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ORIGINAL ARTICLE

Associating Liver Partition and Portal Vein Ligation for Staged


Hepatectomy Offers High Oncological Feasibility With Adequate
Patient Safety
A Prospective Study at a Single Center
Fernando A. Alvarez, MD, Victoria Ardiles, MD, Martin de Santibanes, MD, Juan Pekolj, MD, PhD,
and Eduardo de Santibanes, MD, PhD

Objective: To determine the safety, feasibility, and efficacy of associating


liver partition and portal vein ligation for staged hepatectomy (ALPPS) in a
single high-volume hepatobiliary center.
Background: The ALPPS approach allows achieving resectability of liver
malignancies by a rapid and large future liver remnant (FLR) hypertrophy.
However, this proposal has been associated with high morbidity and mortality
rates.
Methods: This was a single-cohort, prospective, observational study [NCT
02164292]. Between June 2011 and April 2014, patients with liver malignancies considered unresectable due to an insufficient FLR who underwent
ALPPS were included.
Results: Thirty patients were treated. Median age was 58.6 years (range =
3581) and 19 patients were males (63%). In a median of 6 days (range = 4
67), the median FLR hypertrophy was 89.7% (range = 21287). Twenty-nine
patients completed the second stage (97% feasibility). Morbidity according
to the Dindo-Clavien classification was 53% (grade IIIa 43% and grade
IIIb 31%). The mortality rate was 6.6%. Total parenchymal transection was
identified as an independent risk factor for complications (P = 0.049). There
was not significant difference in terms of FLR hypertrophy between total or
partial parenchymal transection (P = 0.45). Median hospital stay was 16 days
(range = 1162). The overall and disease-free survival at 1 year was 78% and
67% and at 2 years was 63% and 40%, respectively.
Conclusions: This prospective study on the largest reported single-center experience shows that ALPPS has acceptable morbidity and mortality, together
with a high oncological feasibility and hypertrophic efficacy. Partial parenchymal transection seems to reduce morbidity without negatively impacting FLR
hypertrophy.
Keywords: ALPPS, hepatectomy, liver failure, hypertrophy, scintigraphy
(Ann Surg 2015;261:723732)

omplete resection of liver malignancies remains as the best treatment to offer the possibility of long-term survival or cure.1 At
diagnosis, many patients have locally advanced disease that often
precludes a curative resection. During the past 2 decades, a better assessment of resectability through modern imaging techniques

From the General Surgery Service, Hospital Italiano de Buenos Aires, Buenos
Aires, Argentina.
Disclosure: None of the authors has any direct or indirect commercial/financial
incentive associated with the publication of this article. The funding involved
in this work has been provided by our institution.
Reprints: Eduardo de Santibanes, MD, PhD, General Surgery Service and
Liver Transplant Unit, Hospital Italiano de Buenos Aires, Juan D. Peron
4190, C1181ACH, Buenos Aires, Argentina. E-mail: eduardo.desantibanes@
hospitalitaliano.org.ar.
C 2014 Wolters Kluwer Health, Inc. All rights reserved.
Copyright 
ISSN: 0003-4932/14/26104-0723
DOI: 10.1097/SLA.0000000000001046

Annals of Surgery r Volume 261, Number 4, April 2015

along with new multimodal therapies and the introduction of modern chemotherapy regimens have allowed to increase the pool of
candidates for surgical treatment in patients with locally advanced
disease.1,2 The current principles for safe liver resections focus
mainly on the liver parenchyma that remains after resection rather
than the liver resected.24 In fact, one of the main conditioning factors
of posthepatectomy liver failure (PHLF) is the amount and quality
of future liver remnant (FLR).3,4 The induction of hypertrophy of
healthy parenchyma using either portal vein embolization (PVE) or
ligation (PVL), in the setting of 1-stage or 2-stage liver resections,
is nowadays considered the standard of care for patients with locally
advanced liver tumors and small FLR.2,58 However, the need for long
intervals between interventions (612 weeks) results in resectability
rates that rarely exceed 60% to 80%.6,7
In 2012, Schnitbauer et al9 introduced a novel 2-stage technique that allowed tumor resection in 25 patients from 5 German
centers with marginally resectable or primarily nonresectable disease
by means of a rapid and large FLR hypertrophy. This technique was
later popularized with the acronym ALPPS for Associating Liver
Partition and Portal Vein Ligation for Staged Hepatectomy.10 The
promising preliminary results obtained with this new surgical proposal in terms of hypertrophy and the possibility of challenging the
previous methods generated a pronounced reaction in the surgical
community worldwide that has rarely been seen in the history of
hepatopancreatobiliary (HPB) surgery.11 However, the possibility of
achieving a short-term hypertrophy and high resectability rates has
been counteracted in most published series by an increased risk of
morbidity and mortality.9,1216 The aim of this study was to prospectively evaluate the results with the ALPPS procedure in a single
high-volume HPB center, with special emphasis in patient safety and
oncological feasibility of this new 2-stage strategy.

