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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_3733_Библиотеки_им_академика_М_И_Перельмана.pdf
Tips
• Smaller beads are more effective in causing tumor necrosis.
• Preparation of beads: Authors mix 1 mL of beads with 20 mL of
contrast material and saline mixture (50:50 dilution) and embolize the
tumor using 0.5–1 mL aliquots of this mixture per 30 s.
• A well-demarcated contrast material accumulation in the tumor on
fluoroscopy is a good end point of embolization.
• Superselective embolization is key to achieve good tumor necrosis
and to avoid liver dysfunction.
• Concomitant use of biologic agents is not a contraindication for
chemoembolization.
Tricks
• All drug-eluting beads do not behave the same way. Follow the
manufacturer’s guidelines when loading drugs. Some beads have
more favorable pharmacokinetic profile than others with certain
drugs.
• Use appropriate-sized microcatheters for delivery of the beads.
CONCLUSIONS
Drug-eluting beads represent a new paradigm shift in the way transarterial
drug delivery and vascular occlusion is applied for treatment of hepatic
tumors. Therapy with drug-eluting beads appears to be safe and superior to
conventional chemoembolization for hepatocellular carcinoma in sicker
patients and in patients with advanced disease. The role of drug-eluting beads
in the management of hepatic metastases is still evolving.
REFERENCES
1. Lewis AL. Drug eluting beads in the treatment of liver cancer. In: Lewis
AL, ed. Drug-Device Combination Products Delivery Technologies and
Applications. Cambridge, United Kingdom: Woodhead Publishing;
2010:154–189.
2. Lewis AL, Gonzalez MV, Lloyd AW, et al. DC bead: in vitro and in
vivo characterization of a drug-delivery device for transarterial
chemoembolization. J Vasc Interv Radiol. 2006;17:335–342.
3. Lewis AL, Dreher MR. Locoregional drug delivery using image-guided
intra-arterial drug eluting bead therapy. J Control Release.
2012;16:338–350.
4. Lewis AL, Gonzalez MV, Leppard SW, et al. Doxorubicin eluting beads
1: effects of drug loading on bead characteristics and drug distribution. J
Mater Sci Mater Med. 2007;18:1691–1699.
5. Taylor RR, Tang Y, Gonzalez MV, et al. Irinotecan drug eluting beads
for use in chemoembolization: in vitro and in vivo evaluation of drug
release properties. Eur J Phram Sci. 2007;30:7–14.
6. Liapi E, Lee KH, Georgiades CC, et al. Drug-eluting particles for
interventional pharmacology. Tech Vasc Interv Radiol. 2007;10:261–
269.
7. Gonzales MV, Tang Y, Phillips GJ, et al. Doxorubicin eluting beads 2:
methods for evaluating drug elution and in vitro:in vivo correlation. J
Mater Sci Mater Med. 2008;19:767–775.
8. Kaiser J, Thiesen J, Kramer I. Stability of irinotecan-loaded drug eluting
beads (DC bead) used for trans-arterial chemoembolization. J Oncol
Pharm Pract. 2010;16:53–61.
9. Hong K, Khwaja A, Liapi E, et al. New intra-arterial drug delivery
system for the treatment of liver cancer: preclinical assessment in a
rabbit model of liver cancer. Clin Cancer Res. 2006;12:2563–2567.
10. Varela M, Real MI, Burrel M, et al. Chemoembolization of
hepatocellular carcinoma with drug eluting beads: efficacy and
doxorubicin pharmacokinetics. J Hepatol. 2007;46:474–481.
11. Namur J, Citron SJ, Sellers MT, et al. Embolization of hepatocellular
carcinoma with drug-eluting beads: doxorubicin tissue concentration and
distribution in patient liver explants. J Hepatol. 2011;55:1332–1338.
12. Jordan O, Denys A, De Baere T, et al. Comparative study of
chemoembolization loadable beads: in vitro drug release and physical
properties of DC bead and hepasphere loaded with doxorubicin and
irinotecan. J Vasc Interv Radiol. 2010;21:1084–1090.
13. Blummel J, Reinhardt S, Schäfer M, et al. Drug-eluting beads in the
treatment of hepatocellular carcinoma and colorectal cancer metastases
to the liver. Eur Oncol Haematol. 2012;8:162–166.
14. Lammer J, Malagari K, Vogl T, et al; PRECISION V Investigators.
Prospective randomized study of doxorubicin-eluting-bead embolization
in the treatment of hepatocellular carcinoma: results of the PRECISION
V study. Cardiovasc Intervent Radiol. 2010;33:41–52.
15. Sacco R, Bargellini I, Bertini M, et al. Conventional versus doxorubicineluting bead transarterial chemoembolization for hepatocellular
carcinoma. J Vasc Interv Radiol. 2011;22:1545–1552.
16. Malagari K, Pomoni M, Kelekis A, et al. Prospective randomized
comparison of chemoembolization with doxorubicin-eluting beads and
bland embolization with BeadBlock for hepatocellular carcinoma.
Cardiovasc Intervent Radiol. 2010;33:541–551.
