Hepatocellular Carcinoma: Targeted Therapy and Multidisciplinary P14 potx

9 Liver Resection for Hepatocellular Carcinoma 115
Fig. 9.2 Japanese algorithm for resection in cirrhosis (Adapted from [22] used with permission)
are safe; ICGR15 30–39%, only wedge resections are safe; ICGR15 ≥40%, only
enucleations are safe). This algorithmic approach was prospectively validated
in 107 patients; the 30-day mortality rate was zero, and there were no major
complications [29].
Evaluation of Future Liver Remnant Volume
Computed tomography (CT) can now provide an accurate, reproducible method for
preoperatively measuring the volume of the future liver remnant (FLR). The FLR
is measured directly by three-dimensional CT volumetry, and the total liver vol-
ume is calculated using a mathematical formula that relies on the linear correlation
between liver size and body surface area (BSA). The ratio of the CT measure FLR
volume/calculated total liver volume (TLV) is defined as the standardized FLR and
it provides the percent of TLV remaining after resection [30]. The formula used to
estimate TLV based on BSA was recently evaluated in a meta-analysis and recom-
mended as one of the least biased and most precise formulas for the estimation of
the total liver volume in adults [31] (Fig. 9.3).
Although there is a general consensus that the extent of resection that is safe
is mainly limited by the function, attention has also focused on the FLR volume
after major hepatectomy. In general, a FLR of 20% is considered the minimum
safe volume needed following extended hepatic resection in patients with normal
underlying liver, while an FLR of 40% is required in patients with chronic l iver
disease (cirrhosis or hepatitis) [32, 33] (Fig. 9.4). Current suggested indications for
PVE in normal, injured, and cirrhotic liver are presented in Fig. 9.5.
116 D.Zorzietal.
Fig. 9.3 Method of systemic preoperative liver volume calculation using three-dimensional CT
volumetry. CT outline of the segments included in the measurement of future liver remnant (FLR)
volume for a planned extended right hepatectomy (white outline = FLR). (a) The FLR is measured
directly by three-dimensional CT volumetry, and the total liver volume (TLV) is calculated using a
mathematical formula that relies on the linear correlation between liver size and body surface area
(BSA). The ratio of the CT measure FLR volume/calculated total liver volume (TLV) is defined as

the standardized FLR (sFLR) and it provides the percent of TLV remaining after resection
Preoperative Therapy
Transarterial Chemoembolization (TACE) and Portal Vein Embolization
(PVE)
In patients who are otherwise candidates for hepatic resection, an inadequate
FLR volume – ≤20 or <40% of the estimated TLV in patients with normal or
cirrhotic liver, respectively – may be the only obstacle to curative resection. Three-
dimensional CT volumetry and calculation of the FLR allows the planning of hepatic
resection to be individualized for each patient. Portal vein embolization (PVE) can
be performed to prime the growth of the anticipated FLR, thereby making a major
or extended hepatectomy possible.
PVE is safe with less than a 5% complication rate, causes little periportal
reaction, and generates durable portal vein occlusion especially when used in com-
bination with coils. PVE has been shown to increase both the size of the FLR as
well as the percentage of indocyanine green (ICG) excretion and bile volume flow
in the remnant liver. In addition, in patients with chronic liver disease PVE has also
been reported to decrease the incidence of postoperative complications, intensive
care unit stay, and the total hospital stay after major hepatic resection. Thus, the
9 Liver Resection for Hepatocellular Carcinoma 117
Fig. 9.4 Standardized calculation of future liver remnant (FLR) volume accurately predicts the
likelihood of postoperative complications after hepatic resection in normal liver (a) and in chronic
liver disease (b). (a) Complication rate stratified by standardized future liver remnant (% FLR)
volume in relation to FLR in normal liver; 90% of patients with a % FLR of 20% or less had com-
plications; 39% of patients with a % FLR of greater than 20% had complications (P = 0.003) [33].
(b) A comparison of FLR volume of patients who died of liver failure and those without liver fail-
ure after surgery in chronic liver disease. Remnant liver volume in patients who died of liver failure
was significantly smaller than that in patients who did not die of liver failure (P = 0.0008) and it
was never more than 250 mL/m
2
(From [33], used with permission)

