ORIGINAL ARTICLES

Two Hundred Forty Consecutive Portal Vein Embolizations

Before Extended Hepatectomy for Biliary Cancer
Surgical Outcome and Long-term Follow-Up
Masato Nagino, MD, Junichi Kamiya, MD, Hideki Nishio, MD, Tomoki Ebata, MD,
Toshiyuki Arai, MD, and Yuji Nimura, MD

which was similar to the 132 patients with cholangiocarcinoma who

Objective: To assess clinical benefit of portal vein embolization
(PVE) before extended, complex hepatectomy for biliary cancer.
Summary Background Data: Many investigators have addressed
clinical utility of PVE before simple hepatectomy for metastatic
liver cancer or hepatocellular carcinoma, but few have reported PVE
before hepatectomy for biliary cancer due to the limited number of
surgical cases.
Methods: This study involved 240 consecutive patients with biliary
cancer (150 cholangiocarcinomas and 90 gallbladder cancers) who
underwent PVE before an extended hepatectomy (right or left
trisectionectomy or right hepatectomy). All PVEs were performed
by the “ipsilateral approach” 2 to 3 weeks before surgery. Hepatic
volume and function changes after PVE were analyzed, and the
outcome also was reviewed.
Results: There were no procedure-related complications requiring
blood transfusion or interventions. Of the 240 patients, 47 (19.6%)
did not undergo subsequent hepatectomy. The incidence of unre-
sectability was higher in gallbladder cancer than in cholangiocarci-
noma (32.2% versus 12.0%, P ⬍ 0.005). The remaining 193 patients
(132 cholangiocarcinomas and 61 gallbladder cancers) underwent
hepatectomy with resection of the caudate lobe and extrahepatic bile
duct (n ⫽ 187), pancreatoduodenectomy (n ⫽ 42), and/or portal vein
resection (n ⫽ 63). Seventeen (8.8%) patients died of postoperative
complications: mortality was higher in gallbladder cancer than in
cholangiocarcinoma (18.0% versus 4.5%, P ⬍ 0.05); and it was also
higher in patients whose indocyanine green clearance (KICG) of the
future liver remnant after PVE was ⬍0.05 than those whose index
was ⱖ0.05 (28.6% versus 5.5%, P ⬍ 0.001). The 3- and 5-year
survival after hepatectomy was 41.7% and 26.8% in cholangiocar-
cinoma and 25.3% and 17.1% in gallbladder cancer, respectively
(P ⫽ 0.011). In 136 other patients with cholangiocarcinoma who
underwent a less than 50% resection of the liver without PVE, a
mortality of 3.7% and a 5-year survival of 27.6% were observed,
From the Division of Surgical Oncology, Department of Surgery, Nagoya
University Graduate School of Medicine, Nagoya, Japan.
Reprints: Masato Nagino, MD, PhD, Division of Surgical Oncology, De-
partment of Surgery, Nagoya University Graduate School of Medicine,
65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. E-mail:
nagino@med.nagoya-u.ac.jp.
Copyright © 2006 by Lippincott Williams & Wilkins
ISSN: 0003-4932/06/24303-0364
DOI: 10.1097/01.sla.0000201482.11876.14
underwent extended hepatectomy after PVE.
Conclusions: PVE has the potential benefit for patients with ad-
vanced biliary cancer who are to undergo extended, complex hep-
atectomy. Along with the use of PVE, further improvements in
surgical techniques and refinements in perioperative management
are necessary to make difficult hepatobiliary resections safer.
(Ann Surg 2006;243: 364 –372)
P ortal vein embolization (PVE), a procedure devised by
Makuuchi et al1,2 and Kinoshita et al,3 is performed widely
as a presurgical treatment of patients undergoing extended hep-
atectomy to minimize postoperative liver dysfunction. We
also have used this radiologic intervention and developed
the “ipsilateral approach” of percutaneous transhepatic
PVE,4 a method of “trisegment” PVE,5,6 and portal plus
arterial embolization.7 Further, we investigated the changes in
volume,8 function,9 and hemodynamics10,11 of the liver that
occur after PVE.
Many authors have documented clinical utility of PVE
before hepatectomy for metastatic liver cancer12–14 or hepa-
tocellular carcinoma.15–17 The efficacy, however, of PVE for
biliary cancer has been described in few reports with limited
numbers of patients.2,18 –20 Hepatectomy for biliary cancer,
unlike that for metastatic liver cancer or hepatocellular car-
cinoma, is a difficult procedure, often requiring caudate
lobectomy and extrahepatic bile duct resection with bilioen-
teric anastomosis, portal vein resection with reconstruction,21
and pancreatoduodenectomy.22 This surgery, especially in
patients with obstructive jaundice, is still risky and risk
reduction remains a primary challenge for hepatobiliary sur-
geons. In this study, we outlined our experiences of PVE in
240 consecutive patients with biliary cancer and discussed the
benefits of PVE before extended hepatectomy.
PATIENTS AND METHODS
Patients
This study involved 240 consecutive patients with bil-
iary cancer who underwent PVE before a planned extended

