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Chapter17:Assessment, triage, and chemoembolization forCRLM
http://internalmedicinebook.com
Colon Mets
Resectable
[3-6 months chemo]
resect
liver dominant
unresectable
labs and PS OK
<3 cm ablate
3-6 cm embo/ablate
not liver dominant
OR
contraindication to embo
systemic
Figure 17.1 Algorithm for triage of
patients with liver metastases (Mets).
PS = performance status.
>6 cm embo
MRI is required to assess the future liver remnant. Patients
with insucient future liver remnant volume can undergo
portal vein embolization, details of which are covered in a
separate chapter. Similarly, patients with bilobar disease may
systemic
potent tumor targeting while avoiding the biliary and gastrointestinal toxicities caused by non-selective chemoinfusion.
Radioembolization for colorectal metastases is covered in
another chapter.
be candidates for two-stage hepatectomy with interval portal
vein embolization. Any potential surgical approach would be
preceded by neoadjuvant chemotherapy to test sensitivity of
the tumor for subsequent adjuvant therapy, and to provide a
“tincture of time” to test the biology of the tumor. Patients
who are not initially felt to be candidates for resection may
become so aer neoadjuvant systemic chemotherapy and/
or embolotherapy. Evaluation by a multidisciplinary team
is essential to coordinate care with this endpoint in mind.
Patients who achieve adequate reduction in disease burden to
enable resection have improved overall survival compared to
those who donot.
Ablation
For patients with limited disease who are not surgical candidates, percutaneous or surgical ablation may be possible, with
disease control rates similar to those achieved by resection.12
Ablation of metastases is covered in the previous chapter.
Intra-arterial chemoinfusion
For metastatic colorectal cancer, National Comprehensive
Cancer Network (NCCN) and European Society for Medical
Oncology guidelines recommend sequential triplet systemic
chemotherapy regimens, supplemented by biological agents
that target angiogenesis and EGFR.13 Despite the excellent
response rates obtained by these regimens,
develop disease progression within months. Liver-directed
intra-arterial (IA) therapies oer higher objective response
rates and longer hepatic progression-free survival than systemic therapy alone. is was initially observed with hepatic
artery chemoinfusion of uoropyrimidines, but randomized
trials not permitting crossover failed to detect a long-term survival benet over systemic therapy, largely because of the high
toxicity rate associated with IA chemoinfusion.17 Improvements
in technique, including percutaneous catheter placement by
interventional oncologists, and availability of new drugs have
led to renewed interest in this approach, which is covered in
more detail in another chapter.18 More selective therapy with
chemoembolization or radioembolization provides similarly
14,15,16
most patients
Systemic therapy
Almost all patients seen by an interventional oncologist will
have received one or more cycles of systemic chemotherapy.
Image-guided therapies for liver metastases usually take place
in the setting of an integrated care plan incorporating sys-
temic therapy. Hence it is important to be conversant with the
regimens, their toxicities, and their sequencing in order to be
able to advise patients and engage colleagues at tumor boards.
First-line systemic chemotherapy consists of 5-uorouracil
(5-FU) or capecitabine (Xeloda, an oral uoropyrimidine)
combined with leucovorin and either irinotecan (FOLFIRI)
or oxaliplatin (FOLFOX, XELOX/CAPOX), followed aer
progression or development of intolerance by the other triplet
combination. FOLFOX is oen limited by oxaliplatin-induced
peripheral neuropathy, while a major toxicity of irinote-
can is diarrhea. Patients with KRAS and BRAF wild-type
tumors receiving EGFR inhibitors develop a characteristic
pustularrash.
Chemoembolization
Chemoembolization involves the simultaneous infusion of
chemotherapeutic drugs and embolic agents. Embolization
slows the passage of chemotherapy through the hepatic circula-
tion, achieving drug concentrations in the tumor up to 25 times
greater than with infusion alone, and retention within tumor
cells for as much as 1month aer infusion, greatly magnifying
the drug concentration area under the curve compared to infu-
sion alone.
in tumor hypoxia. Sublethal hypoxia potentiates the eects of
cytotoxic drugs by increasing their uptake and retention by
tumor cells.23 Recent studies in animal models and humans with
hepatocellular carcinoma suggest that embolization-induced
ischemia stimulates angiogenesis through upregulation of hyp-
oxia inducible factor-1 and vascular endothelial growth fac-
tor, possibly triggering growth of surviving tumor cells.
