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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_3733_Библиотеки_им_академика_М_И_Перельмана.pdf
DEVICE/MATERIALS
Currently, there are three commercially available drug-eluting beads. These
are U.S. Food and Drug Administration (FDA) approved for the treatment of
hypervascular tumors and arteriovenous malformations. The drug-loading
feature is not yet FDA-approved. However, all these beads carry CE mark
approval status for drug loading in Europe. These include LC Beads (DC
Beads in Europe) manufactured by Biocompatibles UK, Ltd. (Farnham,
Surrey, United Kingdom), QuadraSphere (HepaSphere in Europe)
manufactured by Merit Medical Systems, Inc. (South Jordan, Utah), and
Oncozene beads (Embozene Tandem in Europe) manufactured by CeloNova
BioSciences, Inc. (San Antonio, Texas). Although the drug loading and drug
elution of these beads are based on ion exchange mechanism, the differing
physical and chemical properties of the beads lead to variable drug-loading
and drug-eluting characteristics, embolic effect, and intratumoral distribution.
LC Beads
LC beads (LC = low compression), also known as DC beads in Europe (DC =
drug capable), are biocompatible, hydrophilic, nonresorbable, deformable
polyvinyl alcohol acrylic polymer hydrogel microspheres produced by
inverse polymerization with 2-acrylamido-2-methylpropane sulfonate.3 The
negatively charged sulfonate groups allow interaction with positively charged
drugs such as doxorubicin and irinotecan, which bind reversibly by an ion
exchange mechanism, allowing for a high loading efficiency. The beads are
available in various sizes ranging from 100 to 900 µm (100 to 300 µm, 300 to
500 µm, 700 to 900 µm). They are distributed in a 2-mL aliquot and
delivered in a 10-mL vial. There are approximately 200,000 beads per vial of
100- to 300-µm beads; 38,000 beads per vial of 300- to 500-µm beads; and
10,000 beads per vial of 500- to 700-µm beads. Recently, smaller 70- to 150µm beads known as the LC BeadM1 are marketed for more distal
intratumoral penetration. There are approximately 1,300,000 beads in a 2-mL
aliquot of LC BeadM1.
The time required to load the LC beads with doxorubicin depends on the
size of the beads (which affects the available surface area of the beads for
drug loading), drug concentration within the medium, and absence of any
other positively charged particles in the medium. Smaller diameter beads load
quickly. When loading 25 mg of doxorubicin per 1 mL of beads, greater than
99% is loaded on to the 100- to 300-µm beads in less than 10 minutes,
whereas it requires closer to 2 hours to completely load the 700- to 900-µm
beads to the same concentration. No significant difference in maximum
loading capacity is seen for LC beads of sizes between 100 and 900 µm, with
an average maximum loading capacity of 39 mg doxorubicin per milliliter
observed.4 The loading characteristics of irinotecan parallel those of
doxorubicin. At 2 hours, 100- to 300-µm beads load 98.1% of 50 mg/mL of
irinotecan, whereas 700- to 900-µm beads load 93.5% of the drug. The
maximum loading capacity is 50 mg of irinotecan per 1 mL of beads,
irrespective of the size of the beads.
5
Drug loading leads to loss of water in the hydrogel and results in a
decrease in the diameter of the bead (an average of 35% diameter reduction
of the beads with doxorubicin and 20% to 40% decrease with irinotecan) and
reduction in the compressibility of the bead.
5,6
These physical changes do not
affect delivery of the beads through microcatheters of appropriate size (2.4-Fr
for 100 to 500 µm, 2.7-Fr for 500 to 700 µm, and 3-Fr for 700 to 900 µm).
The manufacturer does not recommend mixing LC beads with Lipiodol.
The elution of chemotherapeutic drugs from LC beads appears to be a
function of bead size (smaller beads elute faster) and ionic strength and
composition of elution media (no drug elution in pure water but increasing
rates of elution with increasing concentration of ionic solution) and is
influenced by drug–bead interactions (irinotecan elutes faster than
doxorubicin due to weak ionic bond) and drug–drug interactions.7 Rapid
elution of irinotecan (burst) from LC beads of up to 10% has been observed
with mixing of the beads with certain contrast materials.8 Therefore,
premixing contrast material with the beads during preparation in the
pharmacy has been discouraged.
8
Preclinical and clinical studies have shown elevated and sustained
retention of doxorubicin within the tumor after chemoembolization with
drug-eluting beads and decreased systemic doxorubicin plasma levels (both
peak drug concentration and area under the curve) compared to conventional
chemoembolization.
9,10
The location of vascular occlusion appears to parallel
the size of the beads: 100- to 300-µm beads block vessels with a mean
diameter of 237-µm penetrating tumor at a mean distance of 3.8 mm.
