Current Oncology Reports (2020) 22: 59

https://doi.org/10.1007/s11912-020-00922-x

INTERVENTIONAL ONCOLOGY (DC MADOFF, SECTION EDITOR)

Improving the Safety of Major Resection for Hepatobiliary

Malignancy: Portal Vein Embolization and Recent Innovations in Liver
Regeneration Strategies
David C. Madoff 1 & Bruno C. Odisio 2 & Erik Schadde 3,4,5 & Ron C. Gaba 6 & Roelof J. Bennink 7 & Thomas M. van Gulik 8 &
Boris Guiu 9

Published online: 16 May 2020

# Springer Science+Business Media, LLC, part of Springer Nature 2020

Abstract
Purpose of review For three decades, portal vein embolization (PVE) has been the “gold-standard” strategy to hypertrophy the
anticipated future liver remnant (FLR) in advance of major hepatectomy. During this time, CT volumetry was the most common
method to preoperatively assess FLR quality and function and used to determine which patients are appropriate surgical
candidates. This review provides the most up-to-date methods for preoperatively assessing the anticipated FLR and summarizes
data from the currently available strategies used to induce FLR hypertrophy before surgery for hepatobiliary malignancy.
Recent findings Functional and physiological imaging is increasingly replacing standard CT volumetry as the method of choice
for preoperative FLR assessment. PVE, associating liver partition and portal vein ligation, radiation lobectomy, and liver venous
deprivation are all currently available techniques to hypertrophy the FLR. Each strategy has pros and cons based on tumor type,
extent of resection, presence or absence of underlying liver disease, age, performance status, complication rates, and other factors.
Summary Numerous strategies can lead to FLR hypertrophy and improve the safety of major hepatectomy. Which is best has yet
to be determined.

Keywords Hepatic regeneration . Future liver remnant . Portal vein embolization . ALPPS . Liver venous deprivation . Radiation
lobectomy

Introduction resected if indicated. However, major hepatic resection places

patients at risk for developing complications related to liver
Hepatic resection remains a potentially curative treatment op- insufficiency, particularly in the perioperative period, before
tion for many types of hepatobiliary malignancy. Owing to its the liver regeneration occurs [1, 2]. Although the causes of
unique ability to regenerate, a large part of the liver can be postoperative liver insufficiency are multifactorial, the volume

This article is part of the Topical Collection on Interventional Oncology

* David C. Madoff 5
Institute of Physiology, Center for Integrative Human Physiology,
david.madoff@yale.edu University of Zurich, Zurich, Switzerland

6
1
Department of Radiology, Interventional Radiology Section,
Department of Radiology and Biomedical Imaging, Section of University of Illinois Hospital, Chicago, IL, USA
Interventional Radiology, Yale School of Medicine, New Haven, CT,
USA 7
Department of Radiology and Nuclear Medicine, Amsterdam UMC,
2 University of Amsterdam, Amsterdam, The Netherlands
Department of Interventional Radiology, The University of Texas
MD Anderson Cancer Center, Houston, TX, USA
8
3 Department of Surgery, Amsterdam UMC, University of
Department of Surgery, Rush University Medical Center, Amsterdam, Amsterdam, The Netherlands
Chicago, IL, USA
4 9
Department of Surgery, Cantonal Hospital Winterthur, Department of Radiology, St-Eloi University Hospital-Montpellier,
Zurich, Switzerland Montpellier, France
59 Page 2 of 20
of the anticipated future liver remnant (FLR) (i.e., volume of
liver that remains after surgery) has been shown to be a strong
independent predictor of postoperative complications [3, 4].
Over the past three decades, various strategies have been de-
veloped to increase the volume and function of the anticipated
FLR in advance of the definitive resection. The original tech-
nique, portal vein embolization (PVE), was first described by
Makuuchi et al. in 1990 [5] to induce left liver hypertrophy
before right hepatectomy in thirteen patients with hilar chol-
angiocarcinoma. Since publication of this inaugural paper,
PVE has become the standard of care worldwide for preparing
patients for major hepatic resection with an inadequate FLR
[6]. Its early adoption was based on data showing that it re-
sulted in the reduction of perioperative complications (includ-
ing liver failure and death) and an extension of resectability for
patients initially considered unresectable due to insufficient
anticipated FLR volume [2, 3, 7].
Despite the success of PVE as a preoperative strategy, it
is not without limitations. These limitations include (a)
insufficient FLR hypertrophy in some patients, especially
those with hepatocellular carcinoma in the setting of cir-
rhosis [8], (b) the lack of treatment to the tumor with the
potential for tumor growth during the waiting period be-
tween PVE and surgery [9–11], and (c) the need for
assessing tumor biology using a “test of time” approach,
which may be viewed to either delay definitive treatment
or negate the performance of futile surgery [12]. To address
these concerns, newer preoperative treatment strategies
have recently been advocated, including associating liver
partition and portal vein ligation (ALPPS), radiation lobec-
tomy (RL), and liver venous deprivation (LVD) [13–15].
This article will review how to assess the FLR in advance
of surgery and each of the currently available methods for
inducing selective hepatic hypertrophy with particular at-
tention to rationale, patient selection/indications, contrain-
dications, technique, available data supporting or criticiz-
ing its use, potential complications, and future directions of
the field of regenerative liver surgery.
Preoperative Assessment of the FLR
Application of liver enhancing techniques largely rely on an
adequate assessment of the regenerative response of the FLR.
Volumetric studies based on CT or MRI imaging are common-
ly used to evaluate the preoperative anticipated liver remnant
as well as to determine if sufficient increase of the FLR oc-
curred in order to determine if a safe resection can be under-
taken. However, volumetric assessment of the whole liver or
part of it only provides indirect information on the actual
functional capacity of the liver, while underlying parenchymal
disease remains unknown. Direct assessment of liver function
is therefore crucial to select those patients who will benefit
Curr Oncol Rep (2020) 22: 59
from regenerative liver surgery prior to extensive resection, as
well as to decide at which point sufficient functional increase
has been achieved in the follow-up of the augmentation
procedure.
Volumetric Assessment Based on Imaging Studies
Gold standard in the assessment of FLR volume is computed
tomography (CT)–based volumetry by which whole liver vol-
ume, tumor volume, and FLR volume are calculated [3]. An
FLR volume of 20–30% has been considered sufficient in
patients without underlying parenchymal disease; however,
in patients with compromised liver (e.g., cirrhosis, bile duct
obstruction), the requirement has been increased to at least
40% [4, 16]. For regenerative liver interventions, CT
volumetry is sequentially applied to monitor volume increase
until the target volume has been attained. However, CT
volumetry is error-sensitive due to varying size and number
of tumors, the presence of dilated bile ducts, variable vascu-
larity, and quality of the liver parenchyma. Although CT
volumetry remains widely used, its role has been reconsidered
[17]. To better predict postoperative outcomes, especially in
the setting of liver regeneration inducing modalities, combi-
nation of CT volumetry with an additional, quantitative liver
function test is now recommended by many expert centers.
To overcome some shortcomings of CT volumetric assess-
ment of the FLR, a modified method of total liver volume
estimation was proposed, based on Western patients’ character-
istics and body surface area (BSA): estimated total liver volume
(eTLV) [cc] = −794.41 + 1267.28 x BSA [18] (Figure 1). This
formula has been compared with other formulas and validated
in several reports [19, 20]. The ratio of FLR volume measured
by CT volumetry and estimated TLV is referred to as the stan-
dardized FLR (sFLR) volume. It is presumed to better predict
liver function than measured FLR volume in %, although no
empiric proof has been presented. Of, course, discrepancies
between measured and estimated volumetric results have been
reported [17]. In an attempt to measure overall FLR volume
growth before and after regenerative liver interventions, the
degree of hypertrophy (DH) (i.e., FLR-post–FLR-pre) is used.
Kinetic growth rate (KGR) is a metric for FLR growth over
time and is calculated by dividing the DH by the number of
weeks after the intervention. KGR may be better predictor of
perioperative outcomes after extended resections than FLR size
in % or sFLR [21].
As an alternative, liver-to-body-weight-ratio (LBWR) has
also been proposed to assess the FLR, consisting of the ratio of
FRL-volume measured by CT volumetry and body weight
[22], expressed in %. Patients with healthy liver and a
LBWR < 0.5% as well as cirrhotic patients with LBWR <
1.4% [23] have been shown to be at risk for post-
hepatectomy liver failure.
Curr Oncol Rep (2020) 22: 59
b c
Fig. 1 Assessment of liver hypertrophy following right and segment 4
portal vein embolization using the estimated the total liver volume
(eTLV) formula based on the body surface area (BSA) on a 62-year-old
female patient with colorectal liver metastasis planned to undergo a right
extended hepatectomy (right hepatic lobe + segment IV resection). a
eTLV on a patient with a BSA of 1.7 resulted in a eTLV of 1359.96 cc;
b Pre-PVE computed-tomography based volumes of the future liver
Functional Assessment Based on Dynamic Studies
Quantitative liver function tests are based on the capacity
of the liver to clear a substance that is mostly or exclu-
sively metabolized by the liver. The indocyanine green
(ICG) clearance test is worldwide the most commonly
used quantitative liver function test in liver surgery and
was initially introduced as a modality for the measure-
ment of blood flow [24]. ICG is removed from the blood
exclusively by the liver and excreted into the bile with-
out intrahepatic conjugation. The ICG elimination rate or
the percentage of retained ICG of all ICG given at
15 min after administration (ICG-R15) are used to ex-
press the results of this test. The ICG clearance test is a
global test that represents function of the whole liver.
Function of specifically the FLR can be calculated by
multiplying ICG-R15 by the proportion of the FRL vol-
ume as determined by CT volumetry. This has been
shown to be predictive of post-hepatectomy liver failure
(PRLF). However, the results rest on the assumption that
liver function is homogeneously distributed [25]. For this
reason, the ICG clearance test is not very useful to assess
the increase in FLR function after liver enhancement as
an increase in function of the regenerated lobe is accom-
panied by a decreased function of the atrophied lobe
resulting in no net effect on total liver function [26].
Page 3 of 20 59
d
remnant (FLR), namely segments I, II, III provided an absolute FLR
volume of 276.1 cc, which represents 20.3% of the eTLV; c Post-PVE
showing adequate embolization of the right portal and segment IV
branches; d Post-PVE computed-tomography based volumes of the
future liver remnant (FLR) performed 4 weeks after the PVE showing
increase of the absolute FLR volume to 430.8 cc, which represents 31.6%
of the eTLV. Patient underwent an uneventful right extended hepatectomy
Scintigraphic Assessment of Liver Function
Nuclear imaging studies are increasingly applied in protocols
to evaluate liver functional increase after induction of liver
regeneration [27]. Scintigraphy provides simultaneous mor-
phologic (visual) and physiologic (quantitative functional) in-
formation of the liver, especially when SPECT-CT cameras
are used. Regional (segmental) differentiation allows func-
tional assessment of specifically, the FLR. Technetium-99 m
(99mTc)-galactosyl serum albumin (GSA) scintigraphy and
99m
Tc-mebrofenin hepatobiliary scintigraphy (HBS) have
been used to identify patients potentially at risk for PRLF.
The use of 99m Tc-GSA is limited in that this radio-
pharmaceutical agent has not been approved by regulatory
agencies in several countries, while 99mTc-mebrofenin is. An
increasing number of centers worldwide are using 99mTc-
mebrofenin HBS with SPECT-CT to assess function of the
FLR in both assessment and monitoring of FLR function in
regenerative liver surgery [28–30]. 99mTc-mebrofenin is an
HIDA (hepatobiliary iminodiacetic acid) agent most suitable
for functional assessment because of its high hepatic uptake,
low displacement by bilirubin, and low urinary excretion.
Camera-based measurement of the hepatic 99mTc-mebrofenin
uptake ratio allows segmental definition of function. The up-
take ratio is divided by the body surface area (BSA) and
expressed as %/min/m2 in order to compensate for differences
59 Page 4 of 20 Curr Oncol Rep (2020) 22: 59

