence compared with resection,
the choice to proceed with transplant must be weighed against the
risk of tumor progression on the waitlist. Living donor liver transplantation, which has been growing in safety and availability through
the United States, may prove to reduce this risk. Some studies have
shown that living donor liver transplantation significantly decreases
risk of death from time of listing due to lower dropout rates.
FUTURE DIRECTIONS
Adjunctive and palliative treatments for HCC patients who are not
resection or transplant candidates at presentation deserve special
mention. These include transarterial chemoembolization, radiofrequency ablation, and other local therapies; they may serve as
adjuvant or palliative therapy, as well as a bridge to definitive therapy. Ablative therapies for recurrences limited to the liver have also
shown promising results. The long-term outcomes of these treatments and their use as a bridge to transplant or resection remain to
be well defined, but these modalities are becoming more widespread,
and indications are expanding.
Resection is the mainstay of therapy for cholangiocarcinoma, but
the majority of patients are deemed unresectable at presentation.
The Mayo protocol for unresectable cholangiocarcinoma treated
with preoperative chemoradiotherapy followed by transplantation
reported impressive results with a 5-year survival rate of 82%. These
results have been questioned as many patients included in the study
were found to be without viable tumor in the hepatectomy specimen.
Multiinstitutional studies using similar protocols showed improved
outcome for transplant over resection for hilar cholangiocarcinoma.
Transplantation for cholangiocarcinoma remains controversial and is
an area for further investigation.
SUMMARY
Any discussion of resection versus transplantation for HCC must
include the degree of liver disfunction, tumor stage, availability of
transplant, potential of recurrence in the remnant, and magnitude
of the liver resection required to render the patient disease free.
Retrospective analysis of resection versus transplantation is difficult
to generalize given the obvious selection bias; patients who undergo
resection are more likely to have less severe liver disease and patients
without liver disease rarely undergo transplantation. These studies
also necessarily exclude those patients on the waitlist who did not
receive a transplant due to tumor progression. Although definitive
data are lacking, most studies and observational experience support
improved disease-free and overall survival in patients undergoing
transplantation compared with resection. Over the past 30 years,
there have been substantial advances in operative techniques of
both liver transplantation and complex hepatic surgery, leading to
improved selection and survival in both groups. There is little debate
that resection can benefit many with isolated liver disease regardless
of tumor size in a noncirrhotic patient. Liver resection offers the
additional advantage of typically being immediately available and not
dependent on the organ donor population. Similarly, HCC patients
with liver failure and obvious decompensation clearly benefit from
transplant provided there is a route to transplantation and the tumor
is within acceptable criteria. The patient with well-compensated cirrhosis and early-stage tumors within transplantable criteria presents
a treatment challenge; the risk of delayed intervention while awaiting
a suitable organ must be weighed against the inferior survival and
disease-free survival rates seen after hepatic resection. When these
patients present early enough to fall within transplantable criteria,
384 MANAGEMENT OF COLORECTAL LIVER METASTASES
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we believe they should be referred to a transplant program to discuss
the options of resection versus transplant. Important considerations
for all HCC patients include the risk of disease progression while on
the transplant waitlist, options for living donor liver transplant, risk
of HCC recurrence in the remnant liver, liver failure following hepatectomy, and liver transplant outcomes in the modern era.
S u g g e S t e d R e a d i n g S
Chapman WC, Klintmalm G, Hemming A, et al. Surgical Treatment of
Hepatocellular Carcinoma in North America: Can Hepatic Resection Still
Be Justified? J Am Coll Surg. 220(4):628–637.
Management of
Colorectal Liver
Metastases
Jordan M. Cloyd, MD, and Timothy M. Pawlik, MD, MPH, PhD
INTRODUCTION
Colorectal cancer (CRC) is a leading cause of cancer-related deaths
throughout the world with up to 50% of patients developing colorectal liver metastases (CRLM) during the course of their disease. For
patients with CRLM, surgical resection provides the only opportunity
for potentially curative therapy. Although improvements in modern
systemic chemotherapy have expanded the number of patients eligible for curative-intent surgery, advances in operative techniques
and perioperative care have simultaneously improved the outcomes
following liver surgery. Given the therapeutic complexity, the management of CRLM requires expert multidisciplinary care by an
experienced oncology team. This chapter provides an overview of
contemporary management of CRLM with an emphasis on surgical
approaches.