364 Annals of Surgery • Volume 243, Number 3, March 2006

Annals of Surgery • Volume 243, Number 3, March 2006
hepatectomy (right or left trisectionectomy or right hepatec-
tomy) at Nagoya University Hospital between January 1991
and May 2005. During this period, we treated 393 patients
with perihilar or intrahepatic cholangiocarcinoma (292 re-
sected, 101 unresected) and 231 patients with gallbladder
cancer (151 resected, 80 unresected). These 240 patients
accounted for 86.2% of a total of 279 patients who received
PVE during the same period.
The subjects comprised 125 men and 115 women, with
an average age of 63 ⫾ 11 years (range, 35– 83 years). A total
of 150 patients had cholangiocarcinoma (142 perihilar and 8
intrahepatic carcinomas) and the remaining 90 had advanced
gallbladder carcinoma involving the hepatic hilus. Of the 240
patients, 193 (80.4%) had jaundice on admission and then
underwent percutaneous transhepatic biliary drainage (PTBD)
before PVE. Another 23 patients without jaundice also under-
went PTBD to relieve cholangitis and/or to determine the extent
of cancer.
PVE
In principle, PVE was indicated when a future liver
remnant was estimated to be less than 40% and was per-
formed 2 to 3 weeks before a scheduled liver resection. In
jaundiced patients, the intervention was carried out after the
serum total bilirubin concentrations had decreased at least
less than 5 mg/dL following PTBD. All PVEs were per-
formed by the ipsilateral approach, in which the portal vein
was accessed by ultrasound-guided puncture of the portal
vein to be embolized.4 – 6 The right anterior portal vein was
accessed in 236 patients, the left portal vein in 3, and the right
posterior portal vein in 1. When right trisectionectomy was
planned, the right portal vein plus the left medial portal vein
were embolized. Similarly, when left trisectionectomy was
scheduled, the left portal vein plus the right anterior portal
vein were embolized, as previously reported.5,6 Four patients
whose hepatic functional reserve was markedly poor under-
went arterial embolization of the segments to be resected 3 to
6 weeks after PVE.7 The actual number of embolized portal
veins is summarized in Table 1.
TABLE 1. Type of Planned Hepatectomy and Embolized Portal Vein
Planned Hepatectomy Embolized Portal Vein
Right trisectionectomy Right and left medial
Right*
Left trisectionectomy Left and right anterior
Left†
Right anterior†
Right hepatectomy Right
Right anterior†
Right posterior†
Total
Data are no. of patients.
*Cases before development of right plus left medial portal vein embolization.
†
The remaining portal vein to be embolized was already occluded due to cancer invasion.
‡
Include 1 patient who underwent arterial embolization after PVE.
§
Include 3 patients who underwent arterial embolization after PVE.
© 2006 Lippincott Williams & Wilkins
Portal Vein Embolization for Biliary Cancer
From 1991 to 2000, fibrin glue (Bolheal; Fujisawa
Pharmaceutical, Tokyo, Japan) mixed with iodized oil (Lipi-
odol; Kodama Pharmaceutical, Tokyo, Japan) was used as the
embolic material (n ⫽ 131). After 2001, absolute ethanol
with embolization steel coils (Cook, Bloomington, IN) were
used (n ⫽ 109)16 because the Prefectural Insurance System
prohibited the use of fibrin glue because of its high price. All
PVEs were carried out by the authors, not by radiologists.
Liver Volume and Function Measurement
Computed tomography (CT) of the liver was used for
volume determination. CT scans at 3- to 10-mm intervals
from the dome to the most inferior part of the liver were
obtained with enhancement by an intravenous bolus injection
of contrast medium. Each slice of the liver was traced with
the cursor, and the corresponding area was calculated by
computer. Total volume of each lobe was obtained by adding
the volumes of individual slices.8 The volume change in the
nonembolized lobe was expressed as the ratio of the volumes
measured after and before PVE and was defined as the
hypertrophy ratio, and that of the embolized lobe was defined
as the atrophy ratio. In this study, the volume of the caudate
lobe was excluded from the volume of the nonembolized lobe
because this lobe was not embolized but was resected in
almost all cases. All patients underwent CT within 3 weeks
after PVE. In 10 (4.2%) patients, laparotomy was postponed
because of an insufficient volume of the future remnant liver,
and repeat CT was taken 2 to 3 weeks after the first post-PVE
CT. Four of the 10 patients underwent arterial embolization
after PVE,7 as mentioned above. Excluding these 4 patients,
the time between PVE and the final CT after PVE was 15 ⫾
5 days (median, 14 days; range, 6 –57 days).
Indocyanine green (ICG) tests were performed 1 to 3
days before and 11 to 13 days after PVE. ICG (0.5 mg/kg of
body weight) was administered via a peripheral vein, and
venous blood was sampled before and 5, 10, and 15 minutes
after injection. Specimens were analyzed for ICG concentra-
tions on a spectrophotometer at 805 nm. The plasma disap-
pearance rate of ICG (KICG) was calculated by linear regres-
Subsequent Surgery
Total Resected Unresected
23 20 3
4 4 0
26 22‡ 4
5 5 0
8 6 2
160 126§ 34
9 7 2
5 3 2
240 193 (80.4%) 47 (19.6%)
365
Nagino et al Annals of Surgery • Volume 243, Number 3, March 2006