PATIENTS AND METHODS


Design and Ethics
This is a single-cohort, prospective, observational study. Data
for all patients undergoing 2-stage hepatectomies with the ALPPS
approach at the HPB Surgery Section of the Hospital Italiano de
Buenos Aires between June 2011 and April 2014 was analyzed on an
intention to treat basis. Patient demographics, clinical characteristics
(body mass index, anesthesiological risk score, Charlson comorbidity index, preoperative chemotherapy), tumor type, surgical details,
FLR hypertrophy, postoperative liver function, postoperative complications, length of hospital stay, and survival were recorded. Informed
consent was obtained for all patients before surgery and the Hospital
Italiano University Ethics Committee gave ethical approval to perform
this study (N 1942). The study protocol has been registered on ClinicalTrials.gov database (identifier NCT02164292). In addition, every
patient of this study entered the ALPPS International Registry.17
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Annals of Surgery r Volume 261, Number 4, April 2015

Alvarez et al

Study Aims

Surgical Technique

Primary endpoints were as follows: (1) Patient safety: morbidity and mortality of the approach; (2) Oncological feasibility:
percentage of patients that complete both stages of the ALPPS approach. Secondary endpoints were to determine the following: (1)
Hypertrophic efficacy: achievement of sufficient short-term (10
days) hypertrophy of the FLR; (2) Short-term oncological results:
disease-free survival (DFS) and overall survival (OS); (3) Clinical or
operative risk factors of postoperative complications and a reduced
kinetic growth rate (KGR 35 cc per day) of the FLR.

The ALPPS was performed with curative intent using the technique previously described, either as an open or as a laparoscopic
approach.20,21 Briefly, during the first stage a complete tumor resection (clean-up) of the FLR was performed if bilateral disease
was present, either trough anatomical or atypical resections.22 Subsequently, the portal vein of the diseased hemiliver (DH) was divided
and either total (up to the inferior vena cava) or partial (up to the
middle hepatic vein) parenchymal transection using the Cavitron Ultrasonic Surgical Aspirator (Valley Lab, Boulder, CO) was carried
out. The decision to perform total or partial parenchymal transection
was not surgeon-dependent. Total transection was performed only
in patients with tumors located close to the FLR boundaries or its
vasculobiliary pedicles to isolate the tumor and prevent FLR infiltration in the interval period. At the end of the first stage, the DH was
either wrapped in a plastic bag or a plastic sheath placed between
the cut surfaces. Once volumetric CT analysis demonstrated enough
FLR hypertrophy and provided the patient was in good condition,
the second stage was carried out the next available operative day resecting the DH. The type of liver resections performed were defined
using the Brisbane 2000 nomenclature.23 The portal pressure (PP)
was measured in some patients using an electronic transducer by direct puncture of the main portal vein with a 25-gauge needle. Baseline
values were recorded at the beginning of the surgical procedure. After
PVL, the hepatic artery of the DH (usually the right hepatic artery,
RHA) was transitorily clamped to record any modification in the PP
during both stages.

Patient Selection and Preoperative Staging


All the patients with marginally resectable or primarily nonresectable locally advanced liver tumors of any origin where discussed
at a multidisciplinary tumor board and considered eligible for inclusion in the study if an insufficient FLR was present. Preoperative staging consisted in 64-row multidetector computed tomographic (CT)
scan of the abdomen and chest in all patients. For a better assessment
in patients with small lesions, a fatty liver or who received chemotherapy, a magnetic resonance imaging (MRI) was performed. Positron
emission tomography was additionally performed in case of tumor
recurrence in patients with a previous liver resection or suspected
distant metastasis.
Inclusion criteria were as follows: A FLR 30% of total liver
volume (TLV) or 0.5% of body weight (BW) in healthy livers or
40% or less of TLV or 0.8% or less of BW in patients with cholestasis,
macrosteatosis, fibrosis, or prolonged chemotherapy regimens, and at
least one of the following: (1) a tumor margin close to the FLR or its
vascular pedicles, (2) bilobar disease with contraindication for PVE,
(3) failure of PVE/PVL, (4) unexpected tumor extension during surgical exploration with a larger than planned surgical resection, or (5)
the need for a large hypertrophy (>65%) in an extremely small FLR.
Exclusion criteria were as follows: unresectable liver metastases in the FLR or unresectable extrahepatic metastases, severe portal hypertension, high anesthesiological risk or unresectable primary
tumor.

Volumetric and Functional Assessment


Volumetric measurement of the intended FLR was performed
preoperatively on the basis of either CT or MRI images and routinely on the sixth postoperative day after the first stage. In case
of insufficient hypertrophy, an additional CT volumetry was performed weekly until a sufficient FLR volume was achieved. Volumetric reconstruction was performed according to previously described specifications.18 In the case of bilateral lesions, the volume of
those present in the FLR was discounted on preoperative volumetric
imaging. The standardized TLV was calculated using the formula:
794.41 + 1267.289 body surface area (m2 ; Mosteller formula).19
The KGR (as cc per day and % per day) was calculated as mean
volume increase per day assuming a linear growth model from the
first stage of ALPPS to final volume measurement before second
stage. Postoperative functional assessment consisted of daily clinical evaluation and liver function blood tests. In those patients with
borderline sufficient FLR volume after the first stage or with doubts
regarding functional sufficiency, hepatobiliary scintigraphy was performed to determine regional FLR function expressed as percentage
of total liver function (TLF) by quantifying 99mTc-dimethyl iminodiacetic acid (HIDA) uptake during 10 minutes (liver uptake phase)
after intravenous injection. Standard planar scintigraphy between 150
and 350 seconds as well as dynamic reconstruction by single photon
emission computer tomography performed thereafter were registered
and fused with CT-scan images.
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Postoperative Complications and Follow-up


Postoperative adverse events were evaluated according to the
Dindo-Clavien classification of surgical complications.24 Major complication was defined as a complication grade IIIa and severe complication was defined as grade IIIb. Mortality was recorded when
death occurred during hospital stay or up to 90 days of the followup period if the patient was discharged before this time point. The
50-50 criteria was used to define PHLF,25 and clinical severity was
classified according to the grades proposed by the International Study
Group of Liver Surgery.26 Follow-up consisted of outpatient clinical
evaluation, routine laboratory tests, tumor markers, and imaging evaluation (CT scan or MRI) 1 month after surgery and every 3 months
thereafter.

