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Chapter18:Radioembolization forCRLM
http://internalmedicinebook.com
Best indicators of overall liver function, according to the
oncologic literature, include prothrombin time, albumin, and
total bilirubin.12 Aserum albumin of >3.5g/dL and a total bilirubin of ≤2.0mg/dL is generally suggested as an inclusion criterion for radioembolization. Carcinoembryonic antigen (CEA)
is the most common tumor blood marker used for screening,
initial staging, and response assessment in colorectal cancer.
Appropriate staging before radioembolization includes
cross-sectional imaging with computed tomography (CT),
magnetic resonance imaging (MRI), and/or positron emission
tomography (PET). An abdominal CT scan is helpful to determine the location of the liver tumor(s), the degree of inltration of the liver, and the presence of any extrahepatic disease.
e use of PET for the staging of patients with liver metastases
is analogous to its clinical use in patients with lymphoma.
13
Alternative therapies include transarterial chemoembolization (TACE) with or without drug-eluting beads and bland
embolization.
14,15
While the presence of PVT without cavernous transformation and hepatopetal ow is a well-accepted
relative contraindication for TACE, radioembolization is
Aer all vessels of concern have been coil-embolized and
are no longer patent on angiography, the use of CT hepatic angiography (CTHA) may be helpful, using large-volume contrast
agent injected through the indwelling arterial microcatheter. CT
images are obtained to delineate the vascular territory served by
the planned catheter placement, and therefore to predict distribution of the microspheres. If any extrahepatic perfusion is detected
on CTHA, additional coil embolization or catheter reposition is
performed until CTHA shows no evidence of persistent extrahepatic enhancement. e patient is then transferred to a nuclear
medicine suite for technetium-99m-labeled macroaggregated
albumin (
99m
size of
99m
Tc-MAA) scintigraphy. In this technique 4–5mCi
Tc-MAA is injected via the hepatic artery catheter. Because the
99m
Tc-MAA closely mimics that of 90Y microspheres, it is
assumed that the distribution of the microspheres will be identical
99m
to
Tc-MAA. Potential lung shunting is assessed using planar or
single-photon emission computed tomography gamma cameras.
If the distribution of
99m
Tc-MAA is largely conned to the liver,
and hepatopulmonary shunting satisfactorily low, patients return
within 1–2weeks for the radioembolization procedure.
usually well tolerated in patients with PVT due to minimal
alteration in vascularity and minimal to moderate embolic
phenomena.
16,17
It can be used in patients with multiple liver
lesions, and for the palliation of painful bulky tumors. It
might also be used before radiofrequency ablation to shrink
the tumor(s) to a size at which radiofrequency ablation
becomes feasible.
Treatment process
e selection of an activity of 90Y to deliver into the liver is a
critical aspect in the treatment process. e activity for each
patient dose is calculated according to the methods described
below, as published previously.25 Microspheres are injected
through a temporary hepatic artery catheter placed percutan-
Preimplantation workup procedure
Mesenteric angiography and the assessment of lung shunting
are essential as part of the preimplantation procedure for radioembolization.
18,19,20
Meticulous, power-injected digital subtraction angiography is necessary to map all relevant vessels in
the hepatic, gastric, and mesenteric beds, including anatomical
variants, extremely small branches, and collateral vessels.
18,21
e
initial angiographic evaluation has been described in detail else-
18,20
where
; it should include an abdominal aortogram, superior
mesenteric and celiac arteriogram, and selective right and le
hepatic arteriogram. During each step of the visceral angiography, assessment for potential gastric or small-bowel ow must be
made. e celiac arteriogram is used to detect arterial variants,
such as the replaced le hepatic artery, double hepatic arteries, or
parasitization of blood ow to the liver tumors.
18,22,23
Depending
on the proximity of the le gastric branch to the other hepatic
branches, coil embolization of this vessel may be necessary to minimize the risk of reux during 90Y infusion.
18,24
e gastroduodenal
artery should be identied and prophylactically coil-embolized.
e right gastric artery should also be identied during angiography. Depending on the anatomic location of the right gastric
artery and the relative ease with which distal catheterization may
be achieved for infusion, prophylactic coil embolization may be
necessary to prevent gastrointestinal deposition of the microsphe
18,23,24
res.
Other vessels that should be identied include the cystic,
supraduodenal, retroduodenal, falciform, accessory le gastric,
and right and le inferior phrenic arteries.
18,20,23
eously through the femoral or brachial artery. Treatment for
bilobar liver disease is usually performed in the same procedure either as a single dose to both lobes (via the hepatic artery
proper) or as divided doses to the le and right lobes. In the
latter case, sequential bilobar administration is performed with
a measured fraction of microspheres injected sequentially into
the right and le hepatic arteries. Alternatively, 90Y may be
administered with one treatment to each target vascular bed
(usually the hepatic lobe or segment) at 30–60-day intervals.25
Because of their specic size microspheres become lodged in
the small arteries of the tumor close to the capillary bed.26 ey
do not pass through into the venous system and therefore cannot be found in the blood, urine, or other body uids.26 e
tumor is then destroyed by the local radiation eect.
