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Chapter14:Y90 radioembolization forHCC
http://internalmedicinebook.com
angiography must be performed to delineate the source(s) of
segmental and/or lobar perfusion. Rotational cone-beam CT
has proven particularly useful for treatment planning as it can
be used to conrm the extent of tumor perfusion during selective and superselective catheterization, dene the volume of
hepatic tissue perfused by a catheterized vessel, as well as to
reveal otherwise undetected extrahepatic perfusion.
12
Because HCC and cirrhosis increase the incidence of
direct hepatic arteriovenous shunts,13 infusion of radioactive microspheres smaller than these shunts would result in
deposition of microspheres in the lungs.14 Technetium-99m
macro-aggregated microsphere (
99m
Tc-MAA) approximates
the size of Y90 microspheres and mirrors their pulmonary
shunting. At the end of the initial mapping angiography,
2–4mCi of
99m
Tc-MAA is administered via the proper, right,
or le hepatic artery, depending on the planned treatment
site. Planar and/or single-photon emission computed tomography (SPECT) gamma camera images are acquired immediately following the mapping angiography in order to calculate
the fraction of administered
in the lungs. Ashort interval between
99m
Tc-MAA activity that arrives
99m
Tc-MAA infusion
and nuclear medicine imaging is critical, as a delay in imaging and the time-dependent degradation of
result in a falsely elevated lung shunt fraction (LSF) calculation.15 Using the LSF, a cumulative pulmonary dose is cal-
99m
Tc-MAA can
culated based on the planned dose to the treatment volume.
Pulmonary doses >30Gy per treatment or >50Gy cumulatively have been associated with the development of radiation pneumonitis.
16
For treatment planning, a simplied matrix has been
described for patients with unresectable HCC based on the
extent of disease and the patient’s total bilirubin level.15 Y90
can be administered via a lobar or segmental injection in the
setting of uninodular HCC and a normal bilirubin. If bilirubin is elevated in the setting of uninodular disease, treatment
should only proceed if a segmental perfusing vessel can be
isolated, which provides high-dose radiation to the tumor and
minimizes microsphere distribution to uninvolved liver paren-
In other words, it is the volume of the liver segments being perfused by the vessel of interest.
Glass microspheres are available in vials of several dierent activities that are dispensed weekly on Wednesday by the
manufacturer and calibrated at 12:00 noon (Eastern Standard
Time (EST)) of the following Sunday. e microspheres have
an approximate activity of 2,500Bq per sphere.
6
e recommended activity that should be administered
to a tumor-containing hepatic lobe should correspond to a
dose between 80 and 150Gy. Patients with signicant cirrhosis should be treated conservatively with doses between 80
and 100Gy, while patients without cirrhosis may be treated
at higher doses between 100 and 150Gy. e most commonly
used dose range at our institution is between 100 and 120Gy.
Activity required to deliver the desired dose can be calculated
according to the equation:
×
A
=
50 1
×
DM
%%LSF
−×−
100
R
1
100
where activity (A) is measured in GBq infused to the target
liver, D is the absorbed dose (Gy) to the target liver mass, M
(kg). Liver volume (mL) is calculated with 3D soware and
converted to mass using a conversion factor of 1.03mg/mL. LSF
(%LSF) is calculated from nuclear medicine images acquired
following the initial mapping angiography. Residual activity
within the vial (%R) is measured aer Y90 administration and
approximated to be 2% for pretreatment dosing calculations.
15
Resin microspheres (SIR-Spheres) are available in 3-GBq
vials dispensed three times per week and calibrated for 6:00p.m.
EST on the date of treatment. Each vial contains 40–80million
microspheres, with an activity per sphere of 50Bq.
6
Resin microsphere dosimetry can be calculated using body
surface area and estimates of tumor burden according to the
equation:
Tumorinvolvement
A =−+BSA
02
.
%
100
chyma. For bilobar disease or multinodular HCC and a normal
bilirubin, staged lobar treatments can be performed. In the setting of abnormal bilirubin and multinodular/bilobar disease,
the risk of Y90 treatment may be unacceptablyhigh.
where activity (A) is GBq infused and BSA is the body surface
areainm2.