in individual metabolic requirements based on body size.
Using a cut-off value of 2.7/min/m2, the test enables identifi-
cation of patients who are at increased risk of liver failure after
major resection irrespective of the quality of liver parenchyma
[31•].
Scintigraphic Assessment of Changes in Liver
Function
Using scintigraphic techniques, it was found that after PVE,
the increase in FLR function exceeded the increase in FLR
volume [32–34] suggesting that the time interval between
PVE and liver resection may be shorter than determined on
the basis of volumetric parameters (Fig. 2). A novel interesting
application of HBS may be the selection of most appropriate
regenerative procedure, PVE, ALPPS, or LVD in patient with
low FLR volume. FLR-function assessed with HBS may be
used as a predictor of future insufficient functional hypertro-
phy after PVE, selecting patients who may be candidates for
upfront ALPPS or LVD [35]. Sequential real time assessment
of function may allow choosing the earliest time point for
resection. As laid out in the ALPPS section, the timing of
stage 2 resection in ALPPS, the removal of the deportalized
liver lobe appears to be important to avoid perioperative mor-
bidity. As volume of regenerating liver tissue does not
correlate with function, interstage CT volumetry may not re-
liably predict FRL function after ALPPS stage 1. A caveat of
the use of HBS is the decreased uptake of 99mTc-mebrofenin
in the presence of cholestasis due to competitive uptake of
bilirubin and mebrofenin by the same cellular transporter sys-
tems, reflecting a true but mostly reversible diminished liver
function possibly at the segmental level. Especially in patients
with bile duct tumors requiring extensive liver resection, com-
plete decompression of the (FLR) biliary system with a reduc-
tion of hypoerbilirubinemia justifies subsequent use of HBS
[36].
Novel Techniques for Functional Assessment
LiMAx is a commercially available carbon-13 ( 13 C)-
methacetin breath test offered as a non-invasive method for
the assessment of global liver function in surgical patients.
Regional function of the liver, similar to ICG, can only be
calculated as a function of CT-based volume and the test re-
sult. In patients undergoing PVE [37], this test was used to
visualize the changes in FLR function after PVE, showing an
increase in FLR function albeit that function of the FLR post-
resection was lower in comparison with the preoperatively
calculated function. Similarly to the ICG clearance test, the
major limitation of the 13C-breath tests is that read-outs