Statistical Analysis
Categorical variables are described using percentages. Continuous variables are expressed as means and standard deviation (SD)
for symmetrically distributed, and median (range) for nonsymmetrically distributed data. Paired t test was used to compare the FLR
volume previous and posterior to the first surgical procedure. Odds
ratios (ORs) and 95% confidence intervals (CIs) were estimated in
univariate and multivariate logistic regression models. P < 0.1 at univariate analysis was required for entry into the multivariate model.
A P < 0.05 was regarded as significant. Kaplan-Meier was used to
estimate OS and DFS. OS was defined as the time from the first stage
to death (all causes) and DFS was defined as the time from the second
stage to the first recorded evidence of recurrence on imaging (local or
distant). Postoperative deaths were excluded from DFS analyses. Statistical analyses were performed using STATA version 12 (StataCorp
LP, TX).

RESULTS
During the study period, among a total of 318 liver resections
at the HPB Surgery Section, 30 ALPPS procedures (9.4%) were
performed in patients with primary (5) or secondary (25) liver tumors.

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Annals of Surgery r Volume 261, Number 4, April 2015

General Characteristics and Preoperative Data


The demographic and clinical characteristics of the patients are
summarized in Table 1. The most common indication for surgery was
metastatic colorectal cancer (n = 19 patients, 63%). Eighteen patients
(60%) received a median of 7 cycles of preoperative chemotherapy
(range = 215) of which 17 had colorectal liver metastases (CRLM).
One patient with CRLM had a previous PVL and PVE with insufficient hypertrophy. Two patients had liver fibrosis (grades F1 = mild
and F3 = severe, according to METAVIR scoring system). Six patients had a previous atypical liver resection and 9 patients had the
primary tumor (6 colorectal, 3 neuroendocrine) in place at diagnosis
of metastatic disease.

Operative Data
Twenty-nine patients successfully underwent both stages of
ALPPS (97% feasibility), the majority of whom completed the strategy during a single hospital stay (90%). Negative resection margins
(R0) were demonstrated in 27 of 29 patients who completed both
stages (93%). The median interval between both surgeries was 7 days
(range = 470). Twenty-nine patients had an ALPPS performed by
the open approach and 1 patient underwent both stages of ALPPS by
a pure laparoscopic technique. The type of liver resection performed
as well as intraoperative data are summarized in Table 2. In 4 patients
in whom an aggressive FLR clean-up was performed, the resulting
FLR comprised segments I and IV in 3 cases and only segment II in
1 patient (Fig. 1). Partial parenchymal transection was performed in

Single-center Safety and Feasibility of ALPPS

70% of the patients. The PP was measured during the first stage in
9 patients, but only in 3 of these it was possible to repeat this maneuver
in the second stage due to firm adhesions that hampered portal vein
recognition. Even though the PP increased slightly in some patients
after clamping the RHA during the first stage, it remained unchanged
during the second stage.

Volumetric Analysis
Twenty-four patients achieved a sufficient hypertrophy within
10 days (80% efficacy) after first stage. The remaining patients presented delayed hypertrophy and finally achieved a sufficient FLR in a
median of 27 days (range = 1667). The median hypertrophy of the
FLR was 89.7% (range = 21287) in a median of 6 days (range =
467), which represented a mean difference between the preoperative and postoperative FLR volume of 308 cc (P < 0.001). The
mean FLR/TLV and FLR/BW ratios increased from baseline values
of 22.1% (SD = 6.1) and 0.47% (SD = 0.13), respectively, to 42.7%
(SD = 10.6) and 0.9% (SD = 0.22) before reoperation. Volumetric
modifications of the FLR between both surgeries in all the patients
are depicted in Figure 2. The mean KGR was 44 cc per day (SD =
24.7) and 13.8% per day (SD = 7.6). Although patients with partial
parenchymal transection had less mean hypertrophy than those with
total transection, this difference did not reach statistical significance
[90% (SD = 20.8) vs 107% (SD = 12.2), P = 0.45]. Furthermore,
when analyzing risk factors for reduced KGR (<35cc per day), partial
parenchymal transection was not associated at univariate or multivariate analysis (Table 3).