For resin microsphere dosimetry calculation, activity is
decreased depending on the degree of LSF: < 10% LSF: no
Dosimetry
reduction; 10–15% LSF: 20% reduction; 15–20% LSF: 40%
reduction; >20% LSF:no treatment.
15
Y90 radiation dosimetry uses volumetric calculations of liver
tissue (glass microspheres) or tumor burden and body surface
area (resin microspheres). Several dierent soware packages are available to calculate three-dimensional (3D) tissue
volumes from triphasic CT or multiphasic contrast-enhanced
magnetic resonance imaging (MRI). Volumetric calculation
and treatment planning require a sound understanding of the
Couinaud hepatic segments and their anatomic landmarks on
cross-sectional imaging.
For glass microsphere (eraSphere) dosimetry, the volume that is measured and used in the dosimetry calculation is
the volume of liver tissue that is perfused by the vessel infused.
Adverse events and toxicities
e most common side eect following Y90 radioembolization
is fatigue, which occurs in approximately 50–60% of patients
and peaks within the rst week aer treatment. Fewer patients
experience low-grade abdominal pain or nausea/vomiting,
both of which are well controlled with oral medications.
Meticulous angiographic technique is absolutely essential
to identify potential routes of extrahepatic non-target radioembolization. Radiation-induced gastrointestinal ulcers
do not respond to proton-pump inhibitors and may require
17
129
Section III:Primary liver cancers
http://internalmedicinebook.com
surgical resection in patients who are already high-risk surgical candidates.
In the largest reported series of biliary complications following Y90 radioembolization, 10% of patients demonstrated
imaging ndings related to the biliary tree, of which 1.8%
required an unplanned interventional or surgical procedure.
Findings included biliary necrosis (3.9%), biloma (1%), biliary
stricture (2.4%), gallbladder wall enhancement (1.8%), and
gallbladder wall disruption (0.9%).
18
Severe liver-related toxicity (grade 3 or 4)has been shown
to occur in approximately one-third of patients with unresectable HCC treated with glass microspheres, and the risk of toxic-
Table 14.1 Median overall sur vival (in months) based on Barcelona Clinic
Liver Cancer (BCLC) stage following Y90 radioembolization
Salem etal.
BCLC A 26.9 – 24.4
BCLC B 17.2 16.4 16.9
BCLC C 7.3 – 10.0
BCLC D 2.5 – –
Table 14.2 Median time to tumor progression (T TP) (in months) for
patients with and without hepatocellular carcinoma portal vein thrombus
(PVT) following Y90 radioembolization
17
Hilgard etal.
24
Sangro etal.
25
ity appears to be related to the pretreatment total bilirubin and
mean liver radiation dose. e majority of the toxicities (approximately 80%) resolve within the short term.19 Toxicity following radioembolization with resin microspheres in patients with
HCC as well as metastatic disease to the liver has been shown
to be related to the activity delivered and the number of prior
treatments.
20
RILD is the most severe potential hepatotoxicity from Y90
Salem etal.17Hilgard etal.
PVT absent CP-A 15.5
CP-B 13.0
PVT present CP-A 5.6
CP-B 5.9
CP = Child–Pugh score.
11.8 13.0
8.0 7.0
24
Mazzaferro
26
etal.
radioembolization. Previously referred to as radiation hepatitis
and originally described in patients receiving external-beam
radiation, RILD demonstrates pathologic ndings of sinusoidal congestion, venous occlusion, and hepatic brosis. RILD
Table 14.3 Median overall survival (in months) for patients with and
without hepatocellular carcinoma portal vein thrombus (PVT) following
Y90 radioembolization
presents clinically with nausea, vomiting, abdominal pain,
jaundice, and ascites, typically 4–8weeks aer radiation exposure, but has been reported to occur between 2 and 24weeks.
Greater than twofold elevation of alkaline phosphatase is the
most specic of liver chemistry abnormalities. Outcomes are
variable, with a minority of patients dying of fulminant hepatic
failure during the acute phase while the majority of patients
survive with chronic liver failure. Rates of RILD following radioembolization have been reported between 4% and nearly 7%,
which includes patients with metastatic disease to the liver previously treated with chemotherapy.