Fig. 2 A 66-year-old man with a

large hepatocellular carcinoma in
the right liver and segment 4 (a)
on CT requiring extended right-
sided hemihepatectomy. FLR-
volume (segments 2–4) was 32%
(b). FRL-function was 2.9%/min/
m2 (35% of total liver function)
and considered sufficient (c). 43-
year-old-female patient with
multiple liver adenomas on the
right side (d, e) requiring a right-
sided hemihepatectomy. FLR-
volume was 27%. FLR-function
(f) was 2.3%/min/m2 (26% of
total liver function) and
considered insufficient.
Hepatobiliary scintigraphy
3 weeks after right PVE (g)
showed increase of FLR-volume
to 47% (h) and FLR-function to
3.6%/min/m2 (58% of total liver
function) (i) considered sufficient
for safe resection
Curr Oncol Rep (2020) 22: 59
represent total liver function, whereas after liver enhancement,
the distribution of function in the regenerated FLR and the
atrophic parts of the liver greatly differ. To determine function
of the FLR according to the share of FLR as part of total liver
volume, therefore, seems less reliable.
Contrast-enhanced MRI is part of the standard preoperative
work-up in patients with liver tumors considered for resection
and has recently also been introduced as a potential technique
for preoperative assessment of liver function [38, 39].
Functional imaging with MRI-Gd-EOB-DTPA facilitates as-
sessment of total and regional liver function in a similar way
as scintigraphic methods. An additional feature of MRI is
regional assessment of parenchymal steatosis or fibrosis,
which potentially supports functional findings [40].
Application of MRI as a “one-stop-shop” modality for both
diagnostic and functional assessment of the FLR in patients
undergoing liver enhancing techniques is promising but still
faces substantial technical challenges concerning the amount
of tracer needed for visualization and quantification of func-
tion [40].
Techniques Used for Preoperative Liver
Regeneration
Portal Vein Embolization
Rationale
Portal vein embolization (PVE) promotes proliferation of the
surviving hepatocytes with consequent hypertrophy and func-
tional shift towards the non-embolized liver segments.
Although not completely elucidated at the present time, this
pathophysiological process is thought to be triggered by
injury-induced growth-factor stimulation, which occurs once
> 10% of the liver is injured [41, 42]. Preoperative PVE is
considered a major advance on modern hepatobiliary surgery
as it allows curative resection in patients with limited antici-
pated future liver volume while providing reduced rates of
postoperative liver failure [43].
Patient Selection
In addition to surgical candidacy evaluation, factors associated
with poor liver regeneration should also be thoroughly
assessed and, whenever possible, addressed before
performing PVE. Those include: presence of underlying he-
patic disease, chronic ethanol consumption, malnutrition, bil-
iary obstruction, diabetes, and infection. There is broad con-
sensus that patients without any underlying liver disease
should undergo PVE if the sFLR < 20% of the TLV. For pa-
tients with hepatic fibrosis or post-chemotherapy hepatic inju-
ry, PVE should be performed if the sFLR < 30% of the TLV.
Page 5 of 20 59
For cirrhotic patients, a sFLR of < 40% of the TLV should
warrant the need of PVE [6, 44]. Not offering preoperative
PVE for patients with FLR volumes below such thresholds
carries a significant risk of post-operative liver insufficiency
and should be discouraged. On the other hand, offering PVE
in patients with FLR above these thresholds may be unneces-
sary overuse of PVE [45, 46].
The only absolute contraindication to PVE is overt clinical
portal hypertension, which itself contraindicates major hepatic
resection. Relative contraindications include portal vein tumor
invasion, uncorrectable coagulopathy, tumor precluding safe
transhepatic access, non-corrected biliary dilation and chole-
stasis, and renal failure. Bilobar tumor extension is no longer
considered a contraindication to PVE since aggressive local
approaches such as two-stage hepatectomy [47, 48] and com-
bined resection and thermal ablation [49, 50] allow curative
resection.
Technique
The two most commonly utilized percutaneous access routes
to the portal venous system are the ipsilateral and contralateral
approaches. Given the similar safety profile for these two ac-
cesses [4, 51, 52], its choice is mainly dictated by operator’s
experience and preference.
In the ipsilateral approach [53], the portal vein is accessed
via the tumor-bearing liver. Its main advantage is to avoid
puncture and excessive instrumentation of the FLR. When
performing this approach, the risk of puncturing through tu-
mor tissue and, consequently, promote tumor seeding should
be recognized [6]. Also, care should be taken during catheter
manipulation to avoid dislodging the surrounding embolic
material. Finally, when right PVE is combined with segment
4 embolization, segment 4 should be embolized first in order
to avoid potential embolic material dislodgment from the right
portal vein to the left portal vein and its branches [6, 52].
Additionally, having the right portal vein patent would main-
tain portal venous flow to the liver in the event of inadvertent
left portal vein thrombosis during segment 4 embolization.
In the contralateral approach [54], care should be taken to
limit the number of punctures in the FLR. For this reason, this
access requires ultrasonography guidance. The main advan-
tage of this approach is that it allows for straight catheteriza-
tion of the right portal vein branches, obviating the potential
need of using a reverse curve catheter. In fact, segment 4
branch catheterization can be challenging when using a con-
tralateral approach via the left portal vein. To overcome this
issue, an adequate distance should exist between the segment
4 branches and left portal entry point. This can be achieved by
obtaining percutaneous access within a peripheral segment 3
portal vein branch [44]. The main drawback of the contralat-
eral approach is the instrumentation of the FLR parenchyma,
which could potentially make it more prone to complications
59 Page 6 of 20
such as bleeding and thrombosis [55]. If this were to occur,
surgical resection could be made more challenging or in the
worst-case scenario, impossible.
Several embolic materials have been used for PVE
[56–59]. To date, there are no large clinical studies comparing
the effects of different embolic materials in the hypertrophy
response. Operator experience, cost, and availability dictate
the embolic agent of choice. N-butyl cyanoacrylate (NBCA),
a relatively low-cost embolic agent, provides fast and reliable
FLR hypertrophy in the hands of experienced operators.
NBCA is thought to result in greater FLR growth when com-
pared with gelatin, sponge, fibrin glue, and PVA based on
recent systematic analysis [56]. Nevertheless, NBCA induces
a periportal inflammation that may make hepatectomy more
challenging. Absolute ethanol is another effective embolic
agent, but its use is associated with significant changes in
the hepatic function and poor patient tolerability due to pain.
The combination of spherical particles and coils is a safe and
effective embolic method, with the former promoting distal
embolization, which limits the development of collateral cir-
culation, while the coils are placed more proximal to reduce
chances of recanalization. The high costs associated with this
combination is the main limitation of its use.
Supporting Data
In a meta-analysis, Abulkhir et al. reported the outcomes of
1088 patients submitted to PVE using both percutaneous and
transilieocolic approaches. Procedures were successful in >
95% of the patients. The FLR volume increase was greater in
patients using a percutaneous approach (11.9%), compared
with those patients using the transileocolic approach (9.7%)
[60]. A recent systematic review of 47 articles included at total
of 1791 patients [56]. The technical success rate was 99.3%,
the mean FLR hypertrophy rate was 37.9 ± 0.1%, and the
clinical success rate was 96.1%. The results of the largest
cohort (level 2b) series published to date are summarized in
Table 1.
Potential Complications
Van Lieden et al. reported the complications described in 29
studies (n = 1179 patients) [56]. Minor complications were
mostly related to post-embolization syndrome such as fever
(36.9%), transaminase elevation (34.8%), abdominal
pain/discomfort (22.9%), nausea and vomiting (1.25), and il-
eus (1.2%). Major complications were portal thrombosis
(0.8%), embolization of non-target vessels (0.6%), liver he-
matoma (0.4%), and infection/abscess (0.4%). Importantly,
complications led to non-resectability in 0.4% of the patients.
Two patients died after PVE due to lethal pulmonary embo-
lism (n = 1) and cholangitis/septic shock (n = 1), resulting in
an overall mortality rate of 0.1%.
Curr Oncol Rep (2020) 22: 59
Nagino et al. reported their experience with PVE in 494
patients with primary biliary cancers [61]. PVE-related com-
plications requiring interventions occurred in 0.6% of the pa-
tients. Also, on a single-institution analysis of 358 patients,
Shindoh et al. reported PVE complication rate of 3.9% [43],
which included portal vein thrombosis (2.2%), coil misplace-
ment (0.8%), subcapsular hematoma (0.6%), and esophageal
bleeding (0.3%).
Future Directions
Currently, the true impact of PVE on tumor growth is unclear
[11, 62, 63]. The sequential use of arterial and portal emboli-
zation relies on the local oncological effects of the transarterial
embolization, which is critical to prevent tumor growth stim-
ulation associated with the hepatic artery buffer response fol-
lowing PVE [64]. In patients with HCC, transarterial emboli-
zation might also help to occlude arterio-portal shunts, which
are thought to negatively impact the FLR growth [65]. Yoo
et al. described their experience on 135 patients with HCC
submitted to sequential TACE followed by PVE (n = 71 pa-
tients) or to PVE-only (n = 64). The TACE + PVE group,
when compared with the PVE-only group, had a significant
increase in the FLR (7.3% vs 5.8%, respectively; P = 0.035),
as well lower rates of hepatic failure following hepatectomy
(4% vs 12%, respectively; P = 0.185). The combination of
TACE and PVE was associated with improved overall (P =
0.028) and recurrence-free (P = 0.001) survival rates on a
comparison using log-rank test. On a recent systematic review
on the use of sequential TACE and PVE on patients with
HCC, Piardi et al. [66] included 171 patients from 4 selected
publications. An increase on the FLR volume was noticed
when the sequential TACE + PVE approach was utilized when
compared with the use of PVE-only (12% vs 8%, respective-
ly). Mortality rates ranged from 0 to 11%, and a 5-year over-
all- (43–72%) and recurrence-free (37–61%) survivals were
recorded. Further refinements in imaging perfusion, along
with recent improvements on understanding of tumor biology,
provide opportunities to evaluate the effects of portal and ar-
terial blood flow modulation in both the functional liver and
tumor growth.
The delivery of hematopoietic cells on the portal system
has been suggested to stimulate hepatic regeneration [67, 68].
The combination of stem cell administration with PVE has
been investigated as a potential driver for augmenting and
accelerating FLR growth process. Furst et al. [69] prospective-
ly evaluated the combination of PVE with bone marrow stem
cell (BMSCs) administration to the non-embolized liver seg-
ments in six patients (BMSCs + PVE group). Compared with
7 other patients in whom only PVE was performed, a signif-
icant increase in the FLR volume was noted in the group
receiving the BMSCs (81.2% ± 34.3, BMSCs + PVE vs
39.8% ± 20.3 m, PVE alone; P = 0.021). No complications
Curr Oncol Rep (2020) 22: 59 Page 7 of 20 59