TABLE 1. Baseline Characteristics of the Study


Population
Variable

Patients (n= 30)

Age, median (range), yrs


Sex, male, n (%)
BMI, median (range), kg/m2
ASA operative risk, n (%)
<3
3
Charlson index, median (range)
Tumor type, n (%)
Colorectal liver metastases
Neuroendocrine metastases
Hepatocellular carcinoma
Hilar cholangiocarcinoma
Lobar cholangiocarcinoma
Other
Bilateral disease, n (%)
Colorectal liver metastases
Neuroendocrine metastases
NCRNNE
Chemotherapy, n (%)
6 cycles
2 lines
Targeted therapy
Diseased parenchyma, n (%)
Chemotherapy induced
Nonchemotherapy induced
Previous abdominal intervention, n (%)
Synchronous primary tumor, n (%)
% FLR/TLV, mean (SD)
% FLR/BW, mean (SD), cc/kg

58.6 (3581)
19 (63)
25.2 (17.731.7)
22 (73)
8 (27)
7 (210)
19 (63)
3 (10)
3 (10)
1 (3.3)
1 (3.3)
3 (10)
19 (63)
15
3
1
18 (60)
13
6
12
14 (46.6)
11
3
19 (63)
9 (30)
22.1 (6.1)
0.47 (0.14)

Metastatic breast cancer (n= 1), metastatic leiomyosarcoma (n= 1), metastatic
esophageal cancer (n= 1).
Two patients had liver fibrosis (METAVIR scores F1 and F3).
ASA indicates American Society of Anesthesiologists; BMI, body mass index;
NCRNNE, noncolorectal non-neuroendocrine metastases.


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TABLE 2. Intraoperative Data in 30 Patients Treated


Characteristic
Type of major liver resection, n (%)
Right hepatectomy
Right trisectionectomy
Left trisectionectomy
FLR clean-up, n (%)
Lesions resected, median (range)
Extrahepatic procedures, n (%)
Colorectal resection
Colorectal resection + RYH
RYH
Small bowel resection
Distal splenopancreatectomy
Distal splenopancreatectomy + LRN
Colostomy
Diaphragmatic resection
Operative time, median (range), min
Intermittent pringle maneuver, n (%)
Duration, median (range), min
Plastic bag used, n (%)
RBC transfusion, n (%)
Packs per patient, median (range)
Portal pressure (mm Hg), n (%)
Baseline, median (range)
After PVL, median (range)
After RHA clamping, median (range)
R0 resection, n (%)

1st Stage

2nd Stage

19 (63)
2 (120)
11 (37)
4
1
1
1
1
1
1
1
315 (160480)
9 (30)
29 (750)
15 (50)
8 (26.6)
2 (14)
9 (30)
12 (718)
15 (1221)
18 (1223)
19 (100)

8 (28)
20 (69)
1 (3)
0
0

120 (60300)
0

13 (43.3)
2 (14)
3 (10)
15 (1317)

15 (1317)
27 (93.1)

LRN indicates left radical nephrectomy; RBC, red blood cells; RYH, roux-en-Y
hepaticojejunostomy.

Three patients received blood transfusion during both stages.


1st stage = % in patients with FLR clean-up. 2nd stage = % in patients who
completed the strategy.

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Annals of Surgery r Volume 261, Number 4, April 2015

Alvarez et al

FIGURE 1. Fifty-five-year-old woman with multiple bilateral colorectal liver metastases. A, First-stage procedure showing complete
parenchymal transection up to the inferior vena cava (IVC) as well as the right hepatic vein (black arrow) and right vasculobiliary
pedicle (white arrow) encircled with light blue ties. A catheter is placed in the cystic duct for hydraulic test and cholangiography
(asterisk). B, At the end of the procedure only segment II is left behind as FLR after resecting segments I and III due to metastatic
compromise. In this particular patient, the transection line for a right trisectionectomy is at the left side of the falciform ligament
(arrow head). C, Preoperative CT-scan depicts the FLR before clean-up during the first stage of ALPPS. D, Abdominal CT-scan
with scintigraphy fusion demonstrates a 170% volumetric hypertrophy of the FLR (segment II) 6 days after first stage. The FLR
represented 26% of the total liver function by scintigraphy.

Liver Function Assessment

Postoperative Complications

Laboratory findings including prothrombin time and total


bilirubin are detailed in Figure 3. Three patients developed a grade
A PHLF and 1 a grade B. In addition, 2 patients developed late liver
dysfunction in the setting of multiorgan failure. Scintigraphic evaluation was performed after the first stage in 11 patients of this series.
The FLR represented more than 25% of the total functioning liver in
all patients before completion of the second stage. Interestingly, none
of the patients with a FLR/TLF greater than or equal to 30% suffered from PHLF. Before reoperation, the median FLR/TLV in these
patients was 40% (range = 2560), which was equal to a FLR/TLF
of 41% (range = 2658). In 4 patients who were discharged after
the first stage due to insufficient hypertrophy, an outpatient HIDA
scintigraphy was performed periodically until the regional functional
activity of the FLR was parallel with a sufficient FLR volume. In these
4 patients, we observed an increase of the FLR function with time,
even to progressively take lead of the overall liver function (FLR/TLF
increased from 38% to 55% in 59 days) despite not as much volume
increase in an 81-year-old man with CRLM.