Dosimetry and dose calculation
25
26
TheraSphere
e recommended activity of eraSphere to be delivered to a
lobe of the liver containing tumor is 80–150Gy. e most commonly used dose range is 120–130Gy, a range that balances safety
and ecacy. Assuming eraSphere 90Y microspheres distribute
in a uniform manner throughout the liver and undergo complete
decay in situ, radioactivity required to deliver the desired dose to
the liver can be calculated using the following formula27:
Activity required GBq
DesireddoseGytargetliver mass k
(
=
(
)
×
)
gg
(
)
50
159
Section IV:Liver metastases
http://internalmedicinebook.com
Given that a fraction of the microspheres will ow into the
pulmonary circulation without lodging in the arterioles, when
lung shunt fraction (LSF) and vial residual (R)are taken into
account, the actual dose delivered to the target volume aer the
vial is infused becomes27:
Dose Gy =
(
)
50 Injected activity GBq1LSF1R
target li
(
×− ×−
)
vvermasskg
(
(
(
)
)
)
Liver volume (cc) is estimated with CT, and then converted to
mass using a conversion factor of 1.03mg/mL.
SIR-Spheres
Assuming SIR-Spheres 90Y microspheres distribute in a uniform manner throughout the liver and undergo complete
decay in situ, radioactivity delivered to the liver can be calculated using one of two available methods.
e rst method incorporates body surface area (BSA) and
estimate of tumor burden as follows5:
SIR-Spheres:Activity required (GBq)=BSA (m2) − 0.2 +
(%tumor involvement/100)
e second method is based on a broad estimate of tumor
burden. e larger the tumor burden, the higher the recommended activity in increments of 0.5GBq per 25% tumor burden. For either SIR-Spheres dosimetry model, activity (GBq)
is decreased depending on the extent of LSF (≤10% LSF:no
reduction, 10–15% LSF: 20% reduction, 15–20% LSF: 40%
reduction, >20% LSF:no treatment).
Calculation of lungdose
25
Radiation pneumonitis is a theoretical concern with 90Y treatment.
Previous preclinical and clinical studies with 90Y microspheres
demonstrated that up to 30Gy to the lungs could be tolerated
with a single injection, and up to 50Gy for multiple injections.
For this reason, patients with
99m
Tc-MAA evidence of
28
potential pulmonary shunting resulting in lung doses greater
than 50Gy should not be treated.
e absorbed lung radiation dose is the total cumulative
dose of all treatments29:
Although there is no evidence for ulcer prophylaxis in the
setting of radioembolization, gastric ulcer studies suggest that
routine proton-pump inhibitor therapy may be valuable to minimize the risks of gastrointestinal irritation.
31,32
In some cases,
unless contraindicated (e.g., diabetes), a tapering 5-day steroid
dose pack is also given to counteract fatigue.25 When corticosteroids are administered in the early postradioembolization period,
aggressive acid suppression should be undertaken.
90
Y is a high-energy pure beta-emitting isotope. Since the
21
radiation penetrates only 2.5mm (maximum 11mm) into tissue, it is conned to the patient and most patients will have less
than 1mrem/h surface readings aer 90Y treatment.25 90Y has a
half-life time of 64.1hours. Aer 5days only 25% of the initial
activity is present and aer 1month it is less than 0.1% and
hardly detectable.26 Hence, standard biohazard precautions are
sucient to protect others from exposure when the patient is
discharged. Trace amounts of free 90Y (25–50kBq/L/GBq) may
be detected in urine during the rst 24hours.
26
Side eects and toxicities
e majority of patients will experience some transient fatigue
aer radioembolization, oen with vague u-like symptoms.
is could be related to radiation eects on the normal liver
23,33
tissue.
unusual several days aer treatment. Other possible side eects
include abdominal pain, nausea, vomiting and, in rare cases,
radiation cholecystitis or radiation-induced liver disease, particularly in patients with compromised liver function at treatment.
Postembolization syndrome (20–30%)
e postembolization syndrome, which is experienced as a
result of radioembolization, is not as severe as that observed
with chemoembolization. It consists of symptoms such as
fatigue, nausea, vomiting, anorexia, fever, abdominal discomfort, and/or cachexia. It is also not uncommon for patients to
experience abdominal pain in the target organ during infusion
of (resin) microspheres. is oen resolves within 30–60minutes with the use of narcotics.
Radiation gastritis/gastrointestinal ulceration/
Symptoms of shaking, chills, and fever are also not
23
pancreatitis(≤5%)
umulativeabsorbedlungradiationondose 50
n
lung mass
∑
i
L
×−A
SSF
i
1
i
where Ai=activity infused (correcting for R in vial), LSFi=lung
shunt fraction during infusion, n = number of infusions,
approximate vascular lung mass (for both lungs, including
blood)=1kg.
30
Postprocedural care and follow-up
Postprocedure considerations
Because 90Y therapy has a low toxicity prole, the treatment can
be performed on an outpatient basis. Immediate postimplantation care includes the monitoring of the patient by qualied
sta for an hour; the patient can then be moved to a general
ward and discharged the sameday.
=×
Treatment of the le liver lobe may cause radiation gastritis
because of the proximity of the le lobe to the stomach. is is
called the attenuated radiation eect, a phenomenon also occasionally seen aer right-lobe treatment, manifesting as right
pleural eusion. Radiation-induced gastroduodenal ulceration is a relatively uncommon but serious complication of 90Y
radioembolization.
31,34,35
It is generally caused by non-targeted
ow of microspheres into the gastrointestinal tract.35 If patients
experience persistent epigastric pain with nausea, vomiting,
and dyspepsia that does not respond to medication, gastrointestinal ulceration must be suspected. e onset of symptoms
can range from hours to days aer radioembolization but may
appear aer some months.35 In most reported studies, the
ulcers completely resolved on conservative therapy.
Non-target administration of microspheres can also result
in pancreatitis which is usually characterized by immediate,
severe unremitting pain.