17. Dhanasekaran R, Kooby DA, Staley CA, et al. Comparison of
conventional transarterial chemoembolization (TACE) and
chemoembolization with doxorubicin drug eluting beads (DEB) for
unresectable hepatocelluar carcinoma (HCC). J Surg Oncol.
2010;101:476–480.
18. Ferrer Puchol MD, la Parra C, Esteban E, et al. Comparison of
doxorubicin-eluting bead transarterial chemoembolization (DEB-TACE)
with conventional transarterial chemoembolization (TACE) for the
treatment of hepatocellular carcinoma [in Spanish]. Radiologia.
2011;53:246–253.
19. Nicolini A, Martinetti L, Crespi S, et al. Transarterial
chemoembolization with epirubicin-eluting beads versus transarterial
embolization before liver transplantation for hepatocellular carcinoma. J
Vasc Interv Radiol. 2010;21:327–332.
20. Guiu B, Deschamps F, Aho S, et al. Liver/biliary injuries following
chemoembolisation of endocrine tumours and hepatocellular carcinoma:
lipiodol vs. drug-eluting beads. J Hepatol. 2012;56:609–617.
21. Reyes DK, Vossen JA, Kamel IR, et al. Single-center phase II trial of
transarterial chemoembolization with drug-eluting beads for patients
with unresectable hepatocellular carcinoma: initial experience in the
United States. Cancer J. 2009;15:526–532.
22. Poon RT, Tso WK, Pang RW, et al. A phase I/II trial of
chemoembolization for hepatocellular carcinoma using a novel intraarterial drug-eluting bead. Clin Gastroenterol Hepatol. 2007;5:1100–
1108.
23. Malagari K, Chatzimichael K, Alexopoulou E, et al. Transarterial
chemoembolization of unresectable hepatocellular carcinoma with drug
eluting beads: results of an open-label study of 62 patients. Cardiovasc
Intervent Radiol. 2008;31:269–280.
24. Martin RC II, Rustein L, Pin L, et al. Hepatic arterial infusion of
doxorubicin-loaded microsphere for treatment of hepatocellular cancer:
a multi-institutional registry. J Am Coll Surg. 2011;213:493–500.
25. Kalva SP, Iqbal SI, Yeddula K, et al. Transarterial chemoembolization
with doxorubicin-eluting microspheres for inoperable hepatocellular
carcinoma. Gastrointest Cancer Res. 2011;4:2–8.
26. Sousa PF, Preto AS, Leão D, et al. Transcatheter arterial
chemoembolization with doxorubicin eluting beads in the treatment of
hepatocellular carcinoma. Acta Med Port. 2011;24:29–36.
27. Burrel M, Reig M, Forner A, et al. Survival of patients with
hepatocellular carcinoma treated by transarterial chemoembolisation
(TACE) using drug eluting beads. Implications for clinical practice and
trial design. J Hepatol. 2012;56:1330–1335.
28. Malagari K, Pomoni M, Spyridopoulos TN, et al. Safety profile of
sequential transcatheter chemoembolization with DC Bead™: results of
237 hepatocellular carcinoma (HCC) patients. Cardiovasc Intervent
Radiol. 2011;34:774–785.
29. Martin RC II, Scoggins CR, Tomalty D, et al. Irinotecan drug-eluting
colorectal liver metastasis with concomitant systemic fluorouracil and
oxaliplatin: results of pharmacokinetics and phase I trial. J Gastrointest
Surg. 2012;16:1531–1538.
30. Vogl TJ, Jost A, Nour-Eldin NA, et al. Repeated transarterial
chemoembolisation using different chemotherapeutic drug combinations
followed by MR-guided laser-induced thermotherapy in patients with
liver metastases of colorectal carcinoma. Br J Cancer. 2012;106:1274–
1279.
31. Martin RC, Joshi J, Robbins K, et al. Hepatic intra-arterial injection of
drug-eluting bead, irinotecan (DEBIRI) in unresectable colorectal liver
metastases refractory to systemic chemotherapy: results of multiinstitutional study. Ann Surg Oncol. 2011;18:192–198.
32. Aliberti C, Fiorentini G, Muzzio PC, et al. Trans-arterial
chemoembolization of metastatic colorectal carcinoma to the liver
adopting DC Bead®, drug-eluting bead loaded with irinotecan: results of
a phase II clinical study. Anticancer Res. 2011;31(12):4581–4587.
33. Fiorentini G, Aliberti C, Tilli M, et al. Intra-arterial infusion of
irinotecan-loaded drug-eluting beads (DEBIRI) versus intravenous
therapy (FOLFIRI) for hepatic metastases from colorectal cancer: final
results of a phase III study. Anticancer Res. 2012;32:1387–1395.
34. Poggi G, Amatu A, Montagna B, et al. OEM-TACE: a new therapeutic
approach in unresectable intrahepatic cholangiocarcinoma. Cardiovasc
Intervent Radiol. 2009;32:1187–1192.
A
Section D Liquid Agents
9
Glue
Yasuaki Arai
rdis first described the synthesis of cyanoacrylates in 1949,1 and
since that time, its use for applications such as wound closure, skin
grafts, and organ anastomoses has been investigated.