sion analysis of plasma ICG concentrations.9 KICG of the
nonembolized (future remnant) lobe was also calculated us-
ing the formula, KICG⫻ % volume of the nonembolized
lobe/100.
Other liver function parameters, such as the serum total
bilirubin, aspartate transaminase, and alanine transaminase
concentrations, were measured regularly before and after
PVE, using standard laboratory methods.
Statistics
Results are expressed as mean ⫾ SD. Continuous data
were evaluated using the paired and unpaired Student t tests.
Categorical data were compared using the ␹2 test and Fisher
exact test, where appropriate. Postoperative survival was
calculated using the Kaplan-Meier method. Differences in
survival curves were compared using the log-rank test. P ⬍
0.05 was considered statistically significant.
RESULTS
PVE-Related Complications
A few patients developed an inflammatory response
manifested by mild fever and/or mild abdominal pain or
discomfort. Transaminase concentrations were elevated, usu-
ally less than triple, in most patients but returned to baseline
within a week. Hepatic enzyme variations after PVE had no
clinical correlation. Serum total bilirubin remained near pre-
embolization concentrations in all patients.
We encountered rare complications in 2 patients. In 1
patient with a hilar cholangiocarcinoma, hypersplenism with
splenomegaly developed after PVE because the right portal
vein was embolized despite marked stenosis of the left portal
vein due to cancer invasion.23 This patient underwent right
hepatectomy with caudate lobectomy and portal vein resec-
tion and reconstruction, as scheduled. Postoperative recovery
was good, but the patient died of recurrence 37 months after
surgery. In another patient with advanced gallbladder cancer,
extensive portal and mesenteric vein thrombosis occurred
after PVE, due to a protein S deficiency.24 After thrombolytic
therapy, surgery was done 51 days after PVE but resulted in
only a laparotomy due to locally advanced cancer. The
patient died of cancer 12 months after laparotomy.
Overall, there were no complications requiring blood
transfusion or radiologic or surgical intervention.
Surgical Outcome After PVE
Of the 240 patients with PVE, 47 (19.6%) did not undergo
subsequent hepatectomy (Table 1): 7 patients showed disease
progression severe enough to preclude curative resection
during the waiting period after PVE and the remaining 40
underwent only laparotomy due to peritoneal dissemination,
liver metastasis, and/or locally advanced cancer. The inci-
dence of unresectability after PVE was significantly higher
in gallbladder cancer than in cholangiocarcinoma (32.2% ⫽
29/90 versus 12.0% ⫽ 18 of 150, P ⬍ 0.005). PVE-related
inconvenience was not encountered in the outcome of these
unresected patients.
A total of 193 patients underwent hepatectomy (Table
2). En bloc resection of the caudate lobe and extrahepatic bile
duct was performed in 187 (96.9%) patients, combined pan-
creatoduodenectomy (PD) in 42 (21.8%), portal vein resec-
tion with reconstruction in 63 (32.6%), and hepatic artery
resection with reconstruction in 2 (1.0%). Simple hepatec-
tomy without combined resection was performed in only 6
patients. All patients underwent regional lymph node dissec-
tion, and some selected patients underwent additional
paraaortic lymph node dissection. Operative time was 714 ⫾
166 minutes (median, 710 minutes; range, 350 –1210 min-
utes), and blood loss was 2860 ⫾ 2529 mL (median, 1940
mL; range, 235–17,114 mL).
Of the 193 patients who underwent hepatectomy, 17
(8.8%) patients died of postoperative complications, includ-
ing intraabdominal bleeding (n ⫽ 2), myocardial infarction
(n ⫽ 1), and liver failure or multiple organ failure (n ⫽ 14)
(Table 3). Surgical mortality was significantly higher in

TABLE 2. Surgical Procedures in 193 Patients Who Underwent Resection

Total Cholangiocarcinoma Gallbladder Carcinoma
Procedure (n ⴝ 193) (n ⴝ 132) (n ⴝ 61)
Type of hepatectomy*
S 1, 4, 5, 6, 7, 8 24 (12.4%) 18 6
S 1, 2, 3, 4, 5, 8 33 (17.1%) 33 0
S 1, 4a, 5, 6, 7, 8 44 (22.8%) 0 44
S 1, 5, 6, 7, 8 86 (44.6%) 75 11
S 5, 6, 7, 8 6 (3.1%) 6 0
Combined resection
Extrahepatic bile duct resection with hepaticojejunostomy 187 (96.9%) 126 61
Portal vein resection with reconstruction 63 (32.6%) 39 24
Pancreatoduodenectomy 42 (21.8%) 21 21
Partial resection of the duodenum 5 (2.6%) 0 5
Hepatic artery resection with reconstruction 2 (1.0%) 2 0
Right hemicolectomy 1 (0.5%) 0 1
*Expressed as Couinaud’s hepatic segment(s) resected.
S4a, inferior part of segment 4.