Considering both stages, the overall morbidity of the study population was 53% and the mortality was 6.6%. A total of 30 events occurred in 16 patients, 53% occurring after the second stage (Table 4).
Major complications (grade IIIa) occurred in 13 patients (43%)
and severe complications (grade IIIb) occurred in 9 patients (31%).
Three of these patients underwent a blank laparotomy after the first
stage, 1 due to a reduced portal flow in a routine Doppler ultrasound
and 2 because of acute onset of abdominal pain. It is important to
note that none of these patients suffered any other complication during hospital stay. In 1 patient with portal vein thrombosis, we decided
to perform a thrombectomy and delayed the second stage. Four patients (13%) experienced a biliary leakage, which had to be treated
by endoscopic retrograde cholangiography and stenting. Two patients
died during hospital stay. One patient was a high-risk 62-year-old
man with a neuroendocrine tumor who underwent a multivisceral
resection (distal pancreatectomy, splenectomy, and nephrectomy) associated with ALPPS and died before completion surgery because
of multiorgan failure at postoperative day 62. The other patient was

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Annals of Surgery r Volume 261, Number 4, April 2015

Single-center Safety and Feasibility of ALPPS

an 80-year-old man with a giant hepatocellular carcinoma who developed biliary fistula, pneumonia and finally died due to multiorgan
failure 35 days after the second stage. The median hospital stay was 16
days (range = 1162). At univariate analysis, a Charlson comorbidity
index greater than or equal to 7 (P = 0.004), and total parenchymal
transection (P = 0.012) were associated with postoperative complications after ALPPS. In addition, there was a nonsignificant trend toward
higher morbidity in patients older than 60 years. However, as shown
in Table 5, only total parenchymal transection remained significant
as independent risk factor at multivariate analysis (P = 0.049). None
of the analyzed factors were associated with 90-day mortality after
ALPPS.

Disease Recurrence and Survival


The mean follow-up of the study cohort was 17 months (range
= 1.533), and none of the patients was lost during this period.
Twelve patients had disease recurrence during follow-up (11 patients
with CRLM and 1 with metastatic esophageal cancer). The median
time to recurrence was 6 months (range = 1.415). Among the
11 patients with colorectal cancer disease progression, 5 developed
extrahepatic metastases (lung metastases 3, peritoneal 1, and brain
1), 4 had recurrent disease in the liver, and 2 had combined liver and
lung recurrences. Three patients with liver-only recurrence were surgically explored, performing a repeated R0 hepatectomy in 2 cases

FIGURE 2. Volumetric increase in terms of FLR to BW ratio


in all patients treated. As observed, only 6 patients did not
reach a sufficient hypertrophy within 10 days of the interval
period (blue dashed line). The red dashed lines indicate the critical FLR/BW ratios for safe liver surgery of 0.5% and 0.8% respectively. In this patient the FLR/total liver volume ratio was
35% and the sectorial FLR function by scintigraphy was 41%
of the overall liver function before reoperation.

TABLE 3. Risk Factors Associated With a Reduced Kinetic Growth of the Future Liver Remnant
KGR <35 cc/d
Yes, n (%)

Variables
Age, yrs
60
<60
Sex
Male
Female
ASA operative risk
3
<3
Charlson Index
7
<7
BMI, kg/m2
25
<25
Chemotherapy
Yes
No
FLR/TLV, %
<20
20
Transfusion, 1st stage
Yes
No
Extrahepatic procedure
Yes
No
Pringle use
Yes
No
Liver partition
Total
Partial
Complication, 1st stage
Yes
No

Univariate
OR (95% CI)

Multivariate
P

OR (95% CI)

2.7 (0.165.3)

0.55

6 (50)
3 (16.7)

5 (0.926.8)

0.06

4 (21)
5 (45.5)

3.1 (0.615.8)

0.16

6 (75)
3 (13.6)

19 (2.5141)

0.004

10.3 (0.8136.8)

0.08

8 (47)
1 (7.7)

10.6 (1.1101)

0.039

0.9 (0.0421)

0.93

4 (25)
5 (35.7)

0.6 (0.12.9)

0.52

4 (22.2)
5 (41.6)

0.4 (0.11.9)

0.26

4 (44.4)
5 (23.8)

0.4 (0.12)

0.26

4 (50)
5 (22.7)

3.4 (0.618.7)

0.16

3 (27.3)
6 (31.6)

0.8 (0.14.1)

0.8

2 (22.2)
7 (33.3)

0.6 (0.13.5)

0.54

5 (55.6)
4 (19.1)

5.3 (0.129.2)

0.055

5.4 (0.3106.3)

0.26

6 (60)
1 (5.6)

8.5 (1.449.5)

0.017

2.9 (0.237.1)

0.42

ASA indicates American Society of Anesthesiologists; BMI, body mass index.


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Annals of Surgery r Volume 261, Number 4, April 2015

Alvarez et al

and a radiofrequency ablation in the remaining patient. A total of


8 patients died during follow-up, 4 due to unrelated causes (acute
myocardial infarction, massive ischemic colitis, severe pneumonia
and stroke) and 4 due to disease progression in patients with CRLM
at 5, 8, 19, and 24 months of the follow-up, respectively. The OS and
DFS for the entire population at 1 year were 78% and 67%, and at
2 years were 63% and 40%, respectively (Fig. 4). Given the reduced
follow-up available for patients with CRLM (only 4 at risk at 2 years),
only 1-year OS and DFS could be properly estimated in this subgroup
of patients, which was 82% and 56%, respectively.

DISCUSSION
The safe removal of large amount of liver parenchyma is still
a challenge in HPB surgery.14 The so-called ALPPS proposal appears to represent a milestone in HPB surgery as one of the ultimate

FIGURE 3. Postoperative kinetics of prothrombin time (PT) and


total bilirubin (TB). Mean values are given at preoperative evaluation and up to 5 postoperative days after each stage for all
patients. PHLF indicates posthepatectomy liver failure.