5,26
160
Chapter18:Radioembolization forCRLM
http://internalmedicinebook.com
Radiation pneumonitis(≤1%)
Radiation pneumonitis is caused by excessive radiation delivery to lung tissue. Routine lung shunt studies with calculation
of a cumulative lung dose of 50Gy maximum should mitigate
the risk of radiation pneumonitis.
27
Radiation hepatitis(≤1%)
Radiation hepatitis is typically characterized by the appearance
of non-malignant ascites coupled with increasing bilirubin and
decreasing albumin within 4–8weeks of radioembolization. It
is attributed to the irradiation of normal liver tissue beyond
that which is tolerated (≥30Gy). Findings associated with this
complication include hepatomegaly, jaundice, and derangement of liver function tests, leading subsequently to anicteric
ascites, liver shrinkage, signicant and permanent decline in
liver function, or fulminant hepatic failure.
21
Lymphopenia(40%)
Lymphopenia is another possible side eect of 90Y treatment,
usually as a result of the sensitivity of lymphocytes to radiation.
Biliary injury (≤10%)
Microspheres may lodge in vessels of the peribiliary plexus and
cause microscopic injury.18 As a result, abscess formation, biliary
necrosis, bilomas, and/or radiation cholecystitis may develop.
Radiation cholecystitis(≤2%)
Radiation-induced cholecystitis is characterized by right upper
quadrant pain. Although this complication can require cholecystectomy, this is not common. Imaging ndings of gallbladder injury (enhancing wall, mural rent) are quite common.
23,36
CT/PET evaluation of tumor response
Approximately 30 days following treatment and then at
2–3-month intervals thereaer, tumor response and overall
clinical status of the patient should be assessed. Liver function tests, complete blood count with dierential and tumor
markers, as well as cross-sectional imaging, are obtained. An
increase in markers at 30days might be caused by tumor lysis
or tumor progression in the liver, or indicate the presence of
extrahepatic disease. If tumor markers are unchanged, this can
be due to an interval stabilization or improvement in tumor
burden.25 Due to the diculty in interpreting clinical response
by tumor markers at 30 days, they should be reserved for
long-term clinical assessment.
25
Regarding the use of imaging to assess tumor response,
CT, MRI, and PET scanning have all been utilized following
90
Y treatment. Follow-up functional imaging such as MRI or
PET may be helpful.
37,38,39
It is important to employ the same
imaging modality both at baseline and follow-up. If MRI is
used, diusion-weighted imaging allows the documentation
of necrosis and cell death.39 CT may limit the ability to denitively document tumor necrosis. However, it provides anatomic information of tumor burden by indirect criteria, such
as size of the lesion and relative alterations in vascularity and
enhancement.25 PET is better at characterizing the functional
status of the tumor, both prior to and following treatment.38
In several studies published by Wong etal., PET was found
to be consistently superior at assessing tumor response to
therapy in metastatic colorectal liver lesions compared with
37,38
CT.
Literaturereview
SIR-Spheres– results
Although radioembolization was initially used as salvage therapy
for patients following sequential chemotherapy, there are currently several randomized controlled studies evaluating its use
when administered concurrently with rst- or second-line chemotherapy. ere are three large phase III RCTs with Sir-Spheres
resin microspheres. e results of the rst study, SIRFLOX (SirSpheres, rst-line FOLFOX6 + radioembolization vs. FOLFOX6
with or without bevacizumab), were announced at ASCO 2015.
ere was no signicant dierence (P = .43) in median PFS at
any site, however the was a signicant improvement in PFS in
the liver 12.6 v 20.5 months in control versus SIRT (P = .002).51
e other two studies, FOXFIORE and FOXFIRE Global have
completed accrual and, combined with SIRFLOX, will be adequately powered to detect a survival advantage. e results of
the combined OS analysis are anticipated in 2017. ere are no
direct comparisons to previous studies, however the CLOCC
(Chemotherapy + Local Ablation vs. Chemotherapy) study
36
showed that control of liver metastasis via a liver-directed therapy translated to an OS benet.
52
Radioembolization combined with rst-line
chemotherapy
Gray etal. reported a phase III randomized controlled trial in
74 patients with unresectable colorectal cancer, evaluating 90Y
microspheres plus rst-line intrahepatic FUDR versus FUDR
alone. Eighteen percent of patients in the intrahepatic chemotherapy arm and 44% in the chemotherapy plus 90Y arm had at
least a partial response (PR). e partial and complete response
(complete response) rate (PR+CR) was signicantly greater
for patients receiving 90Y when measured by tumor area (44%
vs. 17.6%), tumor volumes (50% vs. 24%), and CEA (72% vs.
47%). e median time to disease progression in the liver was
also signicantly longer for patients receiving 90Y compared to
those receiving intrahepatic chemotherapy alone when measured by tumor area (9.7 vs. 15.9months), tumor volume (7.6 vs.
12.0months), or CEA (5.7 vs. 6.7months). e 1- and 2-year
survival for patients receiving 90Y was 72% and 39%, compared
with 68% and 29% for intrahepatic chemotherapy alone. One
patient (3%) underwent a successful complete liver resection
following radioembolization and FUDR.
Van Hazel etal. reported a phase II randomized controlled
trial comparing 90Y microspheres plus rst-line systemic 5-FU/
leucovorin (5-FU/LV) versus 5-FU/LV alone in 21 patients
with unresectable liver metastases from colorectal cancer. e
authors concluded that a single dose of 90Y added to chemotherapy was associated with signicant increases in response
rate (91% vs. 0% of patients demonstrated a PR on follow-up
CT), time to disease progression (18.6 vs. 3.6months), and
median overall survival (29.4 vs. 12.8months) compared with
systemic chemotherapy alone.