Table 1 Summary of the largest portal vein embolization series to date

Article No. Underlying Procedural approach Embolic material used % Complications Complications Surgical
of Pts pathology Increase after PVE after surgery mortality
FLR*

Ebata 494 Biliary Percut. ipsilateral Fibrine glue OR NA 0.6%¥ NA 6.5%

cancer Ethanol + coils
Shindoh 358 Mixed Percut. ipsilateral Particles + Coils 10.2 3.9% 25.8% 3.8%
Giraudo 146 Mixed Percut. contralateral Isobutyl-2-cyanoacrylate 47.7 10 43% NA
De Baere 107 Mixed Percut. contralateral NBCA 69 NA 26.6 NA
Nagino 240 Biliary Percut. ipsilateral Fibrine glue 27.4 No major NA 8.8%
cancer
Di Stefano 188 Mixed Percut. contralateral NBCA 41 and 62 12.8% NA NA
Sakuhara 143 Mixed Percut. Ipsilateral Ethanol 33.6 6% NA 1.6%
(preferable) or
contralateral

FLR future liver remnant, PVE portal vein embolization, Percut percutaneous, NA not available, NBCA n-butyl cyanoacrylate
*Different methods for calculating % FLR among different studies
¥
Complications requiring treatment

were recorded in regard to BMSCs, PVE, and BMSCs deliv-
ery in the portal system. The daily hepatic growth rate in the
BMSCs + PVE group was significantly higher than that in the
PVE-only group (9.5 mL/d ± 4.3 vs 4.1 mL/d ± 1.9, P = 0.03),
as well a short interval from PVE procedure to surgery. Later,
the same group published the outcomes of 11 patients submit-
ted to BMSCs + PVE [70]. Again, a significant higher growth
of the FLR was noted on the BMSCs + PVE group compared
with the PVE-only group (138.66 mL ± 66.29 vs 62.95 mL ±
40.03; P = 0.004). Post hoc analysis also revealed improved
survival for the BMSCs + PVE group compared with the
PVE-only group. Further understanding on the mechanisms
associated with regeneration of the damaged liver following
BMSCs delivery is needed to improve patient selection and
subsequent outcomes.
Lastly, for patients undergoing the two-stage hepatectomy
approach [47], the advent of hybrid IR/OR angiography
rooms allows to combine PVE and first-stage hepatectomy
in the same surgical event [71]. After FLR hypertrophy is
achieved, the second-stage hepatectomy is then performed.
This approach minimizes the number of hospital encounters,
reduces the time between the first- and second-hepatectomy
stages, and allows for early return to intended oncologic
treatment.
by transection of the liver parenchyma 7 to 10 days prior to
resection [14]. ALPPS accelerated liver regeneration to the
point that increases of sFLR and LBWR were achieved
allowing resection after a median of 9 days. To date, the liter-
ature had not supported such a short waiting period between
induction of liver hypertrophy and resection. The authors ar-
gued that their technique “enables curative resection of mar-
ginally resectable liver tumors or metastases in patients that
might otherwise be regarded as palliative” [14]. Their ratio-
nale was to expand resectability of all liver tumors, specifical-
ly those where PVE had been considered due to the small
degree of hypertrophy induced with long waiting time. As
spelled out in an accompanying editorial, ALPPS was devel-
oped to find a solution for difficult intra-operative situations
and as a salvage maneuver, when PVE was unsuccessful [72].
Soon after its initial description, ALPPS was used by many
surgeons worldwide to accelerate the growth of the FLR for all
types of tumors requiring extended resections or two-stage
hepatectomies [73]. A liberal patient selection and the high
physiological severity of the operation impacted perioperative
outcomes [74, 75]. In the initial publications, 90-day mortality
of ALPPS was found to be 9–15%, too high even for complex
and small-FLR-volume liver surgery [14, 76–78].
Technical Aspects

ALPPS ALPPS had barely reached reproducibility and maturity in

Rationale
In 2012, a novel approach was presented to increase the liver
remnant prior to extended hepatectomies by occluding the
portal vein flow to the side of the liver to be removed but also
2014, when modifications were proposed to remedy its high
mortality and morbidity [76, 79]. In the original or “classic”
ALPPS description, the parenchyma is divided along a plane
that completely separates the FLR from part of the liver to be
removed and the portal vein branch into the part to be re-
moved is surgically ligated (Fig. 3) [80]. The first technical
59 Page 8 of 20
Fig. 3 Schematic of ALPPS
procedure. The ALPPS procedure
is a two-stage hepatectomy. In
stage 1, the FLR is “cleaned” of
lesions if necessary, the liver
parenchyma is transected, and the
portal vein is surgically ligated. In
stage 2, after a short waiting time
of only 10 days and about 80%
hypertrophy of the FLR, the
deportalized part of the liver is
removed
modifications proposed alterations in the parenchymal tran-
section using the ALTPS technique (associating liver tourni-
quet ligation and portal vein ligation for staged hepatectomy),
where the parenchyma is tied with a tourniquet instead of
being transected (Table 2). Nevertheless, this technical modi-
fication did not reduce the high morbidity and mortality [81].
In RALPPS (Radiofrequency assisted liver partition with por-
tal vein ligation for staged hepatectomy), a precise 1-cm avas-
cular ablation area was created across the liver instead of sur-
gical transection [82]. The results of a randomized trial of
RALPPS against PVE have been published [83]. The next
modification replaced the ligation of the portal vein with in-
terventional radiology (IR)–based embolization and was
called “hybrid” ALPPS [84]. Comparative data on hybrid ver-
sus classic ALPPS are not yet available. In another modifica-
tion, intraoperative embolization through a catheter threaded
through a mesenteric vessel under fluoroscopy is performed
after transection and was called “mini”-ALPPS with no cur-
rent comparative data [85]. Further, the formal description of a
limited instead of a complete transection was named “partial
ALPPS” [86]. Limited transection was likely performed by
many early ALPPS adopters, because of the concern of injury
to the biliary radicals emanating from the portal plate and the
danger of injury to the vena cava during transection. It has to
be assumed that a fair percentage of early ALPPS cases were
actually performed as “partial” ALPPS cases. Retrospective
comparative reports published on partial ALPPS argue for its
general adoption due to a reduced morbidity and mortality
[87]. Another commonly used modification is to simply wait
longer than 7–10 days to perform the second stage. There is
some experimental evidence that ALPPS hypertrophy is im-
mature at 7–10 days [88] and a longer waiting period may gain
in functional maturity [89]. All the technical modifications,
except for the last, have in common the reduction of the sur-
gical stage 1.
Curr Oncol Rep (2020) 22: 59
Data Supporting and/or Negating Its Adoption
Despite its high morbidity and mortality rates, ALPPS in-
creased resectability rates when compared with PVE in a ret-
rospective cohort study (level 2a evidence) [78] as well as in
the randomized Scandinavian LIGRO trial of ALPPS in pa-
tients with colorectal liver metastases (level 1a evidence)
(Table 3) [90••]. From this trial, 92% of patients underwent
tumor resection in the ALPPS arm compared with 57% of
patients after PVE. The mortality in the LIGRO trial, however,
remained 8.3% for ALPPS. Despite the extensive attention
directed towards ALPPS in the surgical literature [91], its
use in daily practice is currently very limited. Even the
Scandinavian centers where the LIGRO randomized trial
was performed, now use ALPPS only as salvage when other
methods to have failed (pers. communication, Per Sandström,
Linköping, Sweden). A recent update on survival of patients
in the LIGRO trial showed that the median survival of patients
treated with ALPPS was 46 months compared with 26 months
for two-stage hepatectomy [92•].
The largest analysis of ALPPS worldwide is the interna-
tional ALPPS registry, started at the University of Zürich in
2012. The first registry analysis showed an overall periopera-
tive mortality of 9%, but a 90-day mortality in hepatocellular
carcinoma (HCC), intrahepatic cholangiocarcinoma (IHCC),
and perihilar cholangiocarcinoma (PHCC) of 12%, 13%, and
27% respectively (level 2a evidence) [76]. The analysis of
complications was equally worrisome with a major complica-
tion rate of 25%, 43%, and 60% for HCC, IHCC, and PHCC,
respectively [76]. A randomized trial for all tumor types by the
Zurich group had to be stopped due to mortalities after only 8
patients were enrolled (data not published). Subsequent re-
ports of selected large volume centers within the ALPPS reg-
istry showed a trend to use ALPPS mostly in colorectal liver
metastases and an improvement in 90-day mortality to 4%
Curr Oncol Rep (2020) 22: 59 Page 9 of 20 59