EVALUATION
The diagnosis of CRLM is usually based on cross-sectional imaging
obtained during the staging evaluation of patients recently diagnosed with CRC or during surveillance of patients with a history
of treated CRC. A thorough history and physical examination, an
elevated carcinoembryonic antigen (CEA) level, and characteristic
imaging of a liver lesion are generally sufficient to make a diagnosis
of CRLM. When necessary, the diagnosis may be confirmed via
percutaneous image-guided biopsy. Surgical planning for CRLM
requires high-quality imaging. On contrast-enhanced multidetector
computed tomography (CT), CRLMs typically appear as hypoattenuating lesions best visualized on portal venous phases. Arterial phase
images can be helpful to distinguish metastases from benign vascular
lesions, to clarify vascular anatomy for operative planning, and/or if
placement of a hepatic arterial infusion pump is being considered.
Although CT is advantageous given its widespread availability and
ease of use, magnetic resonance imaging (MRI) provides enhanced
sensitivity of smaller tumors and better characterization of indeterminate lesions (Fig. 1).
An evaluation of candidacy for liver resection involves a compre-
hensive assessment along three domains: physical, oncologic, and
Ethun CG, Lopez-Aguiar AG, Anderson DJ, et al. Transplantation
Versus Resection for Hilar Cholangiocarcinoma: An Argument for
Shifting Treatment Paradigms for Resectable Disease. Ann Surg.
2018;267(5):797.
Rea DJ, Heimbach JK, Rosen CB, etal. Liver transplantation with neoadjuvant
chemoradiation is more effective than resection for hilar cholangiocarcinoma. Ann Surg. 2005;242(3):451.
Schadde E, Ardiles V, Robles-Campos R, etal. Early survival and safety of
ALPPS. Ann Surg. 2014;260(5):829–838.
Shindoh J, Tzeng CD, Aloia TA, etal. Safety and efficacy of portal vein embo-
lization before planned major or extended hepatectomy: an institutional
experience of 359 patients. J Gastrointest Surg. 204;18(1):45–51.
technical. First, patients must be healthy enough and have appropriate functional status to undergo major liver surgery. For patients with
prohibitive comorbidities or poor performance status, nonoperative
therapies should be considered. Oncologic resectability refers to the
selection of patients for surgery based on underlying tumor biology.
Relevant factors may include the number or size of metastases, the
presence of extrahepatic disease, the disease-free interval for metachronous tumors, tumor mutation status, and/or the response to
neoadjuvant therapy. Technical resectability refers to the ability to
perform a margin-negative resection while preserving an appropriate
future liver remnant (FLR). In general, the minimum FLR must consist of at least two contiguous segments with intact vascular inflow,
outflow, and biliary drainage. In addition, the estimated FLR volume
should be calculated using liver volumetry to minimize the risk of
posthepatectomy liver failure (PHLF). Although patients with normal hepatic function can safely tolerate resection with a planned FLR
size of >20%, individuals with compromised liver function (obesity,
receipt of chemotherapy for greater than 12 weeks, diabetes mellitus)
should have an FLR >30%, and those with fibrosis/cirrhosis require
an FLR >40% to 50% of total liver volume.
ROLE OF CHEMOTHERAPY
A major contributor to improved survival among patients with
advanced CRC, and a driving factor in expanding the role of surgery
for CRLM, has been the advent of improved systemic therapies.
Contemporary first-line chemotherapy for metastatic CRC primarily consists of fluorouracil-based regimens containing oxaliplatin
and/or irinotecan, namely FOLFOX (fluorouracil, leucovorin, and
oxaliplatin), FOLFIRI (fluorouracil, leucovorin, and irinotecan),
XELOX (capecitabine and oxaliplatin), or FOLFOXIRI (fluorouracil,
leucovorin, oxaliplatin, and irinotecan). Biologic agents, such as bevacizumab or cetuximab, can be added to increase response rates. The
choice of regimen largely depends on the patient’s performance status, prior receipt of chemotherapy, and the presence of RAS or BRAF
mutations. Tumors with evidence of mismatch repair deficiency are
more likely to respond to immunotherapy.
For patients with resectable CRLM, neoadjuvant therapy is
controversial. In the European Organisation for Research and
Treatment of Cancer (EORTC) intergroup 40983 trial, patients
with resectable CRLM were randomized to either upfront surgical
resection or perioperative FOLFOX chemotherapy. Neoadjuvant
therapy led to a 9% absolute improvement in progression-free
survival but no difference in overall survival (OS) (Fig. 2). Therefore, neoadjuvant chemotherapy continues to be used selectively
for patients with high-risk features or unclear resectability. However, prolonged chemotherapy may lead to chemotherapy-associated liver injury (CALI). Specifically, irinotecan-based treatment
LIVER 385
https://t.me/med1917
FIG. 1 Imaging of colorectal liver metastases. (A)Portal venous phase contrast-enhanced liver CT: necrotic mass, with fibrous enhancement centered
on segments 2–4 (arrow).(B)A second hypodense lesion on CT scan is visible in segment 7 (thin arrow).(C)MRI shows peripheral enhancement of both
lesions (arrows).(D)Both lesions are hypermetabolic on PET-CT (arrows).(E)Discovery of an additional lesion on portal venous phase contrast enhanced
MRI (circle).(F)This third lesion was not seen on CT or PET-CT (circle). (From Rahnemai-Azar A, Dillhoff M, Schmidt C, Pawlik T. Colorectal Liver Metastases. In:
Hepatobiliary and Pancreatic Surger y: A Companion to Specialist Surgical Practice, 6, 104–120.)