41
40
161
Section IV:Liver metastases
http://internalmedicinebook.com
Sharma etal. completed a phase Istudy in 20 patients with
inoperable liver metastases from colorectal cancer using 90Y
microspheres with concomitant systemic oxaliplatin and 5-FU/
LV (modied FOLFOX4). e primary endpoint was toxicity.
Five patients experienced grade 3 abdominal pain, with 2 of them
having microsphere-induced gastric ulcers. e dose-limiting
toxicity (recorded in 12 patients) was grade 3 or 4 neutropenia.
One patient experienced an episode of transient grade 3 hepatotoxicity. e reported PR rate was 90%, and stable disease (SD)
10%. Two patients (10%) underwent a partial liver resection
aer radioembolization therapy and 3 of 20 patients (15%) were
down-staged. Median progression-free survival was 9.3months,
and median time to liver progression 12.3months.
42
Radioembolization combined with second- or third-line chemotherapy
Van Hazel etal. conducted a phase Istudy to evaluate the maximum tolerated dose of concomitant irinotecan and radioembolization in 25 uorouracil-refractory patients with colorectal
cancer liver metastases. Amaximum tolerated dose was not
reached and the results were promising, as demonstrated by an
overall response rate of 48%, a disease control rate (CR, PR, and
SD) of 87%, a median progression-free survival of 6months,
time to liver progression of 9.2months and a median overall
survival of 12.2months.
43
Lim et al. reported a prospective multicenter study of
radioembolization (with concurrent 5-FU at investigator discretion) in 30 patients with inoperable liver metastases from
colorectal cancer who had failed 5-FU-based chemotherapy.
One patient (3%) achieved a CR and 33% of patients a PR. e
median duration of response was 8.3months and the median
time to progression 5.3months. One patient (3%) underwent
a complete liver resection following radioembolization and
5-FU. Overall treatment-related toxicity was acceptable.
44
patients (17.2%). On multivariate analysis, radioembolization
was the most signicant predictor of survival.
46
Cosimelli et al. conducted a prospective phase II multicenter trial in 50 patients with highly chemorefractory metastatic colorectal cancer. e reported overall response rate
was 24%, with stable disease in another 24% of patients. e
treatment response aer radioembolization was highly predictive of prolonged survival, with a median overall survival of
13months and a signicant dierence between responders and
non-responders (16 vs. 8months, respectively). Further, two
patients (4%) were suciently downstaged to enable potentially curative liver resection of ≥3 segments.
47
Kennedy et al. reported on a retrospective multicenter
review of 208 patients with unresectable, chemorefractory
metastatic colorectal cancer. Patients had previously failed
irinotecan- and/or oxaliplatin-based standard chemotherapy
and were unsuitable for other liver-directed therapies. e
response rate by CT was 35.5%, with disease stabilization in
another 55% of patients, whereas the response rate by PET
was 85%. Treatment response aer radioembolization was
highly predictive of prolonged survival, with a median overall survival of 10.5months for responders vs. 4.5months for
non-responders or historical controls.
48
TheraSphere– results
Mulcahy etal. conducted an open-label study in 72 patients
with unresectable liver metastases from colorectal cancer who
were treated at a targeted dose of 120 Gy. e reported PR
(World Health Organization criteria) was 40.3%. e median
time to liver progression was 15.4 months, and the median
response duration 15months. Overall median survival from
the rst 90Y treatment was 14.5months, with a 5-year survival
rate of 30% from the time of cancer diagnosis.
Goin etal. reported a dose-escalation study in 43 patients
49
with colorectal liver metastases. e study was aimed to evalu-
Radioembolization as salvage therapy in
chemorefractory metastatic colorectalcancer
Hendlisz etal. conducted a multicenter randomized phase III
study to assess 90Y microspheres plus 5-FU versus 5-FU alone.
All 44 patients had failed oxaliplatin- and irinotecan-based
regimens. e median time to liver progression was signicantly longer in patients receiving radioembolization plus
5-FU (5.5 months) compared to 5-FU alone (2.1 months).
e median time to progression was also signicantly longer
(4.6 vs. 2.1months); median survival was 10.0months in the
radioembolization plus 5-FU treatment arm versus 7.3months
in the 5-FU-only arm. One patient (5%) was reported to have
undergone a complete liver resection following radioembolization and 5-FU.
45
Seidensticker etal. reported a phase II trial of 29 patients
which demonstrated that radioembolization signicantly
extended both overall survival and progression-free survival (8.3 months and 5.5 months, respectively) in patients
with chemorefractory metastatic colorectal cancer, compared
with a matched pair of 29 patients receiving supportive care
(5.5months and 2.1months, respectively). Aer radioembolization, a PR was observed in 12 patients (41.4%) and SD in 5
ate dose-related eects on survival, tumor response, and toxicity. No life-threatening or fatal toxicities were observed. e
median overall survival was 408days. Two patients had a CR,
8 (19%) a PR, and 35 (81%) SD. Higher doses were associated
with greater tumor response and increased survival.
50
Wong etal. conducted a prospective study to evaluate treatment in 13 lobes from 8 patients with unresectable colorectal
liver metastases. A metabolic response aer 90Y treatment,
assessed by PET, was present in a signicantly higher proportion of the lobes than was an anatomic response, evaluated
by CT or MRI (12 vs. 2 lobes, respectively). Five of the eight
patients had an improvement in their tumor activity, as assessed
by PET and conrmed by parallel changes in serum CEA. Since
serum CEA decreased signicantly aer treatment, correlating
with PET but not with CT or MRI, the study demonstrated a
signicant dierence between the metabolic and the anatomic
response following treatment with 90Y-glass microspheres.