Table 2 Main Ttchnical modifications of ALPPS

Modification Abbreviation Full description Grade of evidence Reference

Inaugural description Classic ALPPS Associating liver partition and IV Schnitzbauer et al.14
portal vein ligation for
staged hepatectomy
Tourniquet ligation instead of transection ALTPS Associating liver tourniquet IV Robles et al.56
ligation and portal vein Case series
ligation for staged hepatectomy
Radiofrequency ablation instead of transection RALPPS Radiofrequency assisted liver Ib Jiao et al.58
partition with portal vein RCT
ligation for staged hepatectomy (vs. PVE)
PVE instead of portal vein ligation Hybrid ALPPS Hybrid between ALPPS and portal IV Li et al.59
vein embolization Case series
Intraoperative PVE through a mesenteric Mini ALPPS Minimization of stage 1 ALPPS IV de Santibanes et al.60
catheter instead of portal vein ligation by endovascular embolization Case
series
Incomplete instead of complete transection Partial ALPPS Limited or partial transection of IV Petrowsky et al.61
the parenchymal instead Case series
of complete transection

[93]. However, the LIGRO trial for CRLM, despite higher
resectability of CLRM, still showed an 8% 90-day mortality,
double as high claimed by the self-reported registry and clear-
ly too high for elective liver surgery for colorectal metastases
[90••]. This is especially worrisome in the face of the known
low cure and high recurrence rate in primarily unresectable
CRLM [94, 95]. Contemporary chemotherapy studies with
patients enrolled that could also be ALPPS candidates show
a comparable overall survival between ALPPS and chemo-
therapy alone, but without the postoperative mortality [96].
Even with widespread adoption of partial ALPPS for CRLM
and a further reduction of the 90-mortality, the use of ALPPS
for patients with extensive CRLM had to be viewed with
considerable skepticism from the perspective of oncological
effectiveness.
Potential Complications
A thorough analysis of complications was performed in 320
patients submitted to ALPPS and enrolled in a registry in 2015
(Table 4) [77]. Although ALPPS is a technically challenging
procedure, technical complications like bile leaks were not the
predominant problem. Twenty-eight (8.7%) of 320 patients
had experienced a 90-day mortality, and 20 fulfilled clinical
criteria for liver failure after stage 2, although sFLR volumes
had grown above 30% in 23 of the 28. The study detailed for
all patients with mortalities, whether liver failure criteria were
present (71%), what the direct cause of death was (septic
shock in 68%) and what was the potential root cause of death
(poor patient selection in 50% and inaccurate liver function
assessment in 29%). There were two unexpected findings:
first, it was noted that patients experienced liver failure after
stage 1, i.e. the part of the procedure where only a diminutive
part of liver tissue was removed; second, there was no corre-
lation between liver failure after stage 2 and the liver volumes
achieved by the induction of hypertrophy. The first finding
raised the question into the mechanism by which liver failure
occurs after portal rerouting after the volume of the whole
liver remains unchanged. The second finding raised the ques-
tion of volume-function dissociation after rapid hypertrophy.
The authors advised the use a rigid liver function assessment
prior to resection in stage 2 beyond simply the assessment of
volume changes. Because of the non-availability of HIDA for
direct function assessment in many centers, the use of the
MELD score prior to stage 2 was recommended. MELD, de-
rived from total bilirubin, INR, and creatinine, turned out to be
a reliable predictor of complications after completion hepatec-
tomy. The attempt to improve patient selection and improve
assessment of liver function lead to the development of a
variety of risk scores beyond MELD to improve patient selec-
tion for ALPPS [72, 97]. The use of mebrofenin scintigraphy
demonstrated that the function of liver tissue hypertrophied by
ALPPS and assessed by mebrofenin scintigraphy does not
increase in parallel to the volume observed [98]. This finding
may explain the high mortality and morbidity of classic
ALPPS [99]. It is possible that newer ALPPS modifications
lead to a matching increase in function and volume within the
short period of 1 week to 10 days. A matching rapid increase
of volume and function has recently been demonstrated for the
novel liver venous deprivation (LVD) technique by the
Montpellier group (see below), which also induces rapid liver
hypertrophy like ALPPS [100••]. Immaturity of the rapidly
hypertrophied liver may therefore only apply to classic
ALPPS and not for alternative methods to induce rapid hyper-
trophy. For all other ALPPS modifications, however, such a
demonstration is currently pending [101]. Therefore, the use
59 Page 10 of 20
Table 3 Data supporting/negating the adoption of ALPPS
Year Title
2012 “Right portal vein ligation combined with in suit
splitting induced rapid left lateral liver
lobe hypertrophy…”
2014 “Early survival and safety of ALPPS:
first report of the International ALPPS registry.”
2015 “ALPPS offers a better chance of complete resection…” Feasibility of resection for all tumor
2017 “Risk adjustment in ALPPS is associated
with a dramatic decrease in early mortality…”
2017 “Survival after ALPPS for advanced
colorectal liver metastases…”
2018 “ALPPS improves resectability compared
with conventional Two-stage hepatectomy
in patients with advances CRLM…”
of volume parameters alone to assess functional maturity of
the FLR is discouraged in partial ALPPS or any of the other
ALPPS modifications.
Contraindications
To use ALPPS or any of its modifications as a first-
choice for promoting FLR regeneration requires strong
arguments due to its high procedural risk (Fig. 4)
[102]. Therefore, the first question one should ask is
whether or not ALPPS is appropriate for patients with
bi-lobar CRLM if the tumors are not resectable by a
parenchymal sparing resection instead [103]. If extended
hepatectomy is really required, more than two-thirds of
patients should obtain a sufficient FLR volume increase
by PVE alone because the FLR is rarely lower than 15%.
In patients with extremely small FLR (sFLR < 15%),
PVE with embolization of segment 4 may be attempted
and the volume changes as well as oncological adequacy
of extensive liver surgery evaluated over time. Salvage
ALPPS [104, 105] or additional hepatic vein emboliza-
tion [106, 107] may then be indicated as a salvage ma-
neuver for patients with suboptimal FLR growth, provid-
ed that there are no oncological concerns. Based on the
data available, there is a limited role for a two-stage
hepatectomy, like classic ALPPS, in PHCC [108],
IHCC [76], or HCC [109]. ALPPS variations with a re-
duced stage 1, as described above, may well play a role
in primary liver tumors in the future [110].
Curr Oncol Rep (2020) 22: 59
Main conclusion Oxford level of Reference
evidence
Case series presenting the innovation of IV Schnitzbauer
ALPPS and the effect on hypertrophy et al.14
(Technical feasibilty)
Overall 90-day mortality 9%, but IIc Schadde
prohibitive 90-day mortality in et al.51
HCC (12%), IHCC (13%) and IHCC (27%)
(Safety)
IIIb Schadde
types 83% compared to 66% for et al.58
PVE/PVL in retrospective case
control study
(Short-term oncological outcomes)
Trend to use ALPPS mostly in CRLM and IIc Linecker
improvement in 90-day mortality to 4% et al.67
(Safety)
Overall survival after ALPPS for IIc Olthof
CRLM not better than chemotherapy alone et al.70
(Medium term oncological outcomes)
ALPPS feasibilty of resection for CRLM (92%) Ib Sandstrom
better than for TSH/PVE (57%) et al.65
(Short-term oncological outcomes in CRLM)
Future Directions
ALPPS has been added as a surgical option to promote rapid
liver hypertrophy by portal vein rerouting and has also led to
many clinical innovations and new insights into the mecha-
nisms of liver regeneration. [91] The most promising future
direction of rapid hypertrophy are the reduced stage 1 varia-
tions like ALTPS, RALPPS, hybrid ALPPS, mini-ALPPS,
and partial ALPPS. ALTPS, hybrid, and mini-ALPPS have
only been reported by one group each, while partial ALPPS
is more common, at least in the few centers that still perform
ALPPS at all [93]. If two-stage procedures are going to remain
a true viable option to induce rapid liver regeneration, partial
ALPPS may be the most promising variation, but there are
only limited retrospective data available. Overall, however,
the most promising way to induce rapid hypertrophy may well
turn out to be LVD, a completely endovascular approach to
induce rapid liver hypertrophy, which will be discussed later
in this review.
Radiation Lobectomy
Rationale
The hepatic regenerative strategy termed “radiation lobecto-
my” refers to the lobar transarterial administration of yttrium-
90 (90Y) labeled microspheres with the intent of obliterating
tumor-laden liver tissue while concurrently spurring
Curr Oncol Rep (2020) 22: 59 Page 11 of 20 59