20,21
ere is no predictive model for the development of
RILD following radioembolization. Aretrospective analysis
of 680 radioembolization treatments in 515 patients using
resin microspheres failed to generate a predictive model for
RILD, although the use of an empiric model in the calculation of resin microspheres dosimetry, which is no longer recommended, has been associated with RILD.20 Pathologically
conrmed RILD has not been reported in patients receiving
glass microsphere radioembolization for unresectable HCC.19
Nonetheless, careful patient selection and appropriate radiation dosimetry are critical to minimize the risk of radiation
injury to theliver.
Clinical outcomes
A number of large studies have been published reporting the
long-term outcomes following radioembolization in patients
with intermediate- and advanced-stage HCC (Table 14.1,
Table14.2, and Table14.3). As a context for the natural his-
tory of HCC, a meta-analysis of the reported survival rates
of untreated HCC patients included in randomized controlled trials indicated 1-year survival rates for intermediate
Salem etal.17Hilgard etal.
PVT absent CP-A 22.1
CP-B 14.8
PVT present CP-A 10.4
CP-B 5.6
CP = Child–Pugh score.
16.4 18.0
10.0 13.0
(Barcelona Clinic Liver Cancer (BCLC B)) and advanced
(BCLC C) stage HCC of approximately 50% and 25%,
respectively.
22
While there has been no randomized trial comparing
radioembolization to conventional transarterial chemoembolization (cTACE), a comparative eectiveness report evaluating outcomes following radioembolization and cTACE
in a 245-patient cohort showed that adverse events, clinical toxicities, response rate, and time-to-tumor-progression
(TTP) were improved with radioembolization compared to
cTACE. ere was no dierence in overall survival between
radioembolization and cTACE. Post-hoc analyses concluded
that a sample size of more than 1,000 patients would be
required to establish survival equivalence between cTACE
and radioembolization.
23
A comprehensive report of the long-term outcomes of a
291-patient cohort with intermediate- and advanced-stage HCC
describes toxicity, imaging, and survival outcomes stratied
according to BCLC stage, United Network for Organ Sharing
(UNOS) tumor stage, and Child–Pugh classication.17 e
report demonstrates favorable outcomes following radioembolization that compare well to standard-of-care cTACE, as well
as indicating that, for patients with HCC and advanced liver
Mazzaferro
24
etal.
26
130
Chapter14:Y90 radioembolization forHCC
http://internalmedicinebook.com
disease, Y90 may provide a treatment option that could lead to
successful downstaging and transplant not only in patients with
Child–Pugh Adisease, but also Child–Pugh B disease.
e authors report imaging response rates to radioembolization of 42% and 57% according to World Health Organization
(WHO) and European Association for the Study of the Liver
(EASL) criteria, respectively. Twenty-three percent of patients
had a complete response by EASL criteria. e time to partial response was 6.6months according to WHO criteria and
2.1months by EASL criteria.
Median TTP for the entire cohort was 7.9months, with
median TTP of 15.5months for Child–Pugh Aand 13.0months
for Child–Pugh B in the absence of portal vein thrombosis
(PVT). In the presence of PVT, median TTP decreased to 5.6
and 5.9months for Child–Pugh Aand B, respectively. Median
overall survival was 17.2 months for Child–Pugh A and
14.8months for Child–Pugh B patients with no PVT or extrahepatic disease. Median overall survival was 7.7months for all
Child–Pugh B patients, including those with PVT and extrahepatic disease.
It is important to note that the median TTP for all
Child–Pugh B patients was 8.4months despite a median overall survival of 7.7months, which highlights the competing risks
of death from underlying liver disease and HCC, as well as the
impact of underlying liver function on survival.
e most common side eect was fatigue, occurring in
>50% of patients. Grade 3–4 bilirubin toxicity occurred in 19%
of patients, which is consistent with the natural biology of HCC
and cirrhosis.
A subsequent study of a European cohort of 108 patients
further validated the safety and ecacy of Y90 radioembolization for locally advanced HCC with or without PVT.24 At
3-month follow-up, the authors report a partial response in
15% and stable disease in 79% according to WHO criteria, with
complete response in 3%, partial response in 37%, and stable
disease in 53% according to EASL criteria.
Median TTP for all patients in the cohort was 10.0months.