38
Lewandowski etal. reported a phase II study in 27 patients
with unresectable colorectal metastases who had failed standard systemic chemotherapy regimes. Patients were treated with
a targeted dose of 135–150Gy. Tumor response measured by
PET imaging exceeded CT imaging for rst- (88% vs. 35%)
and second-treated (73% vs. 36%) lobes, respectively. Tumor
162
Chapter18:Radioembolization forCRLM
http://internalmedicinebook.com
replacement of 25% or less (vs. >25%) was associated with a
statistically signicant increase in median survival (339days
vs. 162days).14 Another large randomized controlled study is
currently under way (EPOCH), investigating radioembolization (glass microspheres) plus second-line chemotherapy vs.
second-line chemotherapyalone.
6. Sasson AR, Sigurdson ER. Surgical treatment of liver metastases.
Semin Oncol 2002; 29 (2):107–118.
7. Baker M, Pelley R. Hepatic metastases:Basic principles and
implications for radiologists. Radiology 1995; 197 (2):329–337.
8. Nordlinger B, Van Cutsem E, Rougier P, etal. Does
chemotherapy prior to liver resection increase the potential
for cure in patients with metastatic colorectal cancer? Areport
Conclusion
ere is sucient evidence to date to support the safety and
eectiveness of 90Y therapy in selected patients with colorectal
liver metastases. erapeutic doses of radiation can be delivered
with great selectivity into neoplastic liver tissue in a minimally
invasive procedure while normal liver parenchyma is spared. 90Y
therapy results in measurable tumor responses or delayed disease
progression in the majority of eligible patients with liver metastases from colorectal cancer. An advantage of radioembolization is
that the treatment can be administered to patients with multiple
and large-volume liver metastases, and even in patients who have
been heavily pretreated with chemotherapy. Most adverse events
are mild and transient, with the majority consisting of constitutional symptoms. However, radioembolization also carries
risks for serious complications, such as gastrointestinal ulceration, radiation cholecystitis, or radiation-induced liver disease.
Meticulous vascular mapping during the preimplantation angiogram with coil embolization of the gastroduodenal and right
gastric arteries, as well as other perforating vessels, will minimize
the risk of microsphere deposition into extrahepatic structures.
Careful patient selection and proper dose calculations will further minimize the incidence of severe complications to less than
10% of all treatments. Postprocedural follow-up of the patient to
assess side eects and tumor response is conducted at 30days and
then at 2–3-month intervals aer treatment. Since 90Y therapy is
a complex procedure it requires a skilled practitioner working
with a dedicated multidisciplinary team for safety and the best
outcome for the patient. Although to date clinical results with
radioembolization are promising, large controlled randomized
studies are currently ongoing to support the growing evidence
for its eciency.
from the European Colorectal Metastases Treatment Group. Eur
J Cancer 2007; 43:2037–2045.
9. Messersmith W, Laheru D, Hidalgo M. Recent advances in the
pharmacological treatment of colorectal cancer. Expert Opin
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10. Mulcahy MF, Benson AB, 3rd. Bevacizumab in the treatment of
colorectal cancer. Expert Opin Biol er 2005; 5 (7):997–1005.
11. Ho PM. Future directions in the use of antiangiogenic agents
in patients with colorectal cancer. Semin Oncol 2004; 31 (6 Suppl
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12. Yu AS, Keee EB. Management of hepatocellular carcinoma. Rev
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13. Jerusalem G, Hustinx R, Beguin Y, etal. Evaluation of therapy
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14. Lewandowski RJ, urston KG, Goin JE, etal. 90Y
Microsphere (eraSphere) treatment for unresectable
colorectal cancer metastases of the liver:Response to
treatment at targeted doses of 135–150 Gy as measured by
(18f) uorodeoxyglucose positron emission tomography and
computed tomographic imaging. J Vasc Interv Radiol 2005; 16
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82 (7):1250–1259.
16. Kulik L, Carr B, Mulcahy M. Safety and ecacy of 90Y
radiotherapy for hepatocellular carcinoma with and without
portal vein thrombosis. Hepatology 2008; 47:71–81.
17. Salem R, Lewandowski R, Roberts C. Use of Yttrium-90 glass
microspheres (eraSphere) for the treatment of unresectable
hepatocellular carcinoma in patients with portal vein
thrombosis. J Vasc Interv Radiol 2004; 15:335–345.
18. Liu DM, Salem R, Bui JT, etal. Angiographic considerations in
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Chapter
Assessment, triage, and liver-directed therapies for neuroendocrine tumor metastases
19
Terence P. Gade and Michael C.Soulen
Once considered rare, the incidence and prevalence of neuroendocrine tumors (NET) have increased rapidly, with a more than
vefold increase in incidence in the USA from 1973 to 2004
and a prevalence that is two to ve times that of esophageal
cancer, gastric cancer, pancreatic cancer, and hepatobiliary cancer1 (Figure19.1). e typically long delay in diagnosis of NETs
and their propensity for hepatic metastases create an important
role for liver-directed therapies. Challenged by the shortage of
physicians experienced in the diagnosis and management of
high-power microscopic elds or per 2mm2) or by the proliferative index (the percentage of cells immunolabeling for Ki-67).