Table 4 Key data about mortality

after ALPPS procedure according Number of Proportion Key figures in ALPPS mortality
to Schadde et al.52 patients (%)

320 100 Retrospective study population in 55 centers

28 of 320 9 90-day mortality in all ALPPS patients
20 of 28 71 Criteria for liver failure (ISGLS) present in patients with mortality
23 of 28 82 Appropriate liver volume (sFLR >30%) prior to resection
in patients with mortality
19 of 28 68 Direct cause of death in patients with mortality: septic shock
14 of 28 50 Root cause of death in patients with mortality: wrong patient selection
8 of 28 29 Root cause of death in patients with mortality: inaccurate liver function
assessment
2 90-day mortality of patients younger than 60 years
14 90-day mortality of patients older than 69 years
7 90-day mortality of patients without ISGLS-liver failure
5 days after stage 1
20 90-day mortality of patients with ISGLS-liver failure 5 days after stage 1
5 90-day mortality of patients with MELD < 10 prior to stage 2
22 90- day mortality of patients with MELD > 10 prior to stage 2

ALPPS associating liver partition and portal vein ligation for staged hepatectomy, ISGLS international study group
for liver surgery, sFLR standardized FLR according to Vauthey, MELD model for end stage liver disease

hypertrophy of the non-radiated contralateral liver lobe prior
to liver resection surgery [111]. In radiation lobectomy, a de-
liberate lobar treatment approach is employed, rather than
more selective segmental treatment, in order to purposefully
deliver radiotherapy to non-tumorous liver parenchyma in ad-
dition to liver tumor [112]. This technical approach underlies
the conceptual and mechanistic basis for radiation lobectomy,
which relates to the induction of a liver atrophy-hypertrophy
complex as a regenerative response following radiation in-
duced hepatocyte injury and loss [113]. As a neoadjuvant
therapeutic modality, radiation lobectomy offers a three-fold
theoretical benefit in patients with primary or secondary liver
cancer who may undergo future hepatectomy: [1] locoregional
liver-directed treatment of cancer, inciting tumor and

Fig. 4 Algorithm for contraindications to ALPPS: A variety of
contraindications limit the use of ALPPS: ALPPS in primary liver
tumors results in prohibitive morbidity and mortality and should be
avoided; a large number of extensive colorectal liver metastases can be
resected using a parenchymal sparing approach; PVE may suffice when
FLR volumes are not extremely small and PVE with segment IV
embolization may achieve sufficient FLR hypertrophy; if PVE with
segment IV embolization does not result in sufficient hypertrophy,
salvage HVE or salvage ALPPS may be useful
59 Page 12 of 20
hepatocyte cell death and consequent atrophy of irradiated
liver tissues; [2] compensatory hypertrophy of the contralater-
al, untreated liver lobe, which may serve to enlarge this lobe as
a future liver remnant (FLR) for subsequent surgical resection;
[3] allowance of a biological “test-of-time” to ensure durable
tumor response and lack of cancer progression, which would
contraindicate surgery, as well as appropriate FLR hypertro-
phy to allow safe hepatectomy and avoidance of post-
operative liver failure.
Technique
The technical aspects of radiation lobectomy follow standard
90
Y radioembolization methods, including planning arteriog-
raphy with arterial anatomic mapping, non-target vessel em-
bolization, and technetium-99 m macroaggregated albumin
(99mTc-MAA) scanning for lung shunt fraction calculation,
followed by 90Y dosimetry according to customary methods
with ensuing 90Y labeled microsphere delivery [114]. Patients
who are to undergo radiation lobectomy should be operative
candidates, with normal bilirubin levels, no portal hyperten-
sion, and no significant medical comorbidities which preclude
surgery. In selecting patients for radiation lobectomy, well-
compensated liver disease (Child-Pugh A5 status) and a pre-
treatment FLR less than 50% have been associated with max-
imal contralateral lobar hypertrophy exceeding 10% [115••].
From the standpoint of 90Y dosimetry, a healthy liver injected
dose exceeding 88 Gy has also been linked with maximal
contralateral hemi-liver hypertrophy exceeding 10% [115••].
These selection parameters provide preliminary guidance as to
specific patients who may optimally benefit from the radiation
lobectomy approach.
Supporting Data
Patient and tumor data, procedure technical parameters, and
liver volumetric changes of radiation lobectomy from repre-
sentative publications with cohort sizes exceeding 10 are sum-
marized in the Table 5 [111, 112, 115••, 116,117,118,119••].
Overall, degrees of hypertrophy (DH)—defined as post-
treatment relative FLR volume (FLR volume divided by total
liver volume) minus pre-treatment relative FLR volume,
expressed as a percentage—ranged from 10 to 26%. Time
dependent analyses indicate that FLR volumetric increases
occur steadily over the course of several months after 90Y
radioembolization (Fig. 5), with small degrees of hypertrophy
(around 2–3%) evident by 1-month post-treatment [112, 117].
In contrast to radiation lobectomy, published data indicates
that more selective radiation segmentectomy does not achieve
as substantial FLR hypertrophy, with the degree of hypertro-
phy limited to 2% [119••]. Tumor response rates after radia-
tion lobectomy are high, typically approximating 70–90% ob-
jective imaging response [111, 112, 115••,116,117,118,119••].
Curr Oncol Rep (2020) 22: 59
Tumor progression in the FLR after radiation lobectomy has
been reported to range from 19 to 25% for hepatocellular
carcinoma (HCC) and metastatic colorectal carcinoma, re-
spectively [112]. Reports of surgical outcomes after radiation
lobectomy remain somewhat limited; in one study of 31 HCC
patients who underwent liver resection after radiation lobec-
tomy, 67% of patients with preoperative FLR less than 40%
achieved FLRs exceeding 40% after 90Y treatment [119••].
Following surgery, the incidence of grade IIIA or higher
Clavien-Dindo adverse events was 16%, and 3-year overall
survival was 86% [119••].
Potential Complications
Potential complications of radiation lobectomy primarily relate
to adverse events precipitated by 90Y radioembolization, in-
cluding gastrointestinal ulceration, biliary sequela (e.g. radia-
tion cholecystitis, biloma, and/or abscess), radiation pneumoni-
tis, vascular injury, and lymphopenia, all of which occur with
relatively low incidence [120]. Post-radioembolization
syndrome—consisting of fatigue, nausea, vomiting, anorexia,
a n d f e v e r — i s a n a n t i c i p a t e d s i d e e ff e c t o f 9 0 Y
radioembolization that occurs in one-quarter to one-half of pa-
tients after treatment and is managed conservatively [120].
Liver insufficiency is an uncommon occurrence following ra-
diation lobectomy, as evidenced by lack of serious biochemical
adverse events and no meaningful alterations in Child-Pugh or
Model for End-stage Liver disease scores after treatment in
published series [111, 112, 115••,116,117,118,119••].
Situations in Which to Avoid Radiation Lobectomy
As a neoadjuvant therapy performed prior to potential hepa-
tectomy, radiation lobectomy should not be pursued in pa-
tients who are not operative candidates. Conversely, deliberate
parenchymal irradiation should generally be averted in surgi-
cally unresectable liver cancer patients in order to preserve
functional liver and allow for safe repetition of locoregional
therapy should multiple tumor treatment sessions be required.
Otherwise, radiation lobectomy should also be avoided in sce-
narios in which 90Y radioembolization is contraindicated,
namely in patients with markedly compromised liver function,
poor functional status, active hepatic infection, significant ex-
trahepatic metastases, uncorrectable extra-hepatic arterial
flow, which may result in non-target 90Y microsphere deposi-
tion, and a high lung shunt fraction, which would result in a
single-session lung dose exceeding 30 Gy [114].
Future Directions
Though supported by published retrospective data, continued
investigation of the radiation lobectomy concept is necessary
to solidify this procedure’s standing among liver regenerative
Curr Oncol Rep (2020) 22: 59 Page 13 of 20 59