Fig. 9.5 Indications for portal vein embolization (PVE). There is a consensus that in patients
treated with aggressive preoperative chemotherapy, the remnant liver volume should be at least
30% of the total liver volume to avoid a high risk of complications following hepatic resection.
BMI, body mass index (From [34], used with permission)
selective use of PVE may enable safe and potentially curative extended hepatec-
tomy in a subset of patients with advanced hepatobiliary malignancies who would
otherwise have been marginal candidates for resection.
Palavecino et al. [ 35] reported on 54 patients who underwent major hepatic resec-
tion for HCC with or without PVE before resection. This study demonstrates that
PVE before major hepatectomy for HCC is associated with decreased perioperative
mortality. The overall and disease-free survival rates were similar between patients
118 D.Zorzietal.
Fig. 9.6 Overall survival after major hepatectomy in patients with and without preoperative por-
tal vein embolization (PVE), excluding postoperative deaths (P = 0.35) (From [35], used with
permission)
who underwent major hepatectomy with and without PVE (Fig. 9.6). Thus, PVE
increases the safety of major hepatectomy in patients with HCC without compro-
mising long-term oncologic outcomes.
Because the main blood supply for HCC is the hepatic artery and PVE results
in increased hepatic arterial flow, concerns have been raised about the potential
for accelerated tumor growth after PVE [36, 37]. To avoid this possibility, TACE
has been proposed as a complementary procedure to PVE in patients with HCC
(Fig. 9.7). TACE eliminates the arterial blood supply to the tumor and embolizes
potential arteriovenous shunts resulting from cirrhosis and/or HCC that attenuate
the effects of PVE. In addition, 60–80% complete necrosis of tumor can be achieved
by the combination of TACE and PVE [38, 39]. Our results support a study by
Ogata et al. [38] in which patients who underwent TACE before PVE had improved
disease-free survival and increased FLR hypertrophy than patients who underwent
PVE alone [35] (Fig. 9.8). Our current recommendation for those patients with bilo-
bar HCC and tumor nodules in the FLR is to perform TACE before PVE to avoid

tumor growth in the FLR after PVE.
Chemotherapy
Sorafenib is an oral multikinase inhibitor, which exerts an antiangiogenic
effect by targeting vascular endothelial growth factor receptors (VEGFRs)
9 Liver Resection for Hepatocellular Carcinoma 119
Fig. 9.7 Sequential transartherial chemoembolization (TACE) and portal vein embolization (PVE)
in cirrhotic liver. A 74-year-old male patient HCV genotype 2b with a 12.5 hepatocellular car-
cinoma involving the right liver with periportal fibrosis and focal bridging. (a, b) Future liver
remnant (FLR) volume of segments 1, 2, 3, and 4 equal to 27%. Computed tomography following
TACE and right PVE shows hypertrophy of the FLR (47%) (c). Right hepatectomy was performed.
The specimen indicated complete pathologic response with no residual tumor. The patient had no
evidence of disease 53 months postresection (d)
and platelet-derived growth factor receptor (PDGFR). Recently, a randomized,
placebo-controlled phase III trial of sorafenib reported an improvement in median
overall survival along with increased time to progression and disease control rate in
advanced HCC [40]. There is no evidence that sorafenib has a role as a neoadjuvant
agent in downstaging patients to render them resectable because the response rate
to sorafenib is only 3%.
In contrast the PIAF treatment regimen (platinum, interferon, adriamycin, and
5 FU) allows a selected group of patients with normal liver and HCC confined to the
liver to become eligible for aggressive surgical techniques [41, 42] (Fig. 9.9). Using
the PIAF regimen in patients with preserved liver function Lau et al. found 18%
major tumor response rate (more than 50% reduction in tumor size). Furthermore,
10% percent of the entire cohort, who presented with tumors that were considered
unresectable, underwent subsequent complete resection after chemotherapy; 53% of
the resected patients were alive 3 years after hepatic resection [43].
120 D.Zorzietal.
Fig. 9.8 Sequential arterial and portal vein embolization. Patients who underwent transartherial
chemoembolization (TACE) before portal vein embolization (PVE) had increased future liver rem-
nant (FLR) hypertrophy than patients who underwent PVE alone (P = 0.13) (From [36], used with