Grades 1 and 2 imply well-dierentiated histopathology based
on the proliferative index, with the term carcinoma restricted
to grade 3, which includes high-grade, poorly dierentiated
large-cell or small-cell neuroendocrine carcinomas.4 e WHO
classication system replaces previous terminology, including
carcinoid and apudoma, as well as descriptions of embryonic
origin (Table19.1).
6
this disease, these long-lived patients oen access strong advocacy groups and web-based support sites which direct them to
centers of excellence with physician teams that oer a complete
understanding of the spectrum of their disease.2 It is essential
that interventional oncologists develop an intimate knowledge of the characteristics and management of NETs in order
to know how and when best to apply the armamentarium of
image-guided therapies, and guide patients in integrating these
with surgical, systemic, and supportive therapies.
Dening neuroendocrine disease
Terminology
Comprising a spectrum of epithelial neoplasms that originate
from cells which synthesize peptide hormones released in
response to a neuronal stimulus, neuroendocrine neoplasms
may develop sporadically or as part of familial syndromes
including multiple endocrine neoplasia, von Hippel–Lindau
syndrome, and neurobromatosis.3 ese neoplasms most
oen originate from the foregut gastroenteric, pancreatic, and
pulmonary tissues but may arise from any organ given the widespread distribution of neuroendocrine cells within thebody.
e World Health Organization (WHO) Classication of
Tumours of the Digestive System of 2010 addresses the classication of gastroenteropancreatic NETs.
on the major criteria determining malignant potential, including tumor histopathology or dierentiation, grade, site, size, and
stage, with the premise that all neuroendocrine neoplasms have
malignant potential. Tumor dierentiation describes the extent
to which the neoplasm resembles its non-neoplastic counterpart.
Tumor grade is based on proliferative activity, as determined by
the number of mitoses per unit area of tumor (mitoses per 10
4,5
is classication focuses
Demographics and epidemiology
Despite the relatively low incidence of NETs, they have a relatively high prevalence, estimated to be 123,312 cases as of 2013,
surpassing esophageal (33,839), gastric (72,269), pancreatic
(41,609), and hepatobiliary cancer (41,404), underscoring the
indolent course of neuroendocrine neoplasms relative to other
epithelial malignancies.
e median and mean age at diagnosis have remained stable over the past 30years at 63 and 62years, respectively, with
appendiceal and rectal neuroendocrine neoplasms having the
youngest ages at diagnosis.1 In their analysis of the Surveillance,
Epidemiology, and End Results (SEER) registry data from
2000 to 2004, Yao etal. reported that the gastrointestinal tract
remains the primary site of origin of NETs, comprising 50.6%
of all NETs, with the jejunum/ileum (13.4%) and colon (17.2%)
representing the most common sites of small- and large-bowel
disease, respectively. Lung primaries represent the majority of
extra-gastrointestinal disease, comprising 27% of all neuroendocrine neoplasms.
Diagnosis
Most neuroendocrine neoplasms are asymptomatic at their
early stages and are discovered incidentally on imaging or
surgery performed for unrelated disorders, leading to delayed
diagnosis, which rarely occurs prior to metastasis.7 e propensity for advanced disease at the time of diagnosis is underscored
by the etiology of the presenting symptoms, including local
tumor mass eect, tumor-induced brosis, and tumor-secreted
bioactive amines leading to emesis/abdominal pain, symptoms
of mechanical bowel obstruction, weight loss/abdominal pain,
and rectal bleeding/weight loss/abdominal pain, which are the
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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10000000
1000000
100000
10000
1000
100
10
1
COLORECTAL NET GASTRIC PANCREAS ESOPH HEPATOBIL
Table 19.1 2010 World Health Organization histologic classification of pancreatic neuroendocrine tumors
US Prevalence
Figure 19.1 Prevalence of gastrointestinal
cancers from the Surveillance, Epidemiology,
and End Results database as of 2013 (log
scale). Neuroendocrine tumors (NETs) are
second only to colorectal cancer.
4
Dierentiation Grade Mitoses/10HPF Ki-67 index (%)
Well G1 = Low < 2 ≤ 2
Well G2 = Intermediate 2–20 3–20
Poor G3 = High > 20 > 20
HPF = high-powered field.
most common symptoms of gastric, small-bowel, colon, and
rectal neuroendocrine neoplasms, respectively.8 Symptoms are
oen present for years before a diagnosis is made, with misattribution to irritable-bowel syndrome, asthma, or other confounding diagnoses.
e majority of patients with pulmonary neuroendocrine
neoplasms are asymptomatic at presentation. e classical triad
of cough, hemoptysis, and pneumonia is rarely seen. While
symptoms may vary based on the tumor cell of origin and specic secreted hormone (serotonin, catecholamine, dopamine,
histamine, gastrin, glucagon, prostaglandins), classical carcinoid syndrome, resulting in cutaneous ushing (most common), diarrhea, bronchoconstriction, and right-sided heart
failure, is relatively uncommon. It has been reported with
approximately 20% of small-bowel neuroendocrine neoplasms
and less than 5% of extra-enteric disease.7 Symptoms relating
to the secretion of bioactive amines generally coincide with
the development of liver metastases, since the liver normally
metabolizes hormones secreted by gastropancreatic and midgut NETs. In the presence of hepatic metastases the frequency
of carcinoid syndrome increases to 60%. Carcinoid syndrome
in the absence of liver metastases suggests a thoracic or ovarian origin, where the venous drainage is not ltered by the
liver. e measurement of the serotonin breakdown product
5-hydroxyindole-3-acetic acid within urine has a specicity
of 88% for serotonin-producing neuroendocrine neoplasms,
which encompasses disease within the small intestine.