Explanted livers following chemoembolization with drug-eluting beads
demonstrated 42% of the beads occluding intratumoral vessels. Sustained
cytotoxic levels of drug at the vascular occlusion sites were observed for at
least 1 month. Tumor necrosis was associated with deeper penetration of the
beads and higher concentration of the drug.
11
QuadraSpheres
QuadraSpheres are polyvinyl alcohol–acrylic acid superabsorbent copolymer
beads, which swell up to 64 times their dry volume when hydrated. The
microspheres are shipped dehydrated and are available in 30 to 60 µm, 50 to
100 µm, 100 to 150 µm, and 150 to 200 µm dry diameter corresponding to
120 to 240 µm, 200 to 400 µm, 400 to 600 µm, and 600 to 800 µm hydrated
diameters, respectively. Each 10-mL glass vial contains 25 mg of dry spheres
corresponding to 815,000; 139,000; 28,100; and 9,400 spheres per vial,
respectively. Up to 75 mg doxorubicin can be loaded into each vial of
QuadraSpheres with a 60-minute loading time when loading with
reconstituted powdered doxorubicin and a 120-minute loading time when
loading with presolubilized doxorubicin. QuadraSpheres demonstrate a 10%
diameter reduction when loaded with doxorubicin and less homogenous
loading with both doxorubicin and irinotecan when compared to LC beads
and show comparable doxorubicin release kinetics to LC beads in vitro. A 7minute burst release of nearly 75% of bound irinotecan from the spheres is
reported due to weaker drug–bead interaction. When loaded with
doxorubicin, HepaSpheres become more fragile and prone to fracturing.
12
Oncozene Beads
Oncozene beads are biocompatible, nonresorbable hydrogel microspheres,
which are coated with an inorganic polyphosphazene polymer (Polyzene-F).
These tightly calibrated beads are available in 40 ± 10-µm, 75 ± 15-µm, and
100 ± 25-µm diameter sizes and are supplied in 2- or 3-mL aliquots. The
anionic sodium methacrylate backbone of the microsphere structure provides
a site for loading of the positively charged doxorubicin or irinotecan
molecule. Each milliliter of Oncozene beads can load 50 mg of doxorubicin
or irinotecan and can be loaded in 60 minutes when loading with powdered
doxorubicin and in 30 minutes when loading with irinotecan solution (20
mg/mL) with a 98% loading efficiency. When loaded with drug, Oncozene
beads shrink in diameter by less than 5%. Both doxorubicin and irinotecan
elute more slowly from Oncozene beads when compared to DC bead in vitro,
which may further mitigate side effects of systemic drug exposure, especially
with irinotecan, although further investigation is warranted.
13
TECHNIQUE
To maximize loading of the chemotherapeutic drug onto the carrier bead, the
corresponding manufacturer’s guidelines (“instructions for use”) must be
followed. In general, a total of 25 mg of doxorubicin per milliliter of beads or
50 mg of irinotecan per milliliter of beads is loaded irrespective of the type of
carrier bead, given the common indications for their use.
Loading of Drug-Eluting Beads
LC Beads
When loading LC beads with powdered doxorubicin, a 50-mg vial of
doxorubicin is reconstituted with 2 mL of sterile water. After removing saline
from the LC bead vial, the 2 mL of reconstituted doxorubicin is then added to
the LC bead vial and the vial is occasionally agitated to encourage mixing.
Loading time is up to 120 minutes for the largest LC bead size. When loading
LC bead with irinotecan, solution (20 mg/mL) only should be used. After
removing as much saline as possible from the LC bead vial, 5 mL of
irinotecan solution is added to the vial and the vial is gently agitated to
encourage mixing. A minimum 2-hour loading time is required for all bead
sizes.
QuadraSpheres
QuadraSpheres may be loaded with powdered (lyophilized) or presolubilized
doxorubicin. When loading with powdered doxorubicin, the 50 mg
doxorubicin needs to be reconstituted with preservative-free 0.9% sodium
chloride (not sterile water) and drawn into a 30-mL syringe. After rolling the
QuadraSphere vial several times to disperse the microspheres, 10 mL of the
reconstituted doxorubicin is injected into the vial, and the vial is rotated and
inverted 5 to 10 times and then let stand for 10 minutes. The entire contents
of the vial are then withdrawn into the remaining 10 mL of doxorubicin
solution in the syringe and gently agitated to disperse the contents. The
syringe is recapped and intermittently agitated, requiring an additional 60
minutes to complete loading of the drug onto the beads. After the 60 minutes,
the supernatant can be discarded. A minimum of 20 mL of nonionic contrast
is then added to the beads before delivery. If presolubilized doxorubicin (50
mg/25 mL) is being used to load the QuadraSpheres, the 25 mL of
doxorubicin solution is drawn into a 30-mL syringe. After rolling the vial
several times to disperse the microspheres, 10 mL of the doxorubicin solution
is injected into the vial, and the vial is rotated and inverted 5 to 10 times and
then let stand for 10 minutes. The entire contents of the vial is then
withdrawn into the remaining 15 mL of doxorubicin solution in the syringe
and gently mixed and agitated to disperse the contents. The syringe is
recapped and intermittently agitated, requiring an additional 120 minutes to
complete loading of the drug onto the beads. After the 120 minutes, the
supernatant can be discarded. A minimum of 20 mL of nonionic contrast
material is then added to the beads before delivery.