is associated with steatohepatitis, whereas oxaliplatin-based chemotherapy is associated with sinusoidal congestion (Fig. 3). In
general, if preoperative chemotherapy is used, the duration should
be limited to 4 to 6 cycles (i.e., 2–3 months). In addition, neoadjuvant chemotherapy may lead to disappearing liver metastases,
especially for small (<2 cm), centrally located tumors. If not
surgically resected, these lesions will recur in up to 50% to 80%
of patients.
Similarly, the role of adjuvant chemotherapy following resection of CRLM also remains controversial. Given that data from
randomized controlled trials have produced mixed results, adjuvant chemotherapy is most often used selectively in patients with
386 MANAGEMENT OF COLORECTAL LIVER METASTASES
y
A
Number at risk
chemotherapy
Number at risk
https://t.me/med1917
All randomly assigned patients
100
90
80
70
60
50
40
Overall survival (%)
30
20
10
Overall log-rank test: p=0.34
0
0
Surgery only
Perioperative chemotherap
1
2345678
Surgery only 182 167 138 116 94 79 72 58
chemotherapy
182 165 145 120 107 88 72 66Perioperative
B
100
90
80
70
60
50
FIG. 2 Long-term overall survival of patients
with resectable colorectal liver metastases
randomized to perioperative chemotherapy versus
upfront surgery in the EORTC 40983 trial. All
randomly assigned patients (A) and all eligible
patients (B). (From Nordlinger B, Sorbye H, Glimelius B,
etal. Perioperative FOLFOX4 chemotherapy and surgery
versus surgery alone for resectable liver metastases from
colorectal cancer (EORTC 40983): long-term results of
Surgery only 171 159 133 111
a randomised, controlled, phase 3 trial. Lancet Oncol.
2013;14(12):1208–1215.)
high-risk disease (e.g., number of tumors, margin status, initial
CEA level, etc.). Several nomograms or clinical risk scores have
been developed to aid in prognostication and use of adjuvant therapy however, the use of these tools in the real-world clinical setting
has been variable.
40
Overall survival (%)
30
20
10
0
171 158 139 114 103 86 70 64Perioperative
All eligible patients
Overall log-rank test: p=0.303
012345678
Years since randomisation
91 76 69 56
avoided given the potential for compromising margins and/or inadvertent injury to biliovascular pedicles. Intermittent hepatoduodenal
ligament clamping (i.e., Pringle’s maneuver) can help minimize
blood loss. Enhanced recovery after surgery protocols can reduce
postoperative length of stay and morbidity after liver surgery.
SURGICAL RESECTION
Surgical Technique
While there are several different techniques to divide the liver
parenchyma, the universal goal of resection for CRLM is complete
resection of all metastases with microscopic negative margins. A
comprehensive understanding of liver anatomy is mandatory when
performing hepatic resection of CRLM, as is adept use of intraoperative ultrasound for identifying all tumors, guiding planned surgical
margins, and targeting intraoperative ablation (Fig. 4). Given its
importance to perioperative and oncologic outcomes, strategies to
minimize operative blood loss are paramount. A low central venous
pressure (CVP) maintained by an experienced anesthesiologist is
one of the most important steps. Although numerous parenchymal
transection techniques are available, with none consistently demonstrating superiority over others, excessive use of staplers should be
Margin Status
Although an R0 resection consists of surgical margins >1 mm,
the optimal margin width at the time of liver resection for CRLM
remains controversial. In a seminal study, R1 margin status was associated with worse OS following liver resection for CRLM, but greater
margin widths were not associated with improved outcomes (Fig. 5).
Other studies have demonstrated that wider margins >1 mm are
not advantageous; however, even submillimeter margin widths have
been associated with improved OS compared with microscopically
positive margins. Increasing evidence suggests that margin status
may be more reflective of a biological effect. For example, patients
with RAS mutations are more likely to have positive margins, and
the prognostic significance of R1 margin status is lessened among
patients who respond to neoadjuvant therapy. Therefore the objective of any resection for CRLM should remain a microscopically
negative margin ≥1 mm, yet the direct association between margin
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