Conrmation of the diagnosis of a neuroendocrine neoplasm may be achieved using serum and urine biochemical studies. Measurements of relevant peptides and amines
which may include serotonin, substance P, chromogrannin
A, histamine, gastrin, vasoactive intestinal peptide, glucagon,
bradykinin, neurotensin, human chorionic gonadotropin, neuropeptide K, neuropeptide L, and pancreatic polypeptide, can
be guided by the patient’s symptom complex. Among these,
chromogrannin Ais the most sensitive serum marker of neuroendocrine neoplasm, with a sensitivity of 99% and a signicant correlation of serum levels to tumor volume and burden;
however, this glycoprotein is non-specic and may be seen
with small-cell lung and prostate cancer. False-positive elevations may occur in the setting of atrophic gastritis, chronic
proton-pump inhibition, and renal insuciency.
7
Diagnostic imaging plays an essential role in the management of patients with neuroendocrine neoplasms. A multimodality approach provides optimal evaluation of primary
and metastatic disease, including computed tomography (CT),
magnetic resonance (MR), and scintigraphic imaging. While a
recent study suggests that MRI is more eective than CT in the
detection of liver metastases, both triphasic contrast-enhanced
CT and contrast-enhanced MR are recommended for initial evaluation and may provide complementary information
regarding disease extent and vascular anatomy and facilitate
posttreatment comparisons.
9
Nuclear medicine imaging approaches using tumor-specic
radiolabeled receptor analogs or amine precursors provide an
important adjunct to cross-sectional imaging and oer greater
sensitivity and specicity. e most widely used single-photon
approach takes advantage of the fact that 70–90% of neuroendocrine neoplasms express multiple subtypes of somatostatin
receptors to enable imaging with radioloabeled somatostatin
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analogs, including
93% and 87% sensitivity, respectively.10 is approach also
provides predictive information regarding susceptibility to
therapy with somatostain analogs.11
111
In-octreotide and
idine (MIBG) has become the standard method of imaging
pheochromocytoma and paraganglionomas. Recently, promising positron emission tomography (PET) approaches have
been demonstrated. e development of the universal chelator 1,4,7,10-tetraazacyclodecane-1,4,7,10-tetraacetic acid
(DOTA) has facilitated the development of 68Ga-DOTA-Tyr3
octreotide (DOTATOC) PET imaging for NETs. First
described by Hofmann etal., 68Ga-DOTATOC PET imaging
of NETs has demonstrated superior sensitivity and contrast
as compared to
111
In-octreotide scintigraphy.
11C-5-hydroxytryptophan identied 98% of neoplasms and
demonstrated greater sensitivity than scintigraphy and CT
in a study of 42 patients with neuroendocrine neoplasms.14
Finally, while highly dierentiated tumors do not demonstrate
increased uptake of 18uorodeoxyglucose (FDG), a recent study
111
In-lantreotide, with
123
I-metaiodobenzyl guan-
12,13
In addition,
to 39% for small-bowel disease and 64% for patients with pancreatic neuroendocrine neoplasms.1 Histologic grade also correlates with the stage of disease, with 21%, 30%, and 50% of
patients with well-dierentiated (G1), moderately dierentiated (G2), and poorly dierentiated (G3) tumors presenting with distant metastases, respectively. Hepatic metastases
develop in an estimated 46–93% of patients with NETs.
16,17,18
Metastases are important predictors of survival, with
patients with G1 or G2 NETs with localized, regional, or distant metastatic disease demonstrating median survivals of 223,
111, and 33months, respectively. Interestingly, an examination
of patient survival from 1973 to 2004 demonstrated no change
for patients with localized or regional disease; however, a signicant improvement in median survival was appreciated for
patients with distant metastases beginning around 1988 corresponding with the introduction of the somatostatin analog
octreotide and the widespread adoption of embolotherapy for
liver metastases, mitigating death from hormone-related diarrhea and from liver failure, respectively.
suggests that FDG-PET may be as sensitive as or more sensitive
than scintigraphy for imaging the subset of well-dierentiated
neuroendocrine neoplasms that are characterized by an aggressive phenotype with a high Ki-67 proliferative index.
15
Multidisciplinary triage of neuroendocrine neoplasms
Treatment guidelines for management of metastatic disease
Prognosis
NETs generally evolve with an indolent course. Patients typically develop symptoms with late-stage disease and frequently
present with metastases involving the lymph nodes, bone, and/
or liver. ere is a strong correlation between primary tumor
site and stage of disease. e prevalence of distant metastases at
diagnosis ranges from 5% for rectal neuroendocrine neoplasms
incorporate a variety of approaches across several disciplines,
including systemic therapy with octreotide, proliferation inhibitors, and cytotoxic drugs; surgical resection or cytoreduction
and minimally invasive image-guided therapies.19 e indolent
nature of NET progression allows the application of multiple
treatment strategies over time, underscoring the importance
of a multidisciplinary approach. Figure19.2 presents a general
algorithm for triage of NET patients.
No symptoms
Not progressive
Normal LFTs
<25% liver volume
scan q 3-6 months
consider curative
resection/ablation
Symptoms OR
Progressive
Normal LFTs
<25% liver volume
Symptoms controlled
Tumor stable
NET Liver Metastases
Abnormal LFTs OR
>25% liver volume
Resection
Ablation
Embolization
Symptoms uncontrolled
Tu mor progresses
extensive or symptomatic
extrahepatic disease
Systemic TherapiesSandostatin
Figure 19.2 Treatment algorithm
for neuroendocrine tumor (NET) liver
metastases. LFTs = liver function tests.