Table 5 Patient and tumor data, procedure technical parameters, and liver volumetric changes of radiation lobectomy
90
Author Year Patients Tumor type(s) Y Treated RE sessions Cumulative target dose (Gy) Follow-up time (months) FLR
device lobe (median, (median, range or IQR or mean (median, range or mean ± DH1
range) ± SD) SD) (%)

Jakobs, et al 2008 10 Various 2 Glass Right 1 120 4.6 17

Gaba, et al 2009 20 HCC (17), Glass Right 1.7 (1–5) 175 (103–413) 18 (2–49) 26
CCA (3)
Vouche, et al 2013 83 HCC (67), Glass Right NS 112 (74–215) >9 11
CCA (8),
mCRC (8)
Theysohn, et al 2014 45 HCC Glass Right 1 112 (100–160) 12 22
Lewandowski, 2016 13 HCC (10), Glass Right 1.4 (1–2) 154 (111–298) 1 (1–6) 10
et al CCA (2),
mCRC (1)
Gabr, et al 2018 31 HCC Glass Right 1 (1–3) 128 (113–143) 3 (2–5) 10
Palard, et al 2018 73 HCC Glass Right 1 150 ± 44 5.9 ± 3.4 17

90
Y yttrium-90, RE radioembolization, IQR interquartile range, SD standard deviation, FLR future liver remnant, DH degree of hypertrophy, HCC
hepatocellular carcinoma, CCA cholangiocarcinoma, mCRC metastatic colorectal carcinoma, NS not specified
1
DH = post-treatment relative FLR volume (FLR volume divided by total liver volume) minus pre-treatment relative FLR volume, expressed as a
percentage
2
Including colon, pancreas, neuroendocrine, breast, esophageal, hemangiopericytoma, melanoma, and unknown primary tumors

strategies. First, further delineation of optimal 90Y dosimetry
schemes to induce robust atrophy-hypertrophy complex
formation—as well as continued definition of other prognostic
factors for hepatic volumetric changes—is required to im-
prove the objectiveness of the radiation lobectomy approach
and predictability of the hepatic morphologic response.
Second, the optimal time from 90Y treatment to resection is
unknown. This timing could be critical as disease control rates
are better with a shorter time intervals (e.g., 3 months versus
6 months), and therefore, resectability rates may decrease over
time. Future study in this area is required to better define the
most appropriate time to resection, even in the presence of a
smaller absolute anticipated FLR volume. Third, the
comparative effectiveness of the radiation lobectomy ap-
proach for different tumor types, spanning both primary (i.e.,
HCC) and secondary (e.g. metastatic colorectal carcinoma)
liver malignancies, as well as liver disease stages, need be
investigated. Fourth, the safety, feasibility, and clinical out-
comes of ancillary technical approaches used to further refine
and/or increase the potency of the radiation lobectomy proce-
dure should be studied; for example, combined radiation
segmentectomy aimed at ablative tumor destruction plus con-
current radiation lobectomy aimed at normal liver parenchy-
mal irradiation may optimize tumor obliteration and parenchy-
mal injury but requires further exploration. Finally, direct pro-
spective comparison of the hepatic volumetric response and