For patients with PVT, this decreased to 8.0months, whereas
patients without macrovascular invasion (PVT) had a median
TTP of 11.8months.
Median overall survival for all patients in the cohort was
16.4 months. Child–Pugh A patients had a median overall
survival of 17.2months, whereas Child–Pugh B patients had
a median overall survival of 6months. In the absence of PVT,
median overall survival was 16.4months, while the presence of
PVT decreased overall survival to 10months.
e most common side eect was fatigue, occurring in 61%
of patients, followed by vague abdominal pain, occurring in
56%. Biochemical toxicity, specically grade 3 or 4 elevation
of bilirubin, was more likely to occur in patients with elevated
bilirubin at baseline compared to patients with normal levels at
baseline (20% vs. 3%). Bilirubin levels returned to baseline in
all patients within 4–6weeks.
A multicenter analysis of 325 patients undertaken to evaluate the prognostic factors aecting survival following Y90
radioembolization reported ECOG status, tumor burden (>5
nodules), international normalized ratio >1.2 and extrahepatic
disease as the most signicant independent prognostic factors
in a patient cohort, of which 56% were BCLC C and 26.8% were
BCLC B. Stratied by BCLC stage, median overall survival
was 24.4months for BCLC A, 16.9months for BCLC B, and
10.0months for BCLCC.
25
e rst prospective, phase II trial to evaluate the safety
and ecacy of Y90 radioembolization in intermediate and
advanced HCC included 52 patients and evaluated TTP as
the primary endpoint.26 e median TTP was 11months for
all patients. For patients with PVT, median TTP was 7months
compared to 13months in patients without PVT, although the
dierence was not statistically signicant. Median overall survival was 15months, with a non-signicant trend in favor of
patients without PVT (18months without PVT vs. 13months
withPVT).
Objective tumor response was 40.4%, with complete
response of 9.6%. On multivariate analysis, tumor response
was the only variable aecting TTP, while Child–Pugh class
and tumor response were the two variables aecting survival.
e authors concluded that the TTP and overall survival for
patients with PVT (BCLC C) following Y90 radioembolization
compares favorably to systemic treatment with sorafenib, and
achieves similar outcomes in patients with intermediate-stage
HCC (BCLC B) compared to TACE. e authors also conclude that the study proves that the prognosis of PVT may
be improved with Y90 and conrms prior observations that
PVT is the HCC presentation that benets most from Y90
radioembolization.
26
Y90 radioembolization provides substantial rates of
downstaging HCC patients to potentially curative therapies,
including transplantation, resection, or ablation. e rates of
successful downstaging to transplantation are superior for
Y90 radioembolization compared to cTACE. In one study,
66% of patients who were not eligible for transplantation,
resection, or ablation were successfully downstaged to one of
these treatments aer radioembolization.27 In another study,
58% of patients with UNOS T3 disease (outside transplant
criteria) treated with radioembolization were downstaged to
transplant-eligible T2 disease compared to 31% of patients
treated with cTACE.
28
Diversion of portal venous ow away from the liver parenchyma with a transjugular intrahepatic portosystemic shunt
(TIPS) has raised concern about the use of embolic transarterial therapies in patients with TIPS due to further reduction
in liver perfusion resulting in hepatic ischemia. Aretrospective comparison of patients with and without TIPS undergoing chemoembolization reported signicantly higher
rates of severe hepatotoxicity in the patients with TIPS.29
Radioembolization, however, is minimally embolic and has
previously been shown to be safe and eective in the setting
of partial and branch portal vein thrombosis.
9,10
A recent
report of Y90 radioembolization in the presence of TIPS indicated rates of hepatotoxicity comparable to those previously
reported for Y90 in patients without TIPS. e authors concluded that radioembolization may be safely performed in
patients with unresectable HCC and TIPS, particularly as a
bridge to liver transplantation.
30
131
Section III:Primary liver cancers
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15. Salem R, urston KG. Radioembolization with 90Yttrium
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133
Chapter
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Image-guided therapy of intrahepatic cholangiocarcinoma
15
Michael C. Soulen and William S. Rilling
Our understanding and management of intrahepatic cholangiocarcinoma have evolved substantially over the past 5years,
leading to a new staging system distinct from that used for primary hepatocellular carcinoma (HCC), and identication of
prognostic imaging and histologic phenotypes which provide
more sophisticated guidance for triage.