366 © 2006 Lippincott Williams & Wilkins

Annals of Surgery • Volume 243, Number 3, March 2006 Portal Vein Embolization for Biliary Cancer

TABLE 3. Details of 17 Hospital Deaths After Extended Hepatectomy

Future Remnant Liver
Surgery After PVE
Age (yr)/ Blood Loss Volume Volume
Case No. Sex Disease Procedure (mL) (cm3) (%) KICG Cause of Death
1 74/M GBC S14a5678 ⫹ PD 9100 228 24 0.027 Multiple organ failure (71 days)
2 67/M CC S145678 1758 268 24 0.031 Multiple organ failure (87 days)
3 72/M GBC S14a5678 ⫹ PV 2969 414 34 0.039 Liver failure (53 days)
4 80/M CC S15678 2069 332 33 0.041 Multiple organ failure (57 days)
5 74/M CC S123458 ⫹ PV 5700 868 37 0.042 Liver failure (71 days)
6 71/M GBC S15678 ⫹ PV 10835 522 48 0.044 Liver failure (46 days)
7 72/M GBC S14a5678 1404 319 35 0.046 Multiple organ failure (88 days)
8 70/M GBC S14a5678 ⫹ PD ⫹ PV 7037 384 37 0.048 Multiple organ failure (72 days)
9 70/F GBC S14a5678 ⫹ PD 4922 286 32 0.056 Multiple organ failure (44 days)
10 67/M CC S15678 2803 390 42 0.058 Intra-abdominal bleeding (12 days)
11 62/F GBC S15678 ⫹ PV 2056 513 56 0.063 Myocardial infarction (44 days)
12 74/M CC S123458 ⫹ PV 3594 588 50 0.067 Multiple organ failure (75 days)
13 60/F GBC S14a5678 ⫹ PD ⫹ PV 3263 539 49 0.070 Multiple organ failure (46 days)
14 55/F GBC S14a5678 ⫹ PD ⫹ PV 3156 504 39 0.071 Multiple organ failure (51 days)
15 56/F GBC S14a5678 ⫹ PD ⫹ PV 5955 420 49 0.073 Intra-abdominal bleeding (43 days)
16 76/F CC S145678 ⫹ PV 1531 303 37 0.077 Multiple organ failure (98 days)
17 67/M GBC S14a5678 17114 668 49 0.084 Liver failure (25 days)
Note that cases are arranged in order of KICG of future liver remnant after PVE.
GBC indicates gallbladder cancer; CC, cholangiocarcinoma; PVE, portal vein embolization; PD, pancreatoduodenectomy; PV, portal vein resection.

gallbladder cancer than in cholangiocarcinoma (18.0% versus
4.5%, P ⬍ 0.005). Mortality also was higher in hepatectomy
with combined PD than in that without PD, although statis-
tically not significant. With time, mortality has improved
yearly with the most recent period showing an acceptable
mortality of 4.8% (Table 4).
During the same period, 136 other patients with chol-
angiocarcinoma (126 perihilar and 10 intrahepatic carcino-
mas) underwent a less than 50% resection of the liver without
PVE. The type of hepatectomy performed was as follows:
resection of segments 1, 2, 3, and 4 in 112 patients, resection
of segments 1, 4, 5, and 8 in 8, resection of segments 1, 5, and
8 in 5, resection of segment 1 in 5, and other resections in 6.
Extrahepatic bile duct resection with reconstruction was per-
formed in 128 patients, combined portal vein resection in 35,
and combined pancreatoduodenectomy in 18. The mortality
of these 136 patients was 3.7% (5 of 136), being similar to
mortality of the 132 patients with cholangiocarcinoma who
underwent extended hepatectomy after PVE.
Changes in Hepatic Lobe Volume After PVE
Changes in hepatic lobe volume after PVE were ana-
lyzed in 189 of the 193 hepatectomized patients (4 patients
who underwent portal plus arterial embolization were ex-
cluded). The calculated volume of the nonembolized lobe
increased from 361 ⫾ 119 cm3 (range, 103–700 cm3) before
PVE to 460 ⫾ 120 cm3 (range, 239 –747 cm3) after PVE
(P ⬍ 0.0001), whereas the volume of the embolized lobe
decreased from 688 ⫾ 167 cm3 (range, 341–1172 cm3) before
PVE to 581 ⫾ 149 cm3 (range, 261–1009 cm3) after PVE (P ⬍
0.0001). The volume of the whole liver exhibited no signif-
icant changes. In terms of the volumetric ratio to the whole
liver, the volume of the nonembolized lobe increased from
33% ⫾ 8% (range, 15%– 49%) before PVE to 43% ⫾ 8%

TABLE 4. Mortality After Extended Hepatectomy Following Portal Vein Embolization

1991–1995 1996–2000 2001– Total
Disease
Cholangiocarcinoma
Gallbladder carcinoma
6.3% (1/16)
33.3% (4/12)
7.5% (4/53)
14.3% (4/28)
1.6% (1/63)
14.3% (3/21)
4.5% (6/132)
18.0% (11/61) *兴
Procedure
Hepatectomy without PD 15.0% (3/20) 9.4% (6/64) 3.0% (2/67) 7.3% (11/151)
Hepatectomy with PD 25.0% (2/8) 11.8% (2/17) 11.8% (2/17) 14.3% (6/42)
Total 17.9% (5/28) 9.9% (8/81) 4.8% (4/84) 8.8% (17/193)
*P ⬍ 0.005 between the two groups.
PD indicates pancreatoduodenectomy.