Fig. 5 Representative example of hepatic volumetric response after 90Y
radioembolization. Pre-treatment contrast enhanced axial computed
tomography (CT) scan a demonstrates hypervascular right hepatic lobe
HCC (arrow); right hepatic lobe (outlined by dashed white line)
volume = 1267 mL, left hepatic lobe (outlined by dashed black line)
volume = 628 mL (FLR = 33%). Post-treatment contrast enhanced axial
CT scan b performed 24 months after 1 session of glass 90 Y
radioembolization (dose = 189 Gy) reveals complete radiologic
response in treated right hepatic lobe HCC (arrow); right hepatic lobe
(outlined by dashed white line) volume = 736 mL, left hepatic lobe
(outlined by dashed black line) volume = 1052 mL (FLR = 59%)
59 Page 14 of 20
clinical outcomes of radiation lobectomy combined with other
liver regenerative techniques—such as portal vein
embolization—should be pursued.
Liver Venous Deprivation
General Rationale
Liver venous deprivation (LVD) refers to both portal and he-
patic vein embolization (HVE) [13]. The goal of this strategy
is to accelerate liver regeneration of the FLR, in order to limit
patient’s drop-out from resection. HVE in addition to PVE is
supposed to, as compared with PVE alone, induce more dam-
age to the embolized liver and, thus, increase contralateral
liver regeneration and/or to counteract persistent minute portal
inflow that may occur after PVE. The rationale relies on the
following:
In the Absence of Persistent Minute Portal Inflow After PVE
An increased hepatic arterial inflow is commonly observed
after PVE owing to the hepatic arterial buffer response.
Occlusion of hepatic venous outflow in a context of PVE
decreases the hepatic arterial inflow because of the limited
outflow route [121], either through sinusoids and inter-
lobular communications to reach a zone with preserved out-
flow and/or through intrahepatic arterio-arterial communica-
tions between venous-deprived and venous-preserved areas
[13]. Reduced rather than interrupted arterial inflow might
be preferable to prevent the risk of severe liver ischemia and
liver abscess formation [122] and to safely increase damage to
the embolized liver, in order to further increase the regenera-
tion of the non-embolized liver.
In the Presence of Persistent Minute Portal Inflow After PVE
When embolization of portal vessels is incomplete (e.g. chal-
lenging portal anatomy) or too proximal, PVE is not optimal
with limitation of the atrophy/hypertrophy complex.
Interestingly, HV occlusion in areas with preserved portal in-
flow induces compensatory increase in hepatic arterial flow
and arterio-portal regurgitation with PV acting as a draining
vein with reversed flow [121]. Therefore, persistent minute
portal inflow would be decreased or suppressed, thereby
redirecting all portal inflow to the non-embolized liver.
In 2009, Hwang et al. [107] reported on HVE performed in
12 patients who had shown limited liver regeneration 2 weeks
after PVE. This approach was shown to be safe and effective
in facilitating contralateral regeneration by inducing more se-
vere liver damage than usually observed after PVE. However,
this sequential approach did not spare time to resection com-
pared with PVE alone, as additional waiting time was required
Curr Oncol Rep (2020) 22: 59
to assess whether any additional regeneration occurred follow-
ing the second procedure.
To reduce the time from PVE or sequential PVE and HVE
to resection, the concept of simultaneous PVE and HVE has
recently emerged. Guiu et al. reported the first series of 7
patients prepared using the so-called “LVD technique [13],”
consisting of simultaneous PVE and HVE of right and acces-
sory right HVs when present. Since the middle HV drains
approximately 2/3 of the right paramedian sector [123] and
given the excellent tolerance of LVD, Guiu et al. expanded the
concept into extended LVD (eLVD) by embolizing not only
the right (and accessory right when present) but also the mid-
dle HVs in another series of 10 patients [100••].
In summary, HV occlusion (a) indirectly reduces hepatic
arterial inflow in PV embolized segments thereby causing
more damage herein and (b) reverses portal flow in non PV
embolized segments that might be helpful in case of challeng-
ing portal anatomy or too proximal PVE.
Technical Aspects Associated with Venous
Deprivation
The (e)LVD technique was originally described as a complete-
ly transhepatic procedure (Fig. 6). The HVs (right, accessory
right when present, ± middle) are first accessed under ultra-
sound using a Chiba introducer needle and a micropuncture
set. After opacification, a 0.018-in. Cope Mandril guidewire is
left in place in each HV. PVE is then conducted using a mix-
ture of iodized oil and n-butyl-cyanoacrylate. Each HV access
is used to introduce a 6 or 7F sheath in order to deploy an
Amplatzer Vascular Plug (AVP) II (St-Jude Medical,
Plymouth, MN), with its distal part ~ 15 mm before the junc-
tion with the vena cava to facilitate HV surgical ligation using
a stapler. The plug must be oversized by 75–100% to prevent
device migration. Accurate AVP position should be confirmed
by ultrasound. As soon as plugs are occluded, embolization of
distal branches and potential collaterals (inter-hepatic vein
communications when visible) is conducted with a mixture
of ethiodized oil and n-butyl-cyanoacrylate. Finally, tract em-
bolization of all transhepatic accesses is performed using the
same mixture.
Veno-venous collaterals can be observed both from the
proximal (i.e. near the vena cava) or the distal part of the
HVs [124]. Existing intrahepatic venous collaterals have been
reported in 46% of normal livers (mainly in the right liver),
with a diameter ≤ 1 mm in 73% cases [125]. In LVD, whether
the proximal collaterals are occluded by the plug itself, liquid
agents and especially glue seem to be well-designed to oc-
clude the distal ones safely, provided low dilution and slow
injection of glue. A critical point is to prepare the mixture of
glue and ethiodized oil before deploying the plug and to start
embolization as soon as the plug is occluded, given the rapid
Curr Oncol Rep (2020) 22: 59
Fig. 6 LVD technique in a 67-year-old patient bearing multiple liver
metastases in the right liver. a 0.018 in. guidewire is inserted into the
right HV and right PVE is performed using a mixture of n-butyl
cyanoacrylate and ethiodized oil (1:6). b Then, AVP type 2 (75%
enlargement and development of these collaterals when out-
flow is occluded (Fig. 7).
The concept of “bi-embolization” or “double emboli-
zation” has also been introduced in the literature but
refers only to the deployment of one AVP at the HV
origin through a transjugular access [126]. By defini-
tion, this technique leaves open the distal collaterals,
which may circumvent the AVP within several minutes
after its deployment, as observed when injecting through
a transhepatic access. By embolizing both the proximal
(AVP) and distal part (glue) as well as potential collat-
erals of HVs, LVD should probably be preferred.
Recently, a new technical variation has been proposed in
Klatskin tumors to avoid direct puncture of undrained bile
ducts [127]. Through a transjugular approach, the HV was
embolized from its distal part using several AVPs. After the
Fig. 7 During LVD performed in a 55-year-old patient, opacification
through the 7F-sheath inserted in the right HV, 10 min after AVP
deployment (black arrow). “Spiderweb” appearance of distal veno-
venous collaterals (white arrows) from the right to the middle HV
Page 15 of 20 59
oversizing) is deployed in right HV (white arrow), and slow injection of
n-butyl cyanoacrylate and ethiodized oil (1:2) is performed to fill in distal
branches of the right HV
first plug was released, the next was hooked to the first one to
limit the risk of migration. All but the first centimeters of the
HV was embolized plug by plug.
Data Supporting and/or Negating Its Adoption
So far, LVD has 100% technical success in published
case-series [13, 100, 127]. In the inaugural paper, LVD
increased FLR volume by 53% after 23 days (range: 13–
30 days) in 7 patients [13]. In Klatskin tumors, LVD
combined with biliary drainage increased FLR volume
by 63.4% after 23.5 days (15–29 days) [127]. In 10
patients, eLVD showed fast and great increase in FLR
volume with + 53.4% at day 7, + 62.5% at day 14 and +
63.3% at day 21 [100••]. Kinetic growth rate (KGR)
after eLVD (i.e. 25 cc/day) was far beyond published
KGR following PVE (i.e. 4 cm3/day) or even LVD (i.e.
9 cm3/day) [100••]. Only ALPPS (KGR: 25.4–32.7 cc/
day) can compete with eLVD in terms of volumetric
gain, but it has been shown that liver volume (strongly)
overestimates liver function in ALPPS [98]. To the con-
trary, after eLVD [100••], FLR function evaluated using
99 m-Tc mebrofenin scintigraphy increased the same way
as FLR volume (+ 64.3% at day 21). The same team
compared the perioperative impact of LVD vs. PVE in
28 patients undergoing right hemi-hepatectomy [128].
They showed no difference in terms of morbidity/mortal-
ity, intraoperative bleeding and red blood cell volume,
fluid volume administration, and operative time, thereby
suggesting that LVD does not cause any additional sur-
gical difficulty.
Potential Complications
So far, only minor complications have been reported for LVD
including moderate pain and fever in keeping with post-
59 Page 16 of 20
embolization syndrome, together with moderate transaminase
elevation. Grade 2–3 asthenia has been observed in the first
eLVD patients together with strong depletion in blood pools of
vitamins and ions, given the high energy demand for regener-
ation [100••]. Systematic multivitamin and phosphorus sup-
plementation administered early after eLVD solved this
problem.
Potential complications that may occur with (e)LVD are
migration of embolic material and liver hematoma, but none
of these have been reported so far.
Contraindications
Very little data are available on (e)LVD in the context of cir-
rhosis since only two cirrhotic patients undergoing LVD be-
fore right hemi-hepatectomy have been reported so far [128].
Occluding the outflow (in addition to PVE) in cirrhosis is
likely to increase portal hypertension. In the absence of safety
data in that context, it should be avoided to prepare cirrhotic
patients with LVD outside clinical trials.
Future Directions
The role of eLVD to increase hepatic regeneration of
the anticipated FLR prior to resection must be further
investigated. Whether occluding right and middle HVs
in right hemi-hepatectomy extended to segment 4 is
fully acceptable, eLVD in a context of right hemi-
hepatectomy is more questionable. By causing venous
ischemia in the part of segment 4 drained by the middle
HV, it might provide an attractive and simpler option
than segment 4 PVE [100••], but this must be further
explored. Therefore, randomized controlled trials are
highly needed to better define the place of LVD versus
PVE, with special attention not only to volumetric and
functional gains but also to oncological outcomes.
Indeed, accelerating liver regeneration might also accel-
erate tumor growth and increase the risk of recurrence.
Provided the results are confirmed in randomized con-
trolled trials, (e)LVD would have the potential to become the
standard of care for liver preparation, but the decade-long
history of great efficacy and safety of PVE could rather argue
in favor of tailored liver preparation, which means keeping the
more complex procedure (i.e. (e)LVD) when high functional
gain is needed in the FLR. To aid in the determination of
which patients will benefit from PVE or (e)LVD, future study
will be necessary.
Conclusion
There are many different interventional radiological and sur-
gical options that can be used to promote hepatic hypertrophy
Curr Oncol Rep (2020) 22: 59
prior to curative resection. Although the standard of care for
the past two decades has been PVE, newer approaches have
been used in an attempt to make hypertrophy faster, to enable
patients on the fringe of resection to become surgical candi-
dates and to apply minimally invasive therapies to treat the
tumor while giving the “test of time” to assess its biology
before undergoing a potentially morbid major hepatectomy.
Each of the techniques described herein has advantages and
disadvantages. However, at the present time, only few pro-
spective clinical trial has been published and none comparing
all of these different strategies for preoperative hepatic hyper-
trophy prior to resection. Hopefully, in the coming years, com-
prehensive prospective clinical trials will be performed for
each tumor type to help elucidate which option is best.
Compliance with Ethical Standards
Conflict of Interest David C. Madoff declares that he has no conflict of
interest. Bruno C. Odisio declares that he has no conflict of interest. Erik
Schadde declares that he has no conflict of interest. Ron C. Gaba has
received research funding from Guerbet USA LLC, the United States
Department of Defense, and the National Institutes of Health, and also
has a service contract with Janssen Research & Development LLC.
Roelof J. Bennink declares that he has no conflict of interest. Thomas
M. van Gulik declares that he has no conflict of interest. Boris Guiu
declares that he has no conflict of interest.
Human and Animal Rights and Informed Consent This article does not
contain any studies with human or animal subjects performed by any of
the authors.
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