While primary liver cancer is recognized as among the most
deadly malignancies on the planet, approximately 10% of primary hepatobiliary tumors are cholangiocarcinomas. Ninety
percent of these originate in the extrahepatic ducts, leaving
about 10% as intrahepatic cholangiocarcinomas. ese relatively rare tumors account for less than 10,000 new cancers in the
USA annually and about 3% of gastrointestinal cancers worldwide. e incidence appears to be increasing globally; however,
> 100U/mL (normal up to 37 U/mL) is 68% sensitive and
96% specic for intrahepatic cholangiocarcinoma in patients
without sclerosing cholangitis.10 Less-specic tumor marker
elevations include carcinoembryonic antigen, CA-125, and
alpha-fetoprotein, with 10% having a mixed hepatocholangiocarcinoma histology.
e staging of intrahepatic cholangiocarcinoma has evolved
over the past decade. e current American Joint Committee
on Cancer-7 staging system (2009) invoked revisions that distinguish the important prognostic factors for cholangiocarcinoma from HCC.11 Tumor size is no longer a factor; the critical
features are tumor number, vascular invasion, and metastasis
(Table15.1). is system better discriminates prognosis among
stages than its predecessors.
this is associated with an improvement in immunohistochemical diagnosis, with more tumors previously categorized as adenocarcinoma of unknown primary now recognized as being of
pancreaticobiliary origin, likely cholangiocarcinoma.
1,2,3
Unlike HCC, most patients with intrahepatic cholangiocarcinoma have no known risk factors. Recognized risks include
conditions associated with chronic inammation or infection
of the biliary tree, such as sclerosing cholangitis, choledochal
cyst, biliary cirrhosis, parasitic infections, and hepatic cirrho-
4,5
sis.
However, 90% of patients lack any predisposing condition, so routine surveillance is the exception and diagnosis
is oen delayed until symptoms develop in advanced stages.
Early lymphatic spread, bone metastases, and intrahepatic liver
metastases are more common than in HCC. Macrovascular
invasion is seen similarly toHCC.
Diagnosis of intrahepatic cholangiocarcinoma can be
challenging. Imaging appearance is variable, with three imaging phenotypes described as mass-forming, inltrative, and
intraductal invasion.6 Tumor vascularity is highly variable,
with late enhancement a distinguishing feature from HCC.
7,8,9
orough diagnostic imaging and endoscopy are necessary
to exclude other primaries. Biopsy diagnosis can be dicult
due to desmoplastic stroma and poorly dierentiated histology. Immunohistochemical stains can suggest a biliary origin,
while negative stains help to exclude other tissues of origin
such as primary liver or metastasis from pancreas, colon,
breast, or lung cancer. Tumor markers can be helpful to distinguish cholangiocarcinoma from HCC. A CA-19-9 level
Assessment andtriage
As with all hepatic malignancies, the initial evaluation requires
clinical, laboratory, and imaging data. Assessment of symptoms
and performance status are critical for therapeutic decision
making. Laboratory test results such as liver and kidney function help determine eligibility for potential therapies. Imaging
and pathologic staging guide triage among treatment options.
(Figure15.1).
Curative therapies
e rst decision point is between curative and non-curative
therapies. All patients should be assessed for resectability on
medical and anatomic grounds. Unlike in HCC, positron emission tomography (PET) computed tomography (CT) can be
useful in cholangiocarcinoma, with uorodeoxyglucose (FDG)
avidity in 78–85% of primary tumors and occult metastases
diagnosed in 24–36% of patients, leading to altered management in up to 30% of patients.
In modern series, patients taken to surgery achieved R0
resections in 70–88% of attempts, with median progression-free
survival (PFS) of 12–20months and 5-year overall survival of
25–40% (Table15.2).14 is was conrmed in a recent analysis
of an international registry comprising 301 resected patients.15
Median recurrence-free survival was 20 months and 5-year
disease-free survival was 32%. Sixty-one percent of recurrences
were in the liver only, while 21% were solely extrahepatic.