In clinical practice, addition of antiangiogenic adjuncts such
as bevacizumab and sorafenib to chemoembolization has not
improved clinical outcomes.
19,20,21,22
Embolization also causes ischemia, resulting
27,28
24,25,26
149
Section IV:Liver metastases
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Patient selection for chemoembolization
orough assessment in the interventional oncology clinic is
critical for safe and eective treatment with chemoembolization. is includes a tissue diagnosis with assessment of predictive immunohistochemical markers such as KRAS and
BRAF that inuence concurrent systemic therapy. Historical
factors such as synchronous versus metachronous liver metastases, time interval to appearance of metachronous metastases, and response to prior lines of systemic therapy all impact
future prognosis and treatment plans. Prior surgical history
for the primary tumor and any metastases, prior radiation
therapy, and where the patient stands in the continuum of
NCCN-recommended systemic therapy all provide context
necessary for consideration of image-guided therapies.
Triphasic cross-sectional imaging of the liver depicts disease burden and segmental distribution, arterial anatomy, and
status of the portal and biliary tracts. Conventional CT imaging
of the chest and pelvis is also necessary to exclude signicant
extrahepatic disease. Since metastases are oen inconspicuous
on angiography, the pretreatment triple-phase scan is used to
determine which segments of the liver require embolization,
and, just as importantly, which segments are tumor-free and
can be spared. is is particularly helpful when there is variant
anatomy, obviating the need to selectively catheterize accessory
arteries to non-tumor-bearingliver.
In the initial review of the imaging, the rst question is if the
patient has the potential for cure through resection or ablation,
or could be converted to resectability by portal vein embolization or downstaging of the tumor. Frequently patients coming
from a community setting will not be aware of these options.
At the other extreme, patients with a disease burden >70% of
the liver volume are unlikely to derive long-term benet and
should be discouraged from pursuing chemoembolization.
29
Laboratory studies, including complete blood count, protime/international normalized ratio, creatinine, liver function
tests, and CEA level, should be obtained before each chemoembolization session. Patients with underlying liver dysfunction
should be treated with caution. Asubgroup of patients has
been dened who have a constellation of ndings that preclude
safe treatment with chemoembolization due to the high risk
of liver failure:more than 50% of the liver volume replaced by
tumor, lactate dehydrogenase greater than 425IU/L, aspartate
aminotransferase greater than 100 IU/L, and total bilirubin
greater than 2.0IU/L.30 Bland embolization, leaving out the
chemotherapy, does not decrease the risk for patients with contraindications to hepatic embolization.
Ideal patients have liver metastases only; however, those
with minimal or indolent extrahepatic disease may also benet when the degree of liver involvement drives survival.
Candidates should have an adequate performance status
(ECOG 0–2). Patients with portal vein thrombosis can be
treated safely as long as sucient collaterals exist with hepatopetal ow.31 Patients with biliary obstruction, even with normal serum bilirubin level, are at high risk of biliary necrosis.
Patients whose obstruction is treated with a biliary stent or
who have a biloenteric anastomosis are at very high risk of
Gram-negative bacteremia and liver abscess formation,32
which can be mitigated somewhat with an aggressive periprocedural antibiotic regimen.33 Patients with contraindications to
angiography, such as anaphylactoid reactions to intravascular
radiographic contrast, uncorrectable coagulopathy, or severe
renal insuciency or contraindications to chemotherapy such
as severe cytopenias or severe cardiac dysfunction, cannot
receive chemoembolization.
For patients with single or oligonodular disease with the
dominant lesion of intermediate size, combined therapy with
chemoembolization can be followed by thermal ablation to
achieve complete tumor response in metastases up to 6cm in
diameter.
34
Chemoembolization regimens
“Conventional” cocktails
ere is no standard protocol for chemoembolization, and
the agents used vary widely among centers. Clinical trials
comparing dierent techniques have not revealed a superior
combination.35 In the USA, the most commonly used drugs
include a combination of cisplatin, doxorubicin (Adriamycin),
and mitomycin C, all of which exhibit preferential extraction
when delivered intrahepatically and can achieve favorable
liver/systemic drug concentration ratios, thereby minimizing systemic toxicity.36 Agents used to achieve embolization
also vary widely, including polymeric microspheres, gelatin
sponge, starch microspheres, and collagen particles. Most protocols include Lipiodol, or ethiodized oil, an iodinated ethyl
ester of poppyseed oil (Guerbet, Aulnay-sous-Bois, France).