Oncozene Beads
When loading Oncozene beads with powdered doxorubicin, the desired
amount of powdered doxorubicin is reconstituted in 5.0 mL of sterile water if
preparing 2 mL of beads and in 7.5 mL of sterile water if preparing 3 mL of
beads. After removing excess transport solution from the syringe of
Oncozene beads using a filter needle, the drug is drawn into the microsphere
syringe via sterile needle. The syringe is then inverted every 5 minutes for the
first 30 minutes. Loading time is 30 minutes for irinotecan and 60 minutes for
doxorubicin and epirubicin. Maximum dose is 50 mg/1 mL for each drug.
Delivery of Drug-Eluting Beads
Drug-eluting beads are routinely mixed with nonionic contrast material (10 to
20 mL per 1 mL of beads) for visualization of delivery of the beads to
determine bead distribution and to monitor for change in flow dynamics as
distal arterioles become occluded. There is no consensus on the end point of
embolization. Some operators advocate complete stasis of tumor-feeding
vessels (while preserving segmental and lobar arterial flow) during
chemoembolization with drug-eluting beads (and supplementing with bland
embolization to achieve stasis if drug-eluting beads fail to achieve complete
stasis), whereas others avoid achieving complete stasis to prevent thrombosis
of the feeding artery (in this method, drug-eluting beads are used as a method
of drug delivery), thereby allowing for future repeat transarterial
interventions. Efforts are typically made to be as selective as possible when
performing chemoembolization for oligofocal hepatocellular carcinoma to
maximize delivery of chemotherapy to the tumor while sparing uninvolved
liver parenchyma. When diffuse multifocal disease is present, a lobar
approach can be employed if liver function is preserved. In patients with
metastatic disease, a lobar approach is commonly used given the widespread
multifocal nature of metastases.
CLINICAL APPLICATIONS
Chemoembolization with drug-eluting beads loaded with doxorubicin
(DEBDOX) are used for treatment of hepatocellular carcinoma, whereas the
irinotecan beads (DEBIRI) are used for metastatic colon cancer. Other
cancers such as intrahepatic cholangiocarcinoma, neuroendocrine metastases,
and metastases from breast, choroid (uveal) melanoma, and pancreatic cancer
are treated either with DEBDOX or DEBIRI.
Overall, DEBDOX is well tolerated, with significantly decreased
incidence and severity of transaminitis and doxorubicin-related side effects
compared to conventional chemoembolization. DEBDOX appears to be more
efficacious and safer compared to conventional chemoembolization in
patients with advanced disease (bilobar disease, recurrent disease, and in
patients with Eastern Cooperative Oncology Group [ECOG] performance
status of 1) (Table 8.1
).
10,14–28
The reported objective response rates ranged
from 50% to 100% (Fig. 8.1).
10,14–28
Except for one retrospective study that
reported survival advantage of DEBDOX over conventional transarterial
chemoembolization (cTACE),17 DEBDOX appears to offer similar overall
survival rates compared to that of cTACE. However, survival advantage, if
any, of DEBDOX in advanced stage hepatocellular carcinoma is yet to be
explored.
DEBIRI is well suited for treatment of colorectal metastases given the
high sensitivity of colorectal carcinoma to irinotecan. The reported median
survival following DEBIRI for colorectal hepatic metastases ranges from
15.2 months to 25 months (Table 8.2).
29–33
Drug-eluting beads loaded with
oxaliplatin in combination with systemic chemotherapy have been used for
treatment of intrahepatic cholangiocarcinoma with significantly better overall
survival (30 months vs. 12.7 months) when compared to systemic
chemotherapy alone.
34
Nonhepatic applications of drug-eluting beads are being tested for
treatment of peritoneal carcinomatosis through intraperitoneal delivery, for
treatment of recurrent glioblastoma by direct injections of drug-eluting beads
suspension in to the resection cavity, and transarterial therapy of pancreatic
cancer.
3
POTENTIAL COMPLICATIONS
Complications associated with DEBDOX and DEBIRI are similar to those
encountered with conventional chemoembolization. Many studies have
reported a lower incidence of transaminitis following DEBDOX.
10,14–25
One
study reported a higher incidence of biliary complications with the use of
drug-eluting beads.20 The incidence of liver failure, abscess, cholecystitis,
and nontarget embolization are similar to those encountered with
conventional chemoembolization.28 Intraprocedural pain and hypertension
appear to be very common with DEBIRI, possibly related to burst release of
10% to 20% of the drug during delivery of the beads.
30–34
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