© 2006 Lippincott Williams & Wilkins 367

Nagino et al Annals of Surgery • Volume 243, Number 3, March 2006

TABLE 5. Potential Factors Affecting Hypertrophy and Atrophy After PVE

Hypertrophy Ratio of the Atrophy Ratio of the
Nonembolized Lobe (%) P Embolized Lobe (%) P
Gender
Male (n ⫽ 97) 130 ⫾ 22 NS 86 ⫾ 10 NS
Female (n ⫽ 92) 135 ⫾ 21 83 ⫾ 12
Embolic material
Fibrin glue (n ⫽ 105) 132 ⫾ 21 NS 86 ⫾ 11 NS
Absolute ethanol (n ⫽ 84) 134 ⫾ 22 83 ⫾ 10
Jaundice on admission
Absent (n ⫽ 32) 131 ⫾ 20 NS 86 ⫾ 11 NS
Present (n ⫽ 157) 133 ⫾ 22 85 ⫾ 10
Diabetes mellitus
Absent (n ⫽ 167) 133 ⫾ 22 NS 85 ⫾ 11 NS
Present (n ⫽ 22) 127 ⫾ 21 88 ⫾ 12

(range, 23%– 68%) after PVE (P ⬍ 0.0001). The hypertrophy Staging and Survival in Resected Patients
ratio of the nonembolized lobe was 133% ⫾ 24% (range, Staging of the tumor was described using the TNM
100%–222%), and the atrophy ratio of the embolized lobe Classification of Malignant Tumors by the International
was 85% ⫾ 11% (range, 55%–115%). In the 47 patients with Union Against Cancer (6th edition, 2002).25 Most of the
unresectable tumor, hypertrophy and atrophy ratios were patients with cholangiocarcinoma and all of the patients with
130% ⫾ 27% and 86% ⫾ 13%, respectively, being similar to
those in the hepatectomized patients. Gender, embolic mate-
rial, jaundice on admission, or diabetes mellitus did not affect
volume dynamics after PVE (Table 5).

Association Between Hepatic Functional

Reserve and Surgical Outcome
In the 193 hepatectomized patients, KICG increased
from 0.151 ⫾ 0.034 (range, 0.066 – 0.265) before PVE to
0.157 ⫾ 0.033 (range, 0.080 – 0.259) after PVE (P ⬍ 0.05).
KICG of the future remnant (nonembolized) lobe also im-
proved from 0.050 ⫾ 0.016 (range, 0.018 – 0.094) before
PVE to 0.066 ⫾ 0.016 (range, 0.027– 0.118) (P ⬍ 0.0001).
Before PVE 86 (44.6%) patients had a KICG of the future
liver remnant of ⱖ0.05, while after PVE 165 (85.5%) patients
had a KICG of ⱖ0.05 (Fig. 1).
The hypertrophy ratio of the nonembolized lobe was
not different between the 17 nonsurvivors and the 176 sur-
vivors (136% ⫾ 24% versus 132% ⫾ 21%). However, KICG
of the future liver remnant after PVE was worse in the 17
nonsurvivors than in the 176 survivors (0.055 ⫾ 0.017 versus
0.066 ⫾ 0.016, P ⬍ 0.05). In 28 patients whose KICG of the
future liver remnant after PVE was ⬍0.05, 8 (28.6%) patients
died of postoperative complications, while in 165 patients
whose KICG of the future liver remnant after PVE was
ⱖ0.05, 9 (5.5%) patients died (P ⬍ 0.001) (Fig. 2; Table 3).
In 3 (cases 10, 11, and 15 in Table 3) of these 9 patients, the
cause of death was not directly related to postoperative liver
failure. Two other patients (cases 13 and 14) had a markedly
fatty liver despite having improved ICG test results, which
probably led to organ failure. In another patient (case 17),
liver failure developed due to massive intraoperative bleed- FIGURE 1. Changes in plasma disappearance rate of indo-
ing. The remaining 3 (cases 9, 12, and 16) had intractable cyanine green (KICG) of the nonembolized (future remnant)
septic complications, which resulted in organ failure. lobe before and after portal vein embolization (PVE).

368 © 2006 Lippincott Williams & Wilkins

Annals of Surgery • Volume 243, Number 3, March 2006 Portal Vein Embolization for Biliary Cancer

TABLE 6. TNM Classification and Staging* in 193 Resected

Patients
Cholangiocarcinoma Gallbladder Carcinoma
(n ⴝ 132) (n ⴝ 61)
pT
1 1 0
2 7 0
3 79 17
4 45 44
pN
0 61 22
1 71 39
pM
0 107 42
1 25 19
pStage
Ia 1 0
Ib 7 0
IIa 36 5
IIb 34 8
III 29 29
IV 25 19
*According to UICC, 6th edition.

patients with cholangiocarcinoma who underwent extended

hepatectomy after PVE (Fig. 3).