An eective strategy causes occlusion of both the distal hepatic
arterioles and the portal venules, thus trapping the chemotherapeutic drugs between the two, as occurs with an oily and
particulate-based combination of embolics.
carcinoma selectively takes up Lipiodol, perhaps resulting
in more selective toxicity to the tumor cells;
same phenomenon has not been shown to apply to adenocarcinomas.40 Some regimens call for the delivery of the chemotherapeutic drug(s) and oil emulsion followed by particulate
embolization, or may involve a “sandwich” technique in which
embolization with particles is done rst, followed by injection
of the liquid phase, then further embolization with additional
particles.41 One commonly used protocol combines the liquid
and particulate agents together. Pharmacokinetic data suggest
that the chemotherapeutic drugs in the aqueous phase of the
solution will wash out unless eux is simultaneously arrested
by the particles.
42
37,38
Hepatocellular
38,39
however, the
Drug-eluting microsphere platforms
Drug-eluting microspheres are a novel platform where the
embolic also serves as a carrier of chemotherapuetic drugs,
such as irinotecan or doxorubicin. Irinotecan is a camptothecin
derivative that inhibits the production of the enzyme topoisomerase I, which is essential to DNA replication in cancer
cells. Irinotecan is used as a second-line treatment for advanced
colorectal cancer as part of FOLFIRI (5-FU, leucovorin, and
150
Chapter17:Assessment, triage, and chemoembolization forCRLM
http://internalmedicinebook.com
irinotecan) or as a single agent in patients who have failed an
established 5-FU-containing treatment regimen.
ere are three drug-eluting embolics that are commercially available. DC Beads (Biocompatibles, Farnham,
United Kingdom), known as LC Beads in the USA, the most
extensively studied of the three, is a so deformable device
composed of polyvinyl alcohol hydrogel with sulfonate
groups. Positively charged drugs like irinotecan interact
with the negative anionic charge in the sulfonate group by
an ion-exchange mechanism. e elution of the drug from
the beads requires the presence of counterions such as Na+,
K+, or Ca2+ in the plasma. Drug-eluting microspheres are
approved in Europe for embolization and loading with doxorubicin. In the USA the addition of the chemotherapeutic
agent is considered an “o-label” application. e size varies
from 70 to 900m and the spheres are stored in a phosphate
packaging solution.
Hepasphere N (Biosphere Medical, Roissy, France),
known as Quadrasphere in the USA, is a “superabsorbent,”
non-resorbable microsphere based on a copolymer of polyvinyl alcohol and sodium acrylate bearing carboxyl groups. ey
absorb uids and expand and the expansion rate is dependent
on the ionic concentration of the surroundingmedia.
Jordan etal. compared the in-vitro drug release and physical properties of DC Bead and Hepaspheres loaded with doxorubicin and irinotecan. Almost complete drug loading was
obtained for both microsphere types and drugs. For irinotecan, complete release was obtained for both types of beads. e
release for DC Beads was in a sustained manner over 2–3hours,
versus a signicantly faster 7-minute burst for Hepaspheres.
e study concluded that both drug-eluting microspheres
could be eciently loaded with doxorubicin and irinotecan
and that weaker interactions were observed with irinotecan,
which led to the faster drug release.
43
Oncozene (Celonova BioSciences) microspheres are small
hydrogel microspheres that are non-resorbable and coated with
the proprietary Polyzene-F, an ultrapure and highly biocompatible polymer, which may minimize inammatory response.
is not evidence-based. e procedure is performed while the
patient receives moderate (conscious) sedation.
orough diagnostic visceral arteriography is performed.45
Asuperior mesenteric angiogram identies variant vascular
supply to the liver, including an accessory or replaced right
hepatic artery, retrograde ow through the gastroduodenal artery, and patency and ow direction of the portal vein.
A celiac arteriogram depicts the hepatic branch anatomy,
including the presence of variant supply to the le hepatic lobe,
and non-target branches to the gut and gallbladder. Replaced
and accessory hepatic arteries are quite common and must
be catheterized beyond gastric or mesenteric branches for
safe chemoembolization. Next, selective hepatic arteriograms
should be performed. Careful evaluation of the le hepatic
artery will identify the location of the right or accessory
gastric arteries and, oen, the phrenic and falciform supply.
Aselective right hepatic arteriogram will identify the location
of the cystic artery and any supraduodenal or retroduodenal
vessels, as well. Note that “hand-injected” runs are not sucient to provide adequate detail for safe chemoembolization.