2,3
N-butyl
cyanoacrylate (NBCA) has been used since the 1980s as a liquid embolic
material, mainly for neurointerventional indications; it was approved in the
United States by the U.S. Food and Drug Administration for use in cerebral
arteriovenous malformations in 2000. Since that time, its use in the periphery
has grown significantly. Presently, glue is one of the most important and
indispensable embolic materials in interventional radiology. NBCA is
approved as a medical device in most countries, but its approval for
embolization varies from country to country. Therefore, it is often used offlabel for embolization.
DEVICE DESCRIPTION
NBCA is a liquid embolic agent that consists of a two-carbon ethylene
molecule with a cyano group and an ester (carbonyl group) attached to one of
the carbons; the ester in NBCA is attached to an N-butyl hydrocarbon.
4,5
Polymerization occurs upon contact with any ionic substances (e.g., blood,
saline, ionic contrast media, and vessel endothelium) due to bonding of the
ethylene units after exposure to an anion (such as a hydroxyl group).
1
Because of this mechanism, NBCA is able to flow through the vasculature to
the target lesion as a liquid but leads to embolization once it polymerizes and
becomes solid.
Once administered, the polymerization process causes the release of
formaldehyde, which can contribute to the toxicity of NBCA. The extent of
the toxicity depends on the size of the side chain ester; NBCA is less toxic
than methyl and ethyl cyanoacrylates.6 Embolization with NBCA leads to an
acute inflammatory response in the vessel wall and surrounding tissue.1 With
time, this leads to a chronic granulomatous inflammatory process.
7–9
TECHNIQUE
To use NBCA appropriately as an embolic agent in interventional procedures,
there are two points to keep in mind: visualization under image guidance and
control of the polymerization time. Both of these points can be addressed
with the use of iodized oil (Lipiodol), which can be mixed with NBCA at any
ratio to make it visible under fluoroscopy and to increase its polymerization
time and viscosity (Figs. 9.1 and 9.2).10 The dilution rate is usually 10% to
50% (NBCA/Lipiodol) for most clinical indications.
The viscosity of the NBCA–Lipiodol mixture becomes higher upon
contact with blood and endothelium in vessels. This ultimately leads to
vascular occlusion once blood flow cannot push the mixture due to its high
viscosity. This mechanism of embolization is different when compared with
materials such as microspheres, polyvinyl alcohol (PVA), and gelatin sponge,
which typically occlude vessels at a level within the vasculature, which
matches the size of the embolic agent. An NBCA–Lipiodol mixture also
stops at the point of branching vessels once the mixture cannot get into
smaller vessels due to its high viscosity. Therefore, high-concentration
NBCA–Lipiodol mixtures with a dilution rate of 40% to 50% can be used for
proximal embolization. Dilution rates of 10% to 20% can be used to embolize
long and branching vessels (Fig. 9.3). However, when compared with
particles measuring 100 to 500 µm in diameter, an NBCA–Lipiodol mixture
leads to a more proximal embolization.
When preparing the mixture of NBCA and Lipiodol, attention is
required to avoid any contact between NBCA and Lipiodol and any ionic
substance.5 The author always aspirates NBCA from the NBCA ampule
directly into a new syringe with a new needle and then aspirates the desired
volume of Lipiodol into the same syringe. If a high-diluted NBCA–Lipiodol
is to be prepared, a second Lipiodol-containing syringe should be prepared,
and both should be mixed to obtain the target dilution rate for the NBCA–
Lipiodol mixture (Fig. 9.4). To avoid polymerization, the NBCA–Lipiodol
mixture should not be allowed to be in contact with room air for long period.
The syringe containing the NBCA–Lipiodol mixture should therefore be
capped at all times. The author usually uses the mixture within 10 minutes
after preparation.
When injecting the NBCA–Lipiodol mixture, a coaxial catheter system
must be used because it is difficult to control the injection with a larger lumen
catheter. When the coaxial microcatheter tip reaches the target point, a test
injection of contrast is performed to confirm the position of catheter tip and
to assess blood flow. The catheter is then flushed with a 5% glucose solution
to clear all contrast from the inner lumen.
5,11
This is an important step in the
use of NBCA because it is difficult to distinguish the NBCA–Lipiodol
mixture from contrast under fluoroscopy. Clearing the contrast from the
catheter after the test injection allows the operator to confirm when NBCA is
being administered. Three seconds after an optimal amount of NBCA–
Lipiodol has been injected, the microcatheter should be removed to minimize
the risk that the tip of the catheter will adhere to the vessel wall. A small
amount of time is needed because if the catheter is removed too quickly, the
risk of backflow of unpolymerized NBCA can occur due to the negative
pressure caused by catheter removal. If the intent of the procedure is to inject
a fixed amount of NBCA–Lipiodol mixture, it is possible to push the mixture
with 5% glucose. Following embolization, the microcatheter should be
disposed of immediately because the polymerized NBCA–Lipiodol mixture
may remain in the lumen of the catheter. It may be possible to flush the
catheter with sufficient volume of Lipiodol and 5% glucose if necessary.11 If