12,13
Interventional Oncology, Second Edition, ed. Jean-François H.Geschwind and Michael C.Soulen. Published by Cambridge University Press.
©Cambridge University Press2016
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Chapter15 :Image-guided therapy of intrahepatic cholangiocarcinoma
http://internalmedicinebook.com
Solitary tumor
Not infiltrative
No perineural/lymphovascular
invasion
Neoadjuvant Therapy
Liver Transplantation
Resectable
Not transplant
candidate
Neoadjuvant Therapy
Resect/Ablate
Unresectable
Liver-dominant
CHILDS A/B
PS 0-2
CHILDS C
PS 3-4
Figure 15.1 Triage of intrahepatic
cholangiocarcinoma. PS = performance
status.
Adjuvant Therapy
<3 cm ABLATE
Hospice
3-6 cm EMBO +
ABLATE
>6 cm/multifocal EMBO
Macrovascular invasion, positive nodes, and tumor > 5 cm
were independent predictors for recurrence.
Because lymphatic spread is common and gravely aects
prognosis, patients with suspicion of nodal involvement may
Systemic Therapy
benet from a test of time with neoadjuvant therapy (systemic
and/or liver-directed) before attempting resection. Portal lymphadenectomy is recommended at the time of resection, if
only for prognostic purposes, although the surgical management of node-positive patients is controversial, with some sur-
Table 15.1 American Joint Committee on Cancer-7 staging of
intrahepatic cholangiocarcinoma (2009).11 Stages 1–3 are based solely on
T status, which is determined by multiplicity and invasiveness, but not
tumor size
T1 1 tumor, no MVI
T2 >1 tumor or MVI
T3 Tumor through capsule
Stage 1 T1 N0 M0
Stage 2 T2 N0 M0
Stage 3 T3 N0 M0
Stage 4 Tx N1 or M1
MVI = macrovascular invasion; T = tumor; N = node; M = metastasis.
geons advocating no resection in patients found to have nodal
involvement.16 Most patients recur in the liver aer resection,
with only 20–30% of postoperative failure occurring solely
outside the liver. Because of the high recurrence rate, adjuvant
chemoradiotherapy should be considered.
17,18
Many adjuvant
drug combinations have been studied in the phase II setting
suggesting benet, but randomized data are lacking.
Liver transplantation for intrahepatic cholangiocarcinoma
had fallen into disfavor because of high recurrence rates and
poor long-term survival. Critical analysis has identied risk
factors for posttransplant recurrence which can be identied
on imaging or biopsy:multifocal primary (hazard ratio (HR)
9.6), perineural invasion (HR 8.3), inltrative pattern (HR 5.3),
absence of neoadjuvant therapy (HR 4), sclerosing cholangitis
Table 15.2 Series of patients undergoing resection of intrahepatic cholangiocarcinoma
Author Year No. of patients
Inoue 2000 52 69 18 36 36
Weber 2001 33 88 37.4 55 NR
Endo 2008 82 85 36 NR NR
Konstadoulakis 2008 54 78 NR 49 25
Nakagohri 2008 56 75 22 42 32
Choi 2009 64 86 39 53 40
De Jong 2011 449 81 27 44 31
Fisher 2012 58 84 23 NR NR
Total/mean 848 81 46.5 33
R0 = complete resection; OS = overall survival; NR = not reported.
Modified from Maithel SK, Gamblin TC, Kamel I, et al. Multidisciplinary approaches to intrahepatic cholangiocarcinoma. Cancer 2013; 119: 3929–3942.
R0 resection
rate (%)
Median OS
(months)
3-year OS rate
(%)
5-year OS rate
(%)
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Section III:Primary liver cancers
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100
90
80
70
60
50
free survival
40
% Disease recurrence-
30
P < 0.001
Low risk
Intermediate risk
96% technique ecacy, median PFS of 17months, overall survival of 33months, and 5-year survival of29%.
22
Another Chinese study compared repeat resection (n=32,
44 tumors) to radiofrequency ablation (n = 77, 133 tumors)
for recurrent intrahepatic cholangiocarcinoma.23 All resections were R0. Primary technique eectiveness of ablation was
95%, with A0 ablation achieved in 6/7 patients with residual
tumor following a second ablation procedure. Median PFS was
9.1months following resection and 6.8months aer ablation.