Power-injected angiography should be performed with imaging carried out into the parenchymal phase, so that the course
of every vessel imaged can be tracked against the silhouette
of the liver. Cone-beam CT is an important adjunct for determining blood supply to target and non-target tissue; its routine use has been demonstrated to improve clinical outcomes
in chemoembolization.
46
Complete mesenteric arteriography need be performed
only prior to the rst session. Subsequent chemoembolizations usually only require detailed angiography of the specic
vessel(s) supplying the segments to be treated.
Once the arterial anatomy and tumor supply are clearly
identied, the catheter is advanced superselectively into
the right or le hepatic arterial supply, oen with the aid of
coaxially introduced microcatheters. Whole-liver chemoembolization is not recommended due to an unwarranted high
rate of toxicity.47 Some practitioners advocate segmental or
subsegmental delivery of chemoembolics, particularly when
liver function is marginal. It is important not to induce spasm
Preclinical animal studies with drug-eluting
or pseudostasis by using a standard angiographic catheter in
a small vessel (less than twice the diameter of the catheter).
microspheres
Pharmacokinetics of irinotecan was studied by injecting
it intravenously (IV) or IA, or loaded on to DC Beads in 54
New Zealand white rabbits with VX2 liver tumor, divided into
three groups of 17. Compared with the IV or IA route, DEBIRI
induced lower serum levels of irinotecan, a high and prolonged
intratumoral level, and a greater rate of tumor necrosis at
24hours.
44
Technical aspects of chemoembolization
Typically patients are admitted to the interventional radiology
service on the morning of the procedure, aer having fasted
overnight. Vigorous IV hydration is initiated. Premedication
with prophylactic antibiotics and antiemetics IV, both continued until discharge, is standard practice, although use of antibiotics in patients without a history of prior biliary intervention
When the catheter is removed and spasm relieved, ow to the
tumor will return. Once the catheter is positioned for treatment, a nal arteriogram is performed to conrm the anatomy
before chemotherapy is injected. is can be accomplished
even through a microcatheter. Specically designed high-ow
microcatheters for intrahepatic arterial therapy can tolerate
injection rates of up to 5mL/s at 800psi.
e chemoembolic mixture or emulsion is injected in
1–5-mL increments until near-complete stasis of blood ow
is identied. Excessive embolization must be avoided, particularly for patients in whom repeated chemoembolizations
are anticipated. Most microcatheters have a dead space of
1.0–1.5mL emulsion, and if this additional volume is injected
during a nal ush of the catheter aer an acceptable endpoint
has been reached, overembolization can easily occur. With the
ideal endpoint, the treated arteries appear as a “tree in winter,”
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Section IV:Liver metastases
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with no tumor blush seen, but preservation of ow in the segmental and lobar branches.
Aer the procedure, intravenous hydration, antiemetics
and intravenous antibiotics are continued. Narcotics, perchlorpromazine, and acetaminophen are supplied for symptoms of
pain, nausea, and fever. e patient may be discharged when
oral intake of uids is adequate and parenteral narcotics are no
longer required. A1–2-day hospital stay postprocedure is typical. With increasing pressure from insurers, 23-hour stays and
outpatient chemoembolization have become more common.
Upon discharge, the patient is given prescriptions for oral antibiotics for 5days, as well as antiemetics and oral narcotics as
necessary. e patient returns to the interventional radiology
outpatient oce for follow-up with repeated imaging and laboratory evaluation in 1month or to the interventional suite for
additional chemoembolization. It is not necessary to re-image
the liver until all tumor has been treated, unless the patient is
in a clinical trial. For bilobar disease, patients will require two
to four treatments, depending on the arterial supply. Patients
who respond to treatment are followed every 3months, and
retreatment is considered for responders who develop intrahepatic recurrence.
Side eects aer chemoembolization are common.
Postembolization syndrome, consisting of pain, fever, nausea,
and sometimes vomiting, is seen to some degree in nearly all
patients and is due to hepatic ischemia and tumor necrosis.
Fatigue and anorexia lasting 4–6 weeks are quite common as
well. Patients whose right hepatic artery is chemoembolized
proximal to the cystic artery experience a prolonged postembolization syndrome48 and may develop sterile ischemic chemical cholecystitis that resolves with conservative treatment. e
incidence of major complications aer chemoembolization is
2–7%.49 Major complications of hepatic embolization include
hepatic insuciency or infarction, abscess, biliary necrosis,
and non-target embolization of the gut. Other complications
occur less than 1% of the time, including periprocedural cardiac events, renal insuciency, anemia requiring transfusion,
and complications related to angiography. irty-day mortality
rates have been reported to be1–4%.