FIGURE 2. Association between the surgical outcome and
plasma disappearance rate of indocyanine green (KICG) of
the nonembolized (future remnant) lobe after portal vein
embolization (PVE).
gallbladder cancer had pT3 or pT4 diseases. More than half
of the patients had lymph node metastases. pM1 disease was
found in 25 (18.9%) of the patients with cholangiocarcinoma
(paraaortic node metastases in 15, liver metastases in 6, and
localized dissemination in 4) and 19 (31.1%) of the patients
with gallbladder cancer (paraaortic node metastases in 16,
liver metastases in 4, and localized dissemination in 4; du-
plicated in 5 patients) (Table 6).
The 3- and 5-year survival after extended hepatectomy
following PVE (including all deaths) was 41.7% and 26.8%
in cholangiocarcinoma and 25.3% and 17.1% in gallbladder
cancer, respectively. Survival was significantly improved in
cholangiocarcinoma, as compared with gallbladder cancer
(P ⫽ 0.011). Sixteen patients with cholangiocarcinoma and 5
patients with gallbladder cancer survived more than 5 years
after extended hepatectomy. Survival for the 136 patients
with cholangiocarcinoma who underwent a less than 50%
resection of the liver was almost identical to that of the 132
DISCUSSION
Today, elective liver resection for hepatocellular carci-
noma or metastatic liver cancer can be performed with an
acceptable mortality.26,27 Hepatectomy, however, for biliary
hilar malignancies, including perihilar cholangiocarcinoma
and gallbladder carcinoma involving the hepatic hilus, re-
mains a greater risk.28 –30 Previously, we studied the risk of
postoperative bacteremia in 407 patients who underwent
elective liver resection. Multivariate analysis revealed that
presence of obstructive jaundice on admission increased post-
operative bacteremic risk by 4.7 times and performance of
extended (⬎50%) hepatectomy increased the risk by 2.7
times.31 This indicates that, when a biliary cancer patient with
obstructive jaundice undergoes extended hepatectomy, bac-
teremic risk increases by 12.7 times. Belghiti et al32 also
analyzed operative risks in 747 hepatectomized patients and
showed that the mortality of patients with jaundice was
extremely high (21%), as compared with that of patients with
a normal liver. In addition, they demonstrated that a com-
bined extrahepatic procedure was the only independent pre-
dictor of in-hospital death in patients with malignancy (rela-
tive risk of 7.5). In our series, 80% of the subjects had
obstructive jaundice; all of the resected patients underwent
extended hepatectomy; and 97% of the hepatectomized pa-
tients received extrahepatic procedures. Considering difficul-
ties arising from such a study population, the overall mortal-
ity of 8.8% in this study is acceptable.
Many studies have shown that PVE is effective in induc-
ing hypertrophy of nonembolized hepatic segments.1– 8,12–20