TABLE 4. Postoperative Morbidity According to Severity


Grade
Stage
1st

2nd

Grade24

Number

Event (n)

I
II

2
3

IIIa
IIIb

2
4

IVa
IVb
V
I

1
1
1
5

II
IIIa
IIIb
IVa
IVb
V

1
3
4
1
1
1

Acute renal insufficiency (2)


Pancreatic fistula (2)
Catheter-related infection (1)
Intra-abdominal collection (2)
Abdominal pain (2)
Reduced portal flow (1)
Portal vein thrombosis (1)
Acute renal insufficiency (1)
Intra-abdominal hemorrhage (1)
Multiorgan failure (1)
PHLF/Grade A (3)
Acute renal insufficiency (2)
Intra-abdominal hemorrhage (1)
Pleural effusion (3)
Biliary fistula (4)
PHLF/Grade B (1)
Pneumonia (1)
Multiorgan failure (1)

A total of 30 events were recorded in 16 patients, 10 of which occurred in


2 patients who died because of multiorgan failure.

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major advances to surgically induce fast liver hypertrophy. The rapid


worldwide adoption of ALPPS, after being described in Germany,
has resulted in preliminary single center and cooperative experiences
showing a high morbidity and mortality of this emerging method.
In the large multicenter experiences reported, the Brazilian16 with
39 patients and the German9 with 25 patients, a morbidity of 59%
to 68% and a mortality of 12% to 12.8% were reported. Proponents
of PVE argue that the ALPPS has excessively high morbidity and
mortality rates. However, the recently reported data from 87 patients
who underwent a major hepatectomy after chemotherapy and PVE
or PVL at the Beaujon Hospital in France for initially unresectable
CRLM does not seem to wholly support such asseveration.27 The
overall morbidity and mortality in the referred series were 84% and
10%, respectively (>12 cycles = 19% and <12 cycles = 0%). Moreover, a recent publication aiming to compare a very selected series
of PVE (78% as 1-stage hepatectomy) with the ALPPS multicenter
German experience could not demonstrate a significant difference in
overall morbidity and liver-related mortality between both methods.28
Despite the efforts of comparing ALPPS with PVE in terms of safety,
from the authors own perspective this does not seem completely
accurate given that both strategies are to be used in different scenarios. Metastatic colorectal cancer represents the main indication for
ALPPS in most series published including the present, where 79% of
the patients treated had bilateral disease. Given the growing body of
evidence suggesting that there is a risk of tumor growth stimulation
after PVE, it seems safer to induce hypertrophy in a liver cleared of
metastatic disease.2930 Therefore, because PVE in a 1-stage hepatectomy strategy should not be performed in this setting, it seems in
our opinion that the more reasonable and fair comparison of ALPPS
is with other 2-stage procedures rather than with PVE alone. The
53% overall morbidity and 6.6% mortality in the present series is
lower than previous ALPPS series and compares favorably with most
reported series of 2-stage hepatectomies. In a recent publication from
the MD Anderson Group, among 65 patients who underwent a 2stage hepatectomy, they reported 49% morbidity and 6.4% mortality
rates, considering only the second stage.31 In the published experience at the Hopital Paul Brousse with 2-stage hepatectomies including
59 patients, a morbidity of 59% and mortality of 7% after the second
stage was observed.7 In addition, a cooperative experience from Tsai
and colleagues32 including 45 patients from 2 major hepatobiliary
centers reported an overall mortality of 8.8% (4% after the first stage
and 5% after the second stage). As noted earlier, from the available
data on the most important series of 2-stages hepatectomies, the reported morbidity and mortality rates are similar to that obtained with
the ALPPS approach in the present series. Furthermore, it must be
highlighted that in the subgroup of 19 patients with CRLM from our
series, the mortality was nil. Also, after comparing the mortality of
ALPPS with a recent US nationwide experience describing a 10%
mortality rate among 1194 Medicare beneficiaries who underwent a
major hepatectomy, the mortality of ALPPS does not seem to be the
real issue.33
Contrary to previous cooperative large ALPPS series, the results presented in this study reveal that it is possible to achieve acceptable results in terms of safety with the ALPPS approach. It is worth
highlighting that among 9 patients that suffered severe complications
(IIIb = 31%), 3 underwent a blank laparotomy during the learning
curve without developing any other complication. In addition, 37% of
the patients underwent additional extrahepatic procedures including
8 simultaneous resections of primary tumors. In the present series,
2 patients died most likely as a consequence of inadequate patient
selection. It should not be forgotten that the mortality of 2-stage hepatectomy proposed by the Paul Brousse group dropped from a 15%
in the inaugural series of the year 2000 to 7% in 2008.34 Is therefore
likely that as every new development, the outcomes of ALPPS will

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Annals of Surgery r Volume 261, Number 4, April 2015

Single-center Safety and Feasibility of ALPPS

TABLE 5. Risk Factors Related to Postoperative Complications


Univariate
Complications
Yes, n (%)

Variables
Age, yrs
60
<60
Sex
Male
Female
ASA operative risk
3
<3
Charlson index
7
<7
BMI, kg/m2
25
<25
Chemotherapy
Yes
No
FLR/TLV, %
<20
20
Blood transfusion
Yes
No
FLR clean-up
Yes
No
Extrahepatic procedure
Yes
No
Pringle use
Yes
No
Liver partition
Total
Partial
Plastic bag use
Yes
No

Multivariate

OR (95% CI)

OR (95% CI)

9 (75)
7 (38.9)

4.7 (0.923.6)

0.052

6.1 (0.659)

0.115

11 (57.9)
5 (45.5)

0.6 (0.132.7)