permission)
Surgical Technique
In patients with HCC, the goal of the surgical approach is to optimize the oncologic
resection (negative margin) while sparing the noncancerous hepatic parenchyma.
Advances in anesthetic and surgical techniques, as well as a thorough understanding
of the liver anatomy and tumor biology, have contributed dramatically to the safety
and effectiveness of liver resection for HCC. Modern surgical principles include
anatomic resection, the use of vascular inflow occlusion, and low central venous
pressure anesthesia. New surgical approaches such as the anterior approach and
liver hanging maneuver have been developed along with the use of more effective
instruments for parenchymal transection.
For a safe liver resection, both the bilateral subcostal incision, with or without
superior/midline extension to the xiphoid (hockey-stick incision), and the J-type
incision are valid options. At M.D. Anderson Cancer Center the modified Makuuchi
J-incision where the vertical midline portion converges with the horizontal limb at
the level of the umbilicus. Our modification aims to spare the nerves supplying the
skin and the rectus muscle, thus reducing skin numbness, muscle atrophy, and post-
operative pain [44]. After mobilization of the liver, intraoperative ultrasound (IOUS)
is systematically performed to confirm the extent of disease, review the intrahep-
atic portal and hepatic vein anatomy, and define the parenchymal transection plane.
IOUS identifies new nodules in 15–30% of patients with HCC [45, 46], although
only about 25% of these new nodules are malignant. The classic description of HCC
by IOUS is a mosaic pattern with posterior enhancement and lateral shadowing.
In nodules that lack specific findings of HCC, malignancy is found in 24–30% of
9 Liver Resection for Hepatocellular Carcinoma 121
Fig. 9.9 A 60-year-old male patient with a 15 cm hepatocellular carcinoma involving left lobe,
right anterior sector and abutting the right hepatic vein. (a, b) Computed tomography following six
cycles of chemotherapy with PIAF (platinum, i nterferon, adriamycin, and 5 FU), three cycles of
capecitabine + interferon, and transarterial chemoembolization (TACE) revealed response of the
tumor. (c, d) Extended left hepatectomy with caudate and vena cava resection was performed. The

patient had no evidence of disease 4 years postresection (e, f)
122 D.Zorzietal.
hypoechoic nodules and 0–18% of hyperechoic nodules [45, 46]. IOUS may there-
fore decrease recurrence through the identification of unrecognized multifocal HCC.
In addition, IOUS is considered an essential aid for guidance of resection [47] and
has proven useful in obtaining a margin negative resection [48](seeChapter 10).
Anatomic Resection
HCC has a high propensity to invade the portal and hepatic veins; thus, the spread
of HCC is essentially through the bloodstream – first via the portal vein to cause
intrahepatic metastasis, a primary mechanism of intrahepatic recurrence, and later
to extrahepatic organs such as the lungs, bone, and adrenal glands. These two forms
of spread, vascular invasion and intrahepatic metastasis, are among the risk factors
that most strongly influence the postoperative prognosis. On this basis, Makuuchi
et al. introduced the concept of anatomic resection – segmentectomy and subseg-
mentectomy – which involves systematic removal of a hepatic segment confined
by tumor-bearing portal tributaries that might contain portal metastases or daughter
micronodules.
The theoretical advantage of anatomic over nonanatomic resection has been
demonstrated in two large series in which anatomic resection was found to be an
independent factor for both overall and disease-free survival [49, 50]. Therefore,
segment-oriented anatomical resection should be proposed for any HCC, whenever
technically and functionally possible. The width of a negative resection margin has
also been investigated. A study predating the reports on anatomic resection showed
that the rate of postoperative recurrence of HCC was not related to the width of the
resection margin but rather to microvascular invasion or the presence of microsatel-
lites [51], further supporting the superior value of the anatomic approach. As the
margin size has not been found to be an independent predictor of recurrence across
multiple studies, functional liver should not be sacrificed in an attempt to obtain a
wide margin [51–54].
Resection of Large Right Liver Tumors