© 2006 Lippincott Williams & Wilkins 369

Nagino et al
FIGURE 3. Survival after hepatectomy.
This study also demonstrated a sizable atrophy/hypertrophy
complex after PVE. The potential benefits, however, of this
intervention have not been validated by a randomized con-
trolled trial. In addition, indications for this intervention are
still unclear because of the few data regarding the minimal
hepatic volume required to tolerate surgery without serious
complications. For normal livers, some authors have stressed
that more than 40% of the total liver volume must be
preserved to make the resection safe,33 but the general con-
sensus is that a 25% to 30% remnant is the minimum essential
volume.19,20,34,35 Vauthey et al35 reported that major postop-
erative complications increased when the estimated hepatic
remnant was less than 25%. A larger remnant may be nec-
essary even in normal livers when complex hepatectomy is
planned. Farges et al36 conducted a prospective, but not
randomized, study to assess the benefits of PVE before right
hepatectomy. They demonstrated that PVE has no beneficial
effect on the postoperative course in patients with normal livers
but significantly reduced postoperative complications in patients
with chronic liver diseases. Based on these previous studies,
PVE before extended hepatectomy may be considered in pa-
tients with damaged livers, and also even in patients with normal
livers when planned procedure is complex or estimated hepatic
remnant is less than 25% to 30%.19,34
We demonstrated that the KICG of the future liver
remnant increased after PVE. Before PVE only 86 (44.6%) of
the patients had KICG of the future liver remnant of ⱖ0.05,
while after PVE 165 (85.5%) of the patients had KICG
ⱖ0.05. We also showed that the postoperative mortality was
significantly greater when the KICG of the future liver
remnant was ⬍0.05 (28.6% versus 5.5%). Recently, Cherqui
et al37 recommended “rapid hepatectomy” without preopera-
tive biliary decompression and portal vein embolization in
jaundiced patients with biliary hilar malignancies. If our
patients had undergone “rapid hepatectomy” without preop-
erative intervention, the operative mortality may have in-
370
Annals of Surgery • Volume 243, Number 3, March 2006
creased up to at least 18.3% 关⫽ (86 ⫻ 0.055 ⫹ 107 ⫻
0.286)/193兴. In addition, this study demonstrated that in
cholangiocarcinoma the mortality was similar in patients who
underwent extended hepatectomy following PVE and those
who underwent a less than 50% resection of the liver without
PVE (4.5% versus 3.7%). Furthermore, the survival for these
2 patients groups was similar. Although this study was
retrospective, our observations clearly indicate that PVE has
potential benefits clinically. There is a possibility, however,
that PVE was overused. For example, PVE might have been
unnecessary for patients whose KICG of the future liver
remnant before PVE was good, ie, ⬎0.08. We agree with
Abdalla et al38 who stated that “randomized trial cannot be
recommended to test the efficacy of PVE, for it would be
unethical to deny the benefit of the technique and safer
resection to patients who are otherwise poor candidates for
resection based on inadequate liver size or function.” Con-
tinued prospective analyses of the association between he-
patic volume and function and morbidity and mortality
should clarify the appropriate indication of PVE.
In this study, the hypertrophy ratio of the nonembolized
lobe was not different between the 17 nonsurvivors and the
176 survivors, while KICG of the future liver remnant after
PVE was significantly lower in the former than in the latter.
This observation indicates that hepatic function as well as
liver volume is important as a guide to decision-making in
liver resection.33 In this context, KICG of the future liver
remnant is useful, as this index includes elements of both
function and volume. Based on our results, 0.05 of KICG of
the future liver remnant may be a “cutoff” value for deciding
liver resection. Actually, in the most recent 3 years, we have
used this value for this sake; however, further study is
required to validate whether this cutoff value is appropriate.
Results of PVE in cholangiocarcinoma, including both
the surgical outcome and survival, were acceptable, whereas
the results of advanced gallbladder cancer were poor. First, the
© 2006 Lippincott Williams & Wilkins
Annals of Surgery • Volume 243, Number 3, March 2006
incidence of unresectability after PVE was 32.2% in gallblad-
der cancer, which indicated that approximately one third of
PVEs in gallbladder cancer were unnecessary. Therefore,
staging laparoscopy before PVE is essential, and recently we
have used this diagnostic modality selectively for patients
with gallbladder cancer. Weber et al39 demonstrated that
staging laparoscopy before surgery in patients with biliary
cancer was more useful in cases of gallbladder cancer, than in
cholangiocarcinoma. Second, mortality after extended hepa-
tectomy was significantly higher (approximately 4 times) in
gallbladder cancer than in cholangiocarcinoma. The main
reason for this poor outcome is that combined resections,
including pancreatoduodenectomy and/or portal vein resec-
tion, were performed more frequently in patients with gall-
bladder cancer. Some of the patients with gallbladder cancer
had extremely advanced disease, which impaired the host
immune function40 and may have contributed to the poor
outcome. Survival also was worse in gallbladder cancer
compared with cholangiocarcinoma. All of our patients with
gallbladder cancer had advanced disease with biliary hilar
invasion. Most of these patients were considered to be be-
yond the scope of surgical resection in Western centers with
few 5-year survivors reported.41,42 Thus, the fact that 5
patients survived more than 5 years suggests a potential
benefit of the aggressive surgery after PVE.
CONCLUSION
Although possible overutilization cannot be denied,
PVE may benefit patients with advanced biliary cancer un-
dergoing extended, complex hepatectomy. PVE, however, is
not an omnipotent tool; therefore, further improvements in
surgical techniques and refinements in perioperative manage-
ment are necessary to make difficult hepatobiliary resections
safer.
REFERENCES
1. Makuuchi M, Takayasu K, Takuma T, et al. Preoperative transcatheter
embolization of the portal venous branch for patients receiving extended
lobectomy due to the bile duct carcinoma 关in Japanese兴. J Jpn Soc Clin
Surg. 1984;45:14 –20.
2. Makuuchi M, Thai BL, Takayasu K, et al. Preoperative portal emboli-
zation to increase safety major hepatectomy for hilar bile duct carci-
noma: a preliminary report. Surgery. 1990;107:521–527.
3. Kinoshita H, Sakai K, Hirohashi K, et al. Preoperative portal vein emboli-
zation for hepatocellular carcinoma. World J Surg. 1986;10:803– 808.