0.7

6 (75)
10 (45)

3.6 (0.521.9)

0.1
2.8 (0.324)

0.34

13 (76)
3 (23)

10.8 (1.959)

0.004

10 (62.5)
6 (42.9)

2.2 (0.59.6)

0.4

11 (61.1)
5 (41.7)

2.2 (0.59.7)

0.4

6 (66.7)
10 (47.6)

0.4 (0.92.3)

0.4

10 (55.6)
6 (50)

1.2 (0.35.4)

12 (63.2)
4 (36.4)

3 (0.6414)

0.26

4 (36.4)
12 (63.2)

0.3 (0.71.5)

0.16

7 (77.8)
9 (42.9)

4.6 (0.728)

0.1

8 (88.9)
8 (38.1)

13 (1174)

0.012

7 (46.7)
9 (60)

0.58 (0.132.4)

0.46

15.7 (1244)

0.049

ASA indicates American Society of Anesthesiologists; BMI, body mass index.

improve in the near future. One landmark observation of the present


series is that total parenchymal transection was identified as an independent predictor of postoperative complications during ALPPS.
Most complications in patients with total parenchymal transection
were surgical complications after the first stage. Therefore, because
partial transection has less cut surfaces during the interval period,
probably a less segment IV ischemia, a reduced risk of portal kinking due to accelerated hypertrophy along with a better outflow of
the auxiliary liver might be related to the better results in terms of
liver-related complication in these patients.
Regarding the efficacy of ALPPS, the hallmark of this method
is a very rapid and large FLR hypertrophy. In this series, 80% of the
patients achieved a sufficient FLR hypertrophy in less than 10 days.
Although 2 patients underwent the completion surgery more than 50
days after the first stage and cannot be considered a success from
the short-term hypertrophic perspective, they finally arrived to an R0
surgical resection. The 89.7% median FLR hypertrophy observed in a
median of 6 days is superior to traditional strategies of portal vein occlusion and similar to the reported literature on ALPPS.9,12,14,16 Even
though previous studies have observed proliferative and architectural

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changes at histological level accompanying macroscopic FLR hypertrophy in ALPPS, there is still a paucity of data on whether or not
liver function parallels such volume increase.9,35 Because volumetric
studies do not necessarily correlate with functionality, in this study
the HIDA test was used to evaluate sectorial liver function during
the interval period and it resulted of paramount help to decide the
best timing of the second stage in 4 patients of this series. Because it
is very difficult to accurately assess the percentage of FLR sectorial
function in the preoperative setting due to the lack of a transection
line dividing the liver, we could not calculate an increase in the FRL
function with ALPPS by this method. However, in 4 patients with
delayed hypertrophy, we observed an increase of the FLR function
with time despite not a much volume increase. These findings suggest that the recommended waiting time until operation in these type
of patients may be shorter than indicated by volumetric parameters.
Although an optimum cutoff value above which a patient is relatively safe for surgery remains to be determined, in this study none
of the patients with a FLR/TLF of 30% or more before the second
stage developed PHLF. Even though these results will be pending
confirmation in future studies, we support the use of this practical
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Annals of Surgery r Volume 261, Number 4, April 2015

Alvarez et al

FIGURE 4. DFS and OS of the study population.


method to better assess FLR sufficiency before reoperation in problematic cases (insufficient FLR hypertrophy, abnormal laboratory
tests, old patients, diseased liver parenchyma, etc). More recently, an
intraoperative modality of the indocyanine green clearance has been
proposed as an alternative to evaluate FLR function.36
Despite the surgical interruption of bilateral cross-portal circulation seems to be the main catalyst of the enhanced liver hypertrophy observed in ALPPS, the exact regenerative kinetics behind the
restoration of hepatovascular mass remains poorly understood and
is most likely multifactorial. We have previously hypothesized that
the arterialized DH might act as an auxiliary liver that collaborates allowing the FLR to tolerate portal hyperafflux by modulating
the double hepatic vascular inflow.21,35 High portal vein pressure
(>21 mm Hg) after major hepatectomy has recently been identified as an independent predictor of PHLF and 90-day mortality in
the noncirrhotic liver.37 As well, portal hypertension and hyperafflux
have been associated with impaired liver regeneration and graft failure after liver transplantation due to endothelial damage and liver
dysfunction.37,38 To the best of our knowledge, there are no studies other than the present regarding portal pressure assessment during ALPPS. None of the studied patients had a PP of more than
21 mm Hg during both stages and surprisingly, even though there
was a slight elevation of the PP after clamping the RHA at first stage,
it did not modified when performing this same maneuver during the
second stage after the FLR had hypertrophied. This preliminary results suggest that portal flow modulation and PP might also influence
the hypertrophic phenomenon observed in ALPPS, were the arterialized auxiliary liver may play an alleviating hemodynamic role during
the interval period that becomes less important once the FLR has recover. However, this preliminary observation is drawn from very few
patients and therefore has to be validated in larger series of patients.
The fast and tremendous hypertrophy in ALPPS reduces the
dropout in patients with marginally resectable disease. In this series,
29 patients (97% feasibility) completed the second stage, with an
R0 resection rate of 93.1%. A recent multicentric experience from
Schadde et al39 demonstrated that ALPPS had a higher efficacy in
terms of achieving tumor resection when compared with PVE/PVL
(83% vs 66 %, P = 0.027). In addition, the resectability rate of ALPPS
in the present series is clearly higher than that reported in the series of
2-stage resections from some of the most important oncological centers worldwide.7,31,32 In a recent systematic review from Lam et al40
730 | www.annalsofsurgery.com