PFS at 1year was 37% and 33%, respectively (P=0.69). Overall
survival was almost identical between the groups as a whole,
but among patients with recurrent tumors >3 cm, resection
had superior overall survival. is study suggests that recur-
20
10
High risk
0
0
12 24 36 48 60
Post-transplant month
rences <3cm are equally eectively treated by ablation when
feasible.
Non-curative therapies
For unresectable and metastatic disease, systemic chemotherapy with gemcitabine and cisplatin has an NCCN category 1
Hazard
Variable
Tumor histology and extension
Multifocality
Perineural invasion
Infiltrative growth pattern
Lymphovascular invasion
No neoadjuvant therapy
History of primary sclerosing cholangitis
Figure 15.2 Predictive model for recurrence-free survival following
transplantation for intrahepatic cholangiocarcinoma. (Reproduced from
Hong JC, Petrowsky H, Kaldas FM, et al. Predictive index for tumor recurrence
after liver transplantation for locally advanced intrahepatic and hilar
cholangiocarcinoma. J Am Coll Surg 2011; 212: 514–520, with permission.)
ratio
9.6
8.3
5.3
2.1
4
2.5
p Value
<0.001
<0.001
0.030
0.099
0.005
0.062
recommendation based on a randomized trial demonstrating
improvement in median survival from 8.1 to 11.7months compared to cisplatinum alone.
17,18,24
e majority of patients in
systemic therapy trials have extrahepatic biliary tract cancer, so
it is not possible to dissect out the impact of chemotherapy on
intrahepatic cholangiocarcinomas. Neither the NCCN nor the
European Society for Medical Oncology (ESMO) guidelines
include intra-arterial therapies.
Chemoembolization
In the largest reported series, 115 patients underwent 815
Lipiodol chemoembolization procedures with mitomycin C,
mitomycin + gemcitabine, or mitomycin + gemcitabine + cisplatin.25 Disease control was achieved in 66%, with overall survival following embolization at 1, 2, and 3years of 52%, 29%,
(HR 2.5), and lymphovascular invasion (HR 2.1).19 Combining
these into a risk score, patients with low scores had a 5-year
survival following liver transplantation of 78%, compared to
19% for intermediate scores and 0 for high scores (Figure15.2).
Percutaneous ablation
National Comprehensive Cancer Network (NCCN) guidelines
recommend both resection and ablation for limited disease.
For patients presenting with an appropriately small tumor
burden, or with intrahepatic recurrence aer resection, percutaneous ablation may be an alternative to surgery. A study of
radiofrequency ablation of 29 recurrent nodules in 20 patients
reported 97% technique ecacy with local PFS of 74% at
4years, but overall survival was only 21% at 4years.20 Another
study of radiofrequency ablation of 25 nodules in 18 patients
reported technical success in 23/25, with the two failures both
>6cm in diameter. Five-year overall survival was 30% for the
entire group, but 62.5% for the subset in which the primary
tumor was treated (as opposed to a recurrence). Multiple primary nodules were predictors for recurrence.21 Astudy of 26
tumors among 17 patients in China had similar results, with
and 10%. e drug regimen employed did not impact survival.
Survival was better among patients with hypervascular tumors
(vs. hypovascular) and Child A(vs. B) cirrhosis.
e largest US series is a two-center study of CAM (cisplatin, Adriamycin, mitomycin)–Lipiodol–polyvinyl alcohol chemoembolization in 62 patients (162 procedures).26
Disease control was achieved in 76%, with a median time
to progression of 8months and 28% free of progression at
1year. Overall survival at 1, 2, and 3years was 75%, 39%,
and 17%. Addition of systemic chemotherapy signicantly
improved median survival from 16 to 28months (HR 1.9,
P=0.02).
A meta-analysis of 16 series comprising 542 subjects found
weighted median survivals of 15.7±6months from diagnosis
and 13.4±7months from chemoembolization (Table15.3).27
Objective responses were seen in 23% and stable disease in
54%, for a disease control rate of 77%. Technique varied widely
among the global distribution of centers in the meta-analysis.
Outcomes among the four series employing drug-eluting
beads were not dierent from the remaining series. Outcomes
from chemoembolization were superior to reports of systemic
chemotherapyalone.