4. Nagino M, Nimura Y, Kamiya J, et al. Selective percutaneous transhe-
patic embolization of the portal vein in preparation for extensive liver
resection: the ipsilateral approach. Radiology. 1996;200:559 –563.
5. Nagino M, Nimura Y, Kamiya J, et al. Right or left trisegment portal
vein embolization before hepatic trisegmentectomy for hilar bile duct
carcinoma. Surgery. 1995;117:677– 681.
6. Nagino M, Kamiya J, Kanai M, et al. Right trisegment portal vein
embolization for biliary tract carcinoma: technique and clinical utility.
Surgery. 2000;127:155–160.
7. Nagino M, Kanai M, Morioka A, et al. Portal and arterial embolization
before extensive liver resection in patients with markedly poor func-
tional reserve. J Vasc Interv Radiol. 2000;11:1063–1068.
8. Nagino M, Nimura Y, Kamiya J, et al. Changes in hepatic lobe volume
in biliary tract carcinoma patients after right portal vein embolization.
Hepatology. 1995;21:434 – 439.
9. Uesaka K, Nimura Y, Nagino M. Changes in hepatic lobar function after
right portal vein embolization: an appraisal by biliary indocyanine green
excretion. Ann Surg. 1996;223:77– 83.
© 2006 Lippincott Williams & Wilkins
Portal Vein Embolization for Biliary Cancer
10. Goto Y, Nagino M, Nimura Y. Doppler estimation of portal blood flow
after percutaneous transhepatic portal vein embolization. Ann Surg.
1998;228:209 –213.
11. Kito Y, Nagino M, Nimura Y. Doppler evaluation of hepatic arterial
blood flow velocity after percutaneous transhepatic portal vein emboli-
zation. AJR Am J Roentgenol. 2001;176:909 –912.
12. Kawasaki S, Makuuchi M, Kakazu T, et al. Resection for multiple
metastatic liver tumors after portal embolization. Surgery. 1994;115:
674 – 677.
13. Baere T, Roche A, Elias D, et al. Preoperative portal vein embolization
for extension of hepatectomy indications. Hepatology. 1996;24:1386 –
1391.
14. Azoulay D, Castaing D, Smail A, et al. Resection of nonresectable liver
metastases from colorectal cancer after percutaneous portal vein embo-
lization. Ann Surg. 2000;231:480 – 486.
15. Lee KC, Kinoshita H, Hirohashi K, et al. Extension of surgical indica-
tions for hepatocellular carcinoma by portal vein embolization. World
J Surg. 1993;17:109 –115.
16. Shimamura T, Nakajima Y, Une Y, et al. Efficacy and safety of
preoperative percutaneous transhepatic portal embolization with abso-
lute ethanol: a clinical study. Surgery. 1997;83:135–141.
17. Yamakado K, Takeda K, Matsumura K, et al. Regeneration of the
un-embolized liver parenchyma following portal vein embolization.
J Hepatol. 1997;27:871– 880.
18. Imamura H, Shimada R, Kubota M, et al. Preoperative portal vein
embolization: an audit of 84 patients. Hepatology. 1999;29:1099 –1105.
19. Hemming AW, Reed AI, Howard RJ, et al. Preoperative portal vein
embolization for extended hepatectomy. Ann Surg. 2003;237:686 –
691.
20. Abdalla EK, Barnett CC, Doherty D, et al. Extended hepatectomy in
patients with hepatobiliary malignancies with and without preoperative
portal vein embolization. Arch Surg. 2002;137:675– 681.
21. Ebata T, Nagino M, Kamiya J, et al. Hepatectomy with portal vein
resection for hilar cholangiocarcinoma: audit of 52 consecutive cases.
Ann Surg. 2003;238:720 –727.
22. Nimura Y, Hayakawa N, Kamiya J, et al. Hepatopancreatoduodenectomy
for advanced carcinoma of the biliary tract. Hepatogastroenterology. 1991;
38:170 –175.
23. Nagino M, Yoshihara M, Nimura Y. Acute hypersplenism with spleno-
megaly after portal vein embolization. Surgery. 2002;131:695.
24. Ohkubo M, Nagino M, Kamiya J, et al. Portal and mesenteric vein
thrombosis after portal vein embolization in a patient with protein
S deficiency. J Hepatobiliary Pancreat Surg. 2004;11:338 –341.
25. International Union Against Cancer (UICC). TNM Classification of
Malignant Tumors, 6th ed. New York: Wiley-Liss, 2002.
26. Tsao J, Loftus JP, Nagorney DM, et al. Trends in morbidity and
mortality of hepatic resection for malignancy: a matched comparative
study. Ann Surg. 1994;220:199 –205.
27. Man K, Fan ST, Ng IOL, et al. Prospective evaluation of Pringle
maneuver in hepatectomy for liver tumors by a randomized study. Ann
Surg. 1997;226:704 –713.
28. Pichlmayr R, Weimann A, Klempnauer J, et al. Surgical treatment in
proximal bile duct cancer: a single-center experience. Ann Surg. 1996;
224:628 – 638.
29. Neuhaus P, Jonas S, Bechstein WO, et al. Extended resection for hilar
cholangiocarcinoma. Ann Surg. 1999;230:808 – 819.
30. Tsao JI, Nimura Y, Kamiya J, et al. Management of hilar cholangiocar-
cinoma: comparison of an American and a Japanese experience. Ann
Surg. 2000;232:166 –174.
31. Shigeta H, Nagino M, Kamiya J, et al. Bacteremia after hepatectomy: an
analysis of single center, 10-year experience with 407 patients. Lange-
nbecks Arch Surg. 2002;387:117–124.
32. Belghiti J, Hiramatsu K, Benoist S, et al. Seven hundred forty-seven
hepatectomies in the 1990s: an update to evaluate the actual risk of liver
resection. J Am Coll Surg. 2000;191:38 – 46.
33. Kubota K, Makuuchi M, Kusaka K, et al. Measurement of liver volume
and hepatic functional reserve as a guide to decision-making in resec-
tional surgery for hepatic tumors. Hepatology. 1997;26:1176 –1181.
34. Yigitler C, Farges O, Kianmanesh R, et al. The small remnant liver after
major liver resection: how common and how relevant? Liver Transpl.
2003;9(suppl):18 –25.
371
Nagino et al
35. Vauthey JN, Chaoui A, Do KA, et al. Standardized measurement of the
future liver remnant prior to extended liver resection: methodology and
clinical associations. Surgery. 2000;127:512–519.
36. Farges O, Belghiti J, Kianmanesh R, et al. Portal vein embolization before
right hepatectomy: prospective clinical trial. Ann Surg. 2003;237:208 –217.
37. Cherqui D, Benoist S, Malassagne B, et al. Major liver resection for
carcinoma in jaundiced patients without preoperative biliary drainage.
Arch Surg. 2000;135:302–308.
38. Abdalla EK, Hicks ME, Vauthey JN. Portal vein embolization: rationale,
technique and future prospects. Br J Surg. 2001;88:165–175.
39. Weber SM, DeMatteo RP, Fong Y, et al. Staging laparoscopy in patients
372
Annals of Surgery • Volume 243, Number 3, March 2006
with extrahepatic biliary carcinoma: analysis of 100 patients. Ann Surg.
2002;235:392–399.
40. Cubillos L, Gonzalez S, Sepulveda C, et al. Immunological evaluation of
patients with invasive carcinoma of the gallbladder. J Cancer Res Clin
Oncol. 1993;119:497–500.
41. Fong Y, Jarnagin W, Blumgart LH. Gallbladder cancer: comparison of
patients presenting initially for definitive operation with those presenting
after prior noncurative intervention. Ann Surg. 2000;232:557–569.
42. Ito H, Martos E, Brooks DC, et al. Treatment outcomes associated with
surgery for gallbladder cancer: a 20-year experience. J Gastrointest
Surg. 2004;8:183–190.
© 2006 Lippincott Williams & Wilkins