Technical aspects for drug-eluting
microspheres, particle size, drug loading,
delivery endpoints, peri- and intraprocedural
management
shaken for eective loading. If the beads have been correctly
loaded with irinotecan, the color changes to turquoise. At the
end of the loading time, excess solution must be removed from
the vial and discarded.
e loaded beads can be stored up to14days under refrigerated conditions (2–8°C). e contrast agent should be added in
the angiography suite and used immediately, as some drug elution is initiated in the process. Since the drug release is driven
by ion exchange, non-ionic contrast should be used.51 Saline is
not recommended for preparing suspensions of beads once the
drug is loaded.
Prior to use, any supernatant containing irinotecan should
be removed from the vial before mixing with 5mL of non-ionic
contrast medium and 5mL of water. e syringe is then gently inverted to obtain an even suspension of beads. DC Beads
(100–300 m) are recommended for a standard procedure.
Each vial contains 2mL of beads and is loaded with 100mg
irinotecan (loading dose, 50mg irinotecan/mL of beads).
Transarterial delivery of the beads is performed in the lobar
fashion. Undetected micrometastatic lesions within a lobar
embolization zone can be treated with DEBIRI as eectively as
lesions that are identied preoperatively and more selectively
embolized. ese results support the oncologic rationale for
lobar administration.
52
In patients with unilobar disease two lobar treatments
are planned, each with 100mg irinotecan loaded in one vial
of 100–300 µm DC Beads. e next treatment is separated
by 3–4weeks aer conrmation that the liver enzymes have
returned to baseline.
In patients with bilobar disease, four lobar treatments
should be planned, each with 100mg irinotecan loaded in one
DC Bead vial, every 2weeks (i.e., right lobe > 2 weeks le lobe >
2 weeks right lobe > 2 weeks le lobe). e use of a whole-liver
treatment in a single session, with separate right and le lobar
injections and administration of an overall dose of up to 200mg
irinotecan loaded in two DC Bead vials, has been reported by
Fiorentini etal. in carefully selected patients.
53
Technique for drug-eluting microsphere embolization
For a lobar approach, the catheter should be placed into the
right or le hepatic artery, with attention to identifying the
origin of the cystic artery as well as other arteries supplying
ow to extrahepatic organs. If identied, these vessels must be
either embolized using coils or avoided by placing the catheter tip well beyond the origin of these vessels. e use of a
Loading
e loading is done in the pharmacy under aseptic conditions.
Beads are provided in 10-mL sterile vials containing 2 mL
sedimented beads in phosphate-buered saline. e saline is
removed from the vial and irinotecan is loaded from 5-mL vials
containing 100mg of irinotecan hydrochloride in liquid form.
Loading time is variable, depending on the size of the beads.
Average loading is 2hours. Smaller beads need shorter loading
times due to the greater surface area of the beads in the same
sedimented volume.50 During the loading the beads must be
microcatheter is recommended to prevent vasospasm during
catheterization and help avoid reux during injection. In addition, forward ow into the desired vessel must be maintained
because inadvertent administration or reux of beads into
these extrahepatic vessels would be undesirable.
An injection rate of approximately 1 mL of the
beads–contrast suspension per minute is recommended.
Injection of IA lidocaine (4–10mL split before and near the
end of DEBIRI administration) has been shown to reduce
adverse events and hospital length of stay.54 Rotating the
152
Chapter17:Assessment, triage, and chemoembolization forCRLM
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syringes or using a three-way stopcock to gently suspend the
beads in the solution helps avoid sedimentation of the beads
in the syringe.
11.7months, with a range of 7–21months. It is important to
realize that most of these patients had failed standard-of-care
systemic therapy. ese survival times exceed the 5–8-month
median overall survival expected from third-line systemic sal-
Delivery endpoints
e goal of transcatheter treatment with DEBIRI is to deliver
the planned dose of anticancer agent, not to occlude the vessel.
In a multi-institutional registry, achievement of complete stasis was an independent predictor of adverse events and signicantly greater hospital length of stay.
54
It is important to maintain forward ow into the vessel
throughout the procedure. If “near stasis” is observed during
the injection (i.e., the contrast column does not clear within
2–5 heart beats) before the full planned dose has been administered, the injection should be stopped at that time, regardless of the amount of beads that have been actually delivered,
to avoid reux of embolic material. Additional embolic material of any kind should not be injected following the delivery
of DEBIRI even if the full dose has been delivered with maintained forwardow.