including 459 patients who underwent a 2-stage hepatectomy, 76% finally arrived to the second stage with an R0 resection in 75% of these
cases. From the very beginning, skeptics raised speculative concerns
regarding oncological outcomes of ALPPS as a consequence of tumor manipulation and considered it an all touch technique with risk
of early distant tumor recurrence. Unfortunately, none of the largest
series published, neither the Brazilian nor the German multicentric
experiences, provided a thorough analysis of this aspect, with the
largest median follow-up being only 6 months.9 Unfortunately, given
the short-term follow-up available in a heterogeneous population, no
meaningful conclusion regarding survival can be drawn from this
study either. However, the 1- and 2-year OS-DFS of the overall population (78%63% and 64%35%) as well as the 1-year OS-DFS in the
subgroup of patients with CRLM (82%56%) on an intention to treat
basis are encouraging when compared to that in the few existing series
of 2-stage hepatectomies provided that most reports analyzed only the
survival of patients who arrived to the second stage.40 Moreover, it
must be taken into account, when analyzing survival, that the patients
treated with ALPPS in this study had aggressive disease behavior
and were judged initially unresectable at a multidisciplinary meeting. There is not yet a uniform patient selection criteria for ALPPS
and the population heterogeneity, together with the small number of
patients included in this and other studies, prevents to draw a meaningful conclusion of which are the patients that benefit the most from
the ALPPS approach in terms of tumor origin. Future multicentric
large-scale studies will probably clarify this aspect.
Regarding the technical aspects, a plastic bag was used at the
beginning of the present series to prevent adhesions and contain potential bile leaks. However, the incidence of biliary fistulas in our
series has been lower than the observed in the German inaugural
experience9 (13% vs 20%), most likely due to the routine application
of hydraulic test and cholangiography to rule out bile leaks as well as
the meticulous parenchymal transection with the Cavitron Ultrasonic
Surgical Aspirator. In addition, over the time, we learned that the most
challenging and dangerous adhesions are those that form within the
portal pedicle, where the bag does not make any difference. Therefore, we abandoned the use of a plastic bag after our first 15 cases and
we observed equivalent results using only a plastic sheath between the
cut surfaces. Nowadays, we do not routinely ligate the middle hepatic
vein when performing a right trisectionectomy during the first stage
of ALPPS unless necessary for oncological reasons to give enough
margin in tumors close to the FLR. From the results obtained in this
series, partial parenchymal transection does not seem to jeopardize
liver hypertrophy while it is associated with significantly lower morbidity than total transection (38.1% vs 88.9%, P = 0.049). In our
series, one patient was successfully operated during both stages using
a pure laparoscopic approach. Preliminary experiences from wellknown laparoscopic centers have addressed the potential benefits of
this approach.21,41,42 Laparoscopy might help reducing adhesions,
and even if performed only in the first stage, it seems a promising contribution to enhance interval recovery during ALPPS. More
recently, other promising technical modifications using minimally invasive radiofrequency or microwave ablation (RALPP, LAPS) have
been welcomed in the ALPPS family in an intention to reduce the
surgical impact of the ALPPS approach.43
To date, a suitable FLR was defined as at least 2 contiguous
segments with a proper vascular inflow, outflow and biliary drainage.
The present series introduces a paradigm shift in this regard, because
it was demonstrated that even a single segment of the liver might serve
as adequate liver remnant in extreme situations when performing an
aggressive clean-up of the FLR during ALPPS.
The main limitation of this study is the heterogeneous and relatively small patient population. However, as far as we are concerned,
the presented series represents the largest single-center experience

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Annals of Surgery r Volume 261, Number 4, April 2015

regarding the use of the ALPPS approach. This report is unique because it comes from a single high-volume HPB and liver transplant
center, where all patients were treated by the same surgical team, with
identical technical principles and equal perioperative management.
The results presented in this study are timely, because the ALPPS
is entering the Exploration phase of the IDEAL stages of surgical innovation proposed by the Balliol group44 and the HPB surgical
community is extensively debating and questioning the clinical applicability of this new method considering safety issues at the forefront
of the discussion.15,45

CONCLUSIONS
Contrary to most experiences reported to date, the present
prospective study on the largest reported single-center experience
with ALPPS shows for the first time that this evolving approach can
be performed with sufficient patient safety when compared with traditional 2-stage liver resections. This strategy has a high feasibility in
achieving R0 resection in patients with locally advanced disease and
small FLR, where almost all patients eventually benefit from a curative resection. Because the ALPPS is a challenging short-term 2-stage
hepatectomy, it must be remarked as a word of caution that it should
be performed only by high-volume liver surgeons at a high-volume
hospital, in patients selected by a multidisciplinary team and inside
the ALPPS international registry (www.alpps.net) to offer appropriate
safety during the development of this innovative approach. Although
partial parenchymal transection during ALPPS seems to reduce morbidity without negatively impacting FLR hypertrophy, prospective
controlled studies are needed to confirm these findings.

ACKNOWLEDGMENTS
The authors thank Dr Diego Giunta for the statistical analysis
of the data, Dr Marina Ulla and Ezequiel Levi Yeyati for the volumetric analysis of the liver, and Dr Carlos Collaud for performing the
scintigraphies of the patients.

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