Surgical resection of a large right lobe tumor represents one of the most challeng-
ing situations. With the conventional technique for hepatectomy, mobilization of the
right lobe from the retroperitoneum and anterior surface of the IVC may be chal-
lenging because of the tumor volume and adhesion to the diaphragm and may result
in injury to the right hepatic vein or the venous branches between the IVC and the
posterior aspect of the right lobe.
To overcome these problems, the anterior approach has been proposed [55]. With
this approach, after hilar control of the vascular inflow is achieved, the parenchyma
is transected from the anterior surface of the liver down to the anterior surface of
the IVC, without prior mobilization of the right lobe. After control is achieved of
all venous tributaries to the IVC, including the right hepatic vein, the right lobe
is detached from the diaphragm. In a retrospective comparative analysis, Liu et al.
demonstrated that the anterior approach for large right lobe HCCs resulted in less
9 Liver Resection for Hepatocellular Carcinoma 123
intraoperative blood loss, lower transfusion requirements, a lower in-hospital death
rate, and significantly better overall and disease-free survival compared to the con-
ventional approach to right or extended right hepatectomy [56]. More recently in a
prospective randomized controlled study, Liu et al. confirmed findings of the previ-
ous study, demonstrating improved operative and survival outcomes of the anterior
approach technique compared to the conventional approach [57]. With the ante-
rior approach, it may be difficult to control bleeding in the deeper parenchymal
plane. Because of this, in 2001, Belghiti et al. proposed a new technique of hanging
the liver after lifting it with a tape passed between the anterior surface of the IVC
and the liver parenchyma (“liver-hanging maneuver”) [58]. To allow for passage of
the tape, the space between the right and middle hepatic veins is initially dissected
for 2 cm downward. The dissection of the anterior plane of the IVC begins with
placement of a long vascular clamp posterior to the caudate lobe on the left side
of the right inferior hepatic vein, if present (Fig. 9.10). Then the clamp is gently
pushed cranially in the middle plane of the IVC to allow a blind dissection. When
the clamp appears between the right and middle hepatic veins, the tape is seized and

Fig. 9.10 Hanging Maneuver. Pediatric suction (grafting suction tube, 4-mm tip, 9.5 in. length;
Cardinal Health/V Mueller Products) is used to explore the space of Couinaud and to perform the
liver hanging maneuver (a). Avascular retrohepatic plane between right and middle hepatic veins
(arrow)(b). Intraoperative view after removal of the specimen. Avascular retrohepatic plane is
shown with a dot line (c). Right hepatic vein (RHV), middle hepatic vein (MHV), inferior right
heparic veins (IHRVs), segment 1 vein (Sg1V)
124 D.Zorzietal.
passed around the hepatic parenchyma. The parenchymal dissection is facilitated by
upward traction on the tape, which allows the s urgeon to follow a direct plane and
facilitates exposure and hemostasis of the posterior parenchymal plane in front of
the IVC.
Prevention and Control of Bleeding
Many studies have shown that intraoperative blood loss and transfusion require-
ments are independent predictors of major morbidity and death from surgery. Blood
transfusion can add to the risk of coagulopathy as well as exert immunosuppres-
sive effects. Given this, efforts to minimize blood loss become critical. Techniques
of temporary vascular occlusion such as portal triad clamping and total vascular
exclusion (TVE) have been used to reduce bleeding from the cut edge of the liver.
In a prospective randomized study, portal triad clamping, otherwise known as
the Pringle maneuver, has been shown to significantly reduce blood loss result-
ing in improved postoperative liver function [59]. Further, the authors suggested
that the reduction in blood loss offset the potential adverse effects of ischemia–
reperfusion-induced hepatocellular injury. In a different randomized trial, Belghiti
et al. demonstrated that intermittent Pringle maneuver – 15 min of inflow occlu-
sion followed by 5 min of liver revascularization – is safer than continuous inflow
occlusion in patients with chronic liver disease and should be considered, in this
population, the technique of choice [60]. While Pringle maneuvers exceeding 4 h
have been reported, Wei et al. found that inflow occlusion time exceeding 80 min
was associated with a higher mortality rate [11]. Total vascular exclusion (TVE), a
technique which involves the Pringle maneuver as well as clamping of the supra-

and infra-hepatic vena cava, has not been shown to be more effective in decreas-
ing blood loss when compared to portal triad clamping alone, while associated with
increased morbidity [61]. Indications for TVE are limited to those cases with tumor
involvement of the cavo-hepatic junction [62].
The drawback of hepatic pedicle clamping is that it does not prevent back bleed-
ing from the hepatic veins. In fact, one of the most important factors related to intra-
operative blood loss is pressure within the inferior vena cava (IVC). In a prospective
study examining blood loss and IVC pressure, there was a direct linear correla-
tion between mean caval pressure and blood loss [63]. As hepatic vein pressure
directly reflects the caval pressure, the maintenance of a low central venous pres-
sure is an effective technique to reduce back bleeding from the hepatic veins
[64, 65]. At our institution, all patients who undergo hepatic resection have mainte-
nance of a low central venous pressure (<5 cm H
2
O), with a minimal acceptable
urine output of 0.5 mL/kg/h, until the parenchymal transection is completed.
Infusions and transfusions are minimized, and transient hypotension that can occur
with hepatic mobilization is treated with vasopressor support (usually phenyle-
phrine). When the parenchymal transection is complete and hemostasis achieved,
patients are rendered euvolemic with crystalloid and/or albumin infusions.