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Systemic therapies
Somatostatin analogs were initially developed for the management of hormonal syndromes associated with neuroendocrine
neoplasms.20 e antiproliferative eects of octreotide were
established in the landmark placebo-controlled, double-blind,
prospective, randomized study on the eect of octreotide
LAR in the control of tumor growth in patients with progressive metastatic neuroendocrine midgut tumors, or PROMID
study.21 e PROMID study demonstrated a statistically significant prolongation in median time to progression in patients
with metastatic midgut NETs from 6 months in the placebo
arm to 14.3months in the octreotide LAR arm (Figure19.3).
e benet was independent of the presence of a carcinoid
syndrome and of chromogrannin Alevels. is response, in
combination with the low toxicity, clearly establishes the role
of somatostatin analog therapy in all patients with metastatic
midgut NETs (Table19.2).
Two new agents were approved in 2011 by the Food and
Drug Administration for treatment of metastatic pancreatic
NETs. Everolimus (Anitor) is an inhibitor of the serine/threonine kinase mammalian target of rapamycin (mTOR). e
A
B
Figure 19.3 Results of the PROMID study. (A) Conservative intent-to-
treat analysis of time to progression or tumor-related death. (B) Intent-totreat analysis of overall survival. HR = hazard ratio; CI = confidence
interval. (Reproduced from Rinke A, Muller HH, Schade-Brittinger C, et al.
Placebo-controlled, double-blind, prospective, randomized study on the effect
of octreotide LAR in the control of tumor growth in patients with metastatic
neuroendocrine midgut tumors: a report from the PROMID Study Group.
J Clin Oncol 2009; 27: 4656–4663, with permission.)
1.0
0.8
Placebo, 40 events; median, 6.0 months
Octreotide LAR, 26 events; median, 14.3 months
0.6
0.4
0.2
Patients (proportion)
0
61218
24 30 36
42 48 54 60 66 72 78
Time Since Random Allocation (months)
No. of patients at risk
Placebo 43 21 931 100 00 00
Octreotide LAR
Log-rank test stratified by functional activity: P = .000072, HR = 0.34 (95% Cl, 0.20 to 0.59)
42 30 19 16 15 10 10 9965310
00
1.0
0.8
0.6
0.4
0.2
Patients (proportion)
0612 18
Placebo, 9 events; median, 73.7 months
Octreotide LAR, 7 events; median, >77.4 months
24 30 36
42 48 54 60 66 72 78
Time Since Random Allocation (months)
No. of patients at risk
Placebo 43 41 39 29 27 25 19 14 11 86420
Octreotide LAR
Log-rank test stratified by functional activity: P = .77, HR = 0.81 (95% Cl, 0.30 to 2.18)
42 39 32 31 29 27 20 16 16 10 97
20
RADIANT-2 phase III trial of everolimus in patients with wellor moderately dierentiated metastatic NET with carcinoid
symptoms demonstrated an improvement in progression-free
survival of 5months and a statistically signicant 40% reduction in risk of progression for patients receiving everolimus
plus octreotide LAR as compared to patients receiving placebo plus octreotide.22 e RADIANT-3 study of everolimus
in patients with metastatic pancreatic NETs demonstrated an
improvement in progression-free survival of 7 months with
an associated 65% reduction in risk of progression for patients
receiving everolimus as compared to placebo (Figure19.4).
23
Sunitinib (Sutent) is a multi-tyrosine kinase receptor
inhibitor of vascular endothelial growth factor receptors 1,
2, and 3, and platelet-derived growth factor. Adouble-blind
placebo-controlled phase III clinical trial of sunitinib demonstrated a 7-month improvement in progression-free survival
for patients with metastatic, well-dierentiated pancreatic
24
NETs.
Similar to the PROMID study, neither the everolimus
nor sunitinib trials demonstrated an improvement in overall
survival.
Cytotoxic combination therapy with capecitabine (Xeloda)
and temozoliomide (Temodar) in metastatic well-dierentiated
NETs has demonstrated response rates of 61% with a 14-month
progression-free survival and 83-month median overall survival from diagnosis of liver metastases.25 is oral regimen
has achieved these remarkable objective response rates with
minimal toxicity.
Peptide receptor radiotherapy (PRRT) is a systemic form of
radiation therapy that provides disease control in the majority
of patients with metastases.
26,27
Interventional oncologists participating in the care of NET patients should make themselves
familiar with the relevant literature, as this topic frequently
is brought up by patients who are seeking information on all
possible treatment options. PRRT involves injection of somatostatin analogs chelated to therapeutic doses of Y-90, In-111,
or Lu-177, which then bind to somatostatin receptors on the
tumor cells. is therapy is available at multiple centers in
Europe and is under clinical trial in the USA. I-131 MIBG can
be used similarly for MIBG-avid tumors. While approved for
treatment of pheochromocytoma and paraganglionoma, many
gastroenteropancreatic NETs also take up MIBG. Screening all
NET patients with a diagnostic I-123 MIBG scan will determine who may benet from I-131 MIBG therapy.
28
Surgical management
Surgical resection is potentially curative therapy for neuroendocrine neoplasms and should be considered for all aected
patients.29 Resection of the primary tumor and local lymph
nodes is the treatment of choice for patients with grade 1–2
neuroendocrine neoplasms without distant metastases or
extensive local invasion. Surgery also remains an important consideration for potentially resectable advanced NETs,
including hepatic metastases, with 5-year survival rates of
50–85%.
ease, resection of the primary tumor and subtotal resection
30,31,32
While surgery is the treatment of choice for resectable dis-
168