Peri- and intraprocedural management for drugeluting microspheres
Patients are admitted the night before the procedure and IV
hydration is started with normal saline at the rate of 100mL/
hour. Esomeprazole 40mg IV in 50mL of sodium chloride is
administered by IV piggyback (IVPB) over 30 minutes on day 1,
30 minutes prior to the procedure and on day 2.Aloxi 0.25mg
is given IVPB 30 minutes prior to procedure. Morphine 10mg
IV prior to injection of the beads is followed by a second dose
6hours postprocedure. Additional medications include dexamethasone 20 mg IVPB 30 minutes prior to chemotherapy,
Zofran 8mg IV 30minutes prior to chemotherapy and 8mg
IV 6 hours postchemoembolization. Antibiotic coverage is
with cefazolin 1g IVPB 6 hours prior to chemotherapy and
Flagyl 500mg IVPB q8hours, continued while the patient is
admitted.
Several protocols have been used to achieve pain control,
including IV administration of analgesics and IA injection of
lidocaine.
Outcomes of conventional chemoembolization for
vage regimens, and rival results of second-line systemic regimens, suggesting that chemoembolization could add benet
in the salvage setting and possibly also when combined with
second-line chemotherapy.
Furthermore, the handful of studies reporting survival
from time of diagnosis of liver metastases report median overall survival in the range of 26–38months, which exceeds the
expectations for standard-of-care sequential triplet systemic
chemotherapy and antiproliferative agents, which hover in the
20–26-month range.67 Since chemoembolization has always
been integrated with systemic chemotherapy somewhere along
the course of therapy, these results again support the added
value of combining systemic and liver-directed therapy. Proof
would require a trial randomizing patients to standard-of-care
systemic therapy with or without chemoembolization.
e two largest series permit subgroup analyses providing
additional insights.
Gruber-Rouh et al.66 reported a 10-year series of 564
patients chemoembolized with mitomycin alone (43%), mitomycin and gemcitabine (27%), mitomycin and irinotecan
(15%), or mitomycin, irinotecan, and cisplatin (15%) depending upon their prior systemic therapy, with Lipiodol and starch
microspheres. All patients had progressed or become intolerant of systemic chemotherapy. Patients with liver involvement
of > 70%, or performance status > 1 were excluded. Mean
number of embolizations per patient was 6, with a range of
3–29. Partial response by RECIST was seen in 17%, with disease control in 65%. Median survival from time of chemoembolization was 14.3 months, with no dierence among the
drug regimens. Eighty-four patients (15%) were downstaged
to potentially curative resection or ablation, which was predictive of better survival. Presence of extrahepatic disease
did not aect survival (median 13.8months vs. 12.0months;
P=0.68).
Vogl etal. reported separately on a subset of 224 patients
with up to ve metastases with none larger than 5cm, who
were chemoembolized followed 1month later by thermal ablation with MR-guided laser thermometry.68 Only 2/464 ablated
metastases developed local recurrence. Median time to progression of disease was 8months, almost entirely due to the
colorectal metastases
Since the 1980s, numerous studies for the treatment of metastatic colorectal cancer to the liver have been reported
by centers worldwide. Table 17.1 provides a summary of
over 1,000 patients from series reporting cohorts of 20 or
34,55,56,57,58,59,60,61,62,63,64,65,66
larger.
ese studies used a variety of
anticancer drugs and embolic agents; many include an oily
emulsion. Most of these patients had failed systemic therapy.
Disease control rates average 72% (range 43–94%); however,
the duration is limited, particularly when including extrahepatic disease progression, with median time to progression or
progression-free survival of only 3–9 months. Nonetheless,
median survival from time of chemoembolization averages
appearance of new metastases. Additional chemoembolizations and ablations were performed as indicated for recurrences. Median survival from initiation of chemoembolization
was 23months, with actuarial survival of 88% at 1year, 49% at
2years, and 19% at 5years.
Albert etal.64 reported a retrospective series of 121 patients
chemoembolized with cisplatin, Adriamycin, mitomycin
(CAM), Lipiodol, and polyvinyl alcohol. Disease control rate
was 43%, with median survival of 2months from diagnosis of
metastases and 9 months from time of chemoembolization.
Performance status >ECOG 0 and prior treatment with more
than two lines of systemic therapy were negative prognostic
factors; presence of extrahepatic disease wasnot.