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Chapter15 :Image-guided therapy of intrahepatic cholangiocarcinoma
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Table 15.3 Summary of selected chemoembolization series
Median survival
No. of
a
Kirchhoff
2005 8 Cis/Dox DSM 12 12
Burger 2005 17 CAM PVA,
a
Herber
2007 15 MMC None 16.3 16.3 54.5
Shitara 2008 20 MMC DSM 14.1 60
Kim 2008 49 Cis Gelfoam 12 10 46
Gusani 2008 42 Gem, Cis, Ox Embospheres 9.1
Aliberti 2008 11 Dox DEB 13 76
Poggi 2009 9 Ox DEB 30 70
Kiefer 2010 62 CAM PVA 20 15 75
Andrasina 2010 17 CIS, 5FU none 25.2 88
Schiffman 2011 24 Iri/Dox DEB 17.5 68
Park 2011 72 Cis Gelfoam 12.2 51
Vogl 2012 115 MMC, Cis, Gem DEB 13 52
Kuhlmann 2012 36 Iri/MMC DEB, Gelfoam 10 41.6
Total/mean 489 17.3 14.3 62
TACE = transarterial chemoembolization; OS = overall survival; Cis = cisplatin; Dox = doxorubicin; DSM = degradable starch microspheres; CAM = cisplatin +
doxorubicin + mitomycin C; PVA = polyvinyl alcohol; MMC = mitomycin C; DEB, drug-eluting beads; Gem = gemcitabine; Ox = oxaliplatin; 5FU = 5-fluorouracil;
Iri = irinoteca.
a
Study does not state if survival time is from diagnosis or TACE.
Modified from Ray CE, Edwards A, Smith MT, et al. Metaanalysis of survival, complications and imaging response following chemotherapy-based transarterial
therapy in patients with unresectable intrahepatic cholangiocarcinoma. J Vasc Intervent Radiol 2013; 24: 1218–1226.
Author Year
patients Chemotherapy Embolic
Embospheres
from diagnosis
(months)
23
Median survival
from TACE (months) 1-year OS (%)
Radioembolization
Radioembolization with yttrium-90 microspheres is an appealing alternative to chemoembolization for intrahepatic cholangiocarcinoma, because of the recognized responsiveness of
extrahepatic biliary tract cancers to radiation, and also the lesser
clinical toxicity and impact on quality of life relative to chemoembolization.28 Experience is limited, with only four small
single-institution series reported.
29,30,31,32
ese four series, comprising 123 patients, reported disease control rates of 89–98%
with median survivals of 9–15months from embolization and
22–25months from diagnosis, including those downstaged to
resection. e majority of patients in these series received a
variety of other therapies, including systemic, surgery, and ablation. Commonly observed prognostic factors were multifocal
tumor, inltrative phenotype, and performance status.
2. Shaib YH, Davila JA, McGlynn K, El-Serag HB. Rising incidence
of intrahepatic cholangiocarcinoma in the United States:a true
increase? J Hepatol 2004; 40:472–477.
3. Buc E, Lesurtel M, Belghiti J. Is preoperative histological
diagnosis necessary before referral to major surgery for
cholangiocarcinoma? HPB (Oxford) 2008; 10:98–105.
4. Donato F, Gelatti U, Tagger A, etal. Intrahepatic
cholangiocarcinoma and hepatitis C and B virus infection,
alcohol intake, and hepatolithiasis:a case-control study in Italy.
Cancer Causes Control 2001; 12:959–964.
5. Welzel TM, Graubard BI, El-Serag HB, etal. Risk factors for
intrahepatic and extrahepatic cholangiocarcinoma in the United
States:a population-based case-control study. Clin Gastroenterol
Hepatol 2007; 5:1221–1228.
6. Chung YE, Kim MJ, Park YN, etal. Varying appearances
of cholangiocarcinoma:radiologic–pathologic correlation.
Radiographics. 2009; 29:683–700.
Multidisciplinary approach
Intrahepatic cholangiocarcinoma is a rare and challenging
tumor. Patients benet from a multidisciplinary team approach
employing all possible options either sequentially or concurrently to maximize the duration of disease control while preserving quality oflife.
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