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Section IV:Liver metastases
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Table 17.1 Conventional chemoembolization of colorectal liver metastases
Median
survival from
TTP
Reference n Drug Embolic DCR
Daniels et al.,
55
1992
Lang and
Brown, 1993
Stuart et al.,
57
1995
Sanz-Altamira
et al., 1997
Tellez et al.,
41
1998
Bavisotto
et al., 1999
Salman et al.,
60
2002
Muller et al.,
61
2003
You et al.,
62
2006
Hong et al.,
63
2009
Albert et al.,
64
2011
Nishiofuku
et al., 2013
Gruber-Rouh
et al., 2014
52 CAM Collagen 11
46 Doxorubicin Lipiodol
56
20 5FU, mito Lipiodol
+ GF
40 5FU, mito Lipiodol
58
+ GF
30 5FU, mito collagen 63% 29 8.6
20 Cisplatin PVA 70% 4.4 (3–7) 14.3 (7–16) 57% 19%
59
24 5FU + IFN P VA 63% 3 10 (8–11)
66 Melphalan Lipiodol
88% 8 NR 66%
+ GF
40 5FU + LV Lipiodol 90% 9 16 90% 15%
21 CAM Lipiodol +
PVA/ES
121 CAM Lipiodol +
43% 5 27 9 36% 13%
PVA
24 Cisplatin DSM 94% 6 (1.5–10) 21 (8–24) 67% 42%
65
66
564 Mito,
mito-gem,
Lipiodol +
DSM
65% 38 14.3 62% 28%
(months)
diagnosis
(months)
26.3 7.7 43% 10%
Median
survival from
chemoembolization
(months) 1year 2year
7
10
mito-iri,
mito-iri-ox
Total 1068 Mean of
72% 30.1 11.7 59% 28%
series
DCR = disease control rate; TTP = time to progression; CAM = cisplatin, Adriamycin, mitomycin; 5FU = 5-fluorouracil; LV = leucovorin; GF = Gelfoam;
PVA = polyvinyl alcohol; IFN = interferon; ES = Embospheres; DSM = degradable starch microspheres.
Outcomes with drug-eluting microspheres
Fiorentini et al.53 reported a prospective, multi-institutional
double-arm study of 74 patients randomized to receive DEBIRI
(n=36) or systemic chemotherapy (FOLFIRI) (n=38). Overall
response rate (complete response + partial response) in the
liver in the DEBIRI was 68.6% (n= 24), compared with 20%
(n = 7) in the systemic treatment group. Median survival
was 22months for DEBIRI and 15months for FOLFIRI. At
50months, overall survival was signicantly longer for patients
treated with DEBIRI than for those treated with FOLFIRI.
Progression-free survival was 7months in the DEBIRI group
compared to 4months in the FOLFIRIgroup.
Another study investigating the combination of
FOLFOX + DC Bead with irinotecan ± bevacizumab has
reported pharmacokinetics that show minimal systemic drug
levels following DEBIRI, minimal adverse event rate with no
dose-limiting toxicity, and enhanced tumor response.
154
Martin et al.70 reported a prospective, multi-institutional
single-arm study of 55 patients treated with DEBIRI. Ninety-nine
DEBIRI treatments were performed, with median of 2 (range
1–5) per patient. Response rates were 66% at 6months and 75%
at 12 months. Overall median progression-free survival was
11months with median hepatic-specic progression-free survival of 15months and median overall survival of 19months.
A comprehensive review of ve observational studies and
one randomized controlled trial described the use of DEBIRI
in the treatment of a total of 235 patients.71 e median survival
time in this systemic review was 15–25months. ere was an
improvement in disease-free survival associated with DEBIRI.
e response rate (complete response + partial response)
varied from 36% to 78%. Patients with response at 6months
showed a durable response up to 12months.
Narayanan et al.72 reported a retrospective study of 28
patients treated with 47 DEBIRI procedures. ree patients
69
(15%) had complete response, 6 (30%) had partial response,
Chapter17:Assessment, triage, and chemoembolization forCRLM
http://internalmedicinebook.com
4 (20%) had stable disease, and disease progression was
recorded in 7 (35%); CT scans were unavailable for 8 patients.
e median time from diagnosis of liver metastases to initial
DEBIRI treatment was 19.6months. e median overall survival from rst treatment was 13.3months.
Summary
For the treatment of patients with colorectal liver metastases,
chemoembolization has been shown to be a safe option among
the many treatments with a palliative role in this dicult disease. In the absence of a randomized trial, we cannot quantify
the absolute survival benet for patients with colorectal liver
metastases, but the clear trend is for improvement in survival
among patients with liver-only or liver-dominant disease compared to expectations from systemic therapyalone.
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Chapter
Radioembolization for colorectal liver metastases
18
Lourens Bester, Baerbel Meteling, and David Boshell
Radioembolization is internal brachytherapy that delivers high
doses of beta radiation locally into liver tumors. Glass or resin
microspheres incorporating the radioactive isotope yttrium-90
(90Y) are directly injected into the hepatic arteries feeding the
tumor. Resin microspheres dier from glass microspheres in
that they have lower specic gravity, lower activity, and a higher
number of particles. As part of the selection process for radioembolization, clinical history, laboratory values and performance
status are obtained and patients are initially evaluated and staged
using cross-sectional imaging techniques. Pretreatment imaging
workup is required to visualize the entire liver vasculature and
ow patterns, including the detection and selective occlusion
of vessels which might allow 90Y microspheres to enter extrahepatic tissues. During the treatment procedure, microspheres are
injected through a temporary angiographic catheter placed percutaneously via the femoral or brachial artery. Clinical toxicity is
assessed at the time of treatment and approximately 2–3months
thereaer. Acomprehensive review of the technical and methodological considerations in 90Y has been previously published.
1,2,3
Two radioembolic products are commercially available.
era-Sphere (glass microspheres) gained a Humanitarian
Device Exemption from the Food and Drug Administration
(FDA) in 1999 for the treatment of unresectable hepatocellular carcinoma (HCC) in patients with or without portal vein
thrombosis (PVT) who can have appropriately positioned
hepatic arterial catheters.4 SIR-Spheres (resin microspheres)
gained full premarketing approval from the FDA in 2002 for
the treatment of unresectable colorectal liver metastases in
conjunction with intrahepatic oxuridine (FUDR).
5
Both devices have approval for treatment of liver cancer in
Europe and various Asian countries.
Introduction
Despite advances in systemic chemotherapy and monoclonal
antibodies, the liver usually remains the site of tumor resistance and ultimately the patient’s death. Approximately 60% of
patients diagnosed with colorectal carcinoma eventually develop
hepatic metastases, with the liver as the dominant site of disease.6
Complete surgical resection remains the best option for a cure.7
However, surgical resection is currently only possible in less than
20% of patients with metastatic colorectal cancer.6 Further, about
60–90% of patients treated with neoadjuvant chemotherapy and
liver resection will experience a recurrence of their liver tumors.8
In patients with unresectable liver metastases, with or without
extrahepatic disease, systemic chemotherapy is still the standard
of care for rst- and second-line treatment.
9,10
Chemotherapy
with the addition of angiogenesis inhibitors and surgical resection has become an integral part of rst- and second-line therapies.11 For patients with unresectable liver-only or liver-dominant
disease who have failed standard chemotherapy options, new
treatments such as 90Y radioembolization have a particular application. In such settings, 90Y therapy may be considered to achieve
local control of liver disease, decrease the risk of recurrence, and
potentially prolong survival.
Patient identication and selection
Patient presentation
Patient selection for radioembolization has to be made on
an individual basis. As part of the selection process, an exact
evaluation of patient history, laboratory tests, and Eastern
Cooperative Oncology Group (ECOG) performance status is
performed. Patients with colorectal metastases to the liver must
be unsuitable for surgery and have completed standard-of-care
chemotherapy, unless contraindicated, before they can be considered for radioembolization. Factors inuencing eligibility
are the history of chemotherapy (including prior use of radiosensitizers such as 5-uorouracil (5-FU), capecitabine, and
gemcitabine or the use of microvascularity-altering agents such
as bevacizumab), liver resection (e.g., tumor fully excised or
still in situ, Whipple’s, hepatectomy) and infusion pump placement with surgically altered vascularity.
It is essential that patients have liver-only or liver-dominant
disease with minimal extrahepatic spread, since the eect
of radioembolization is conned to the liver. In patients
with extensive extrahepatic metastases, a systemic treatment
approach must be taken into account. e most important
aspect in the selection of patients for radioembolization is the
evaluation of their clinical condition. is is measured using
recent laboratory tests (ideally including liver function and
complete blood count with dierential), and ECOG performance status. Patients with limited hepatic reserve and clearly
reduced performance status are at higher risk of developing
severe side eects, such as radiation-induced liver disease.
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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