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Chapter20:Preoperative portal vein embolization
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41. Shimamura T, Nakajima Y, Une Y, etal. Ecacy and safety of
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46. Duncan JR, Hicks ME, Cai SR, Brunt EM, Ponder KP.
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47. Ikeda K, Kinoshita H, Hirohashi K, Kubo S, Kaneda K. e
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48. Abdalla EK, Hicks ME, Vauthey JN. Portal vein
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52. Ribero D, Chun YS, Vauthey JN. Standardized liver volumetry
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53. Ribero D, Amisano M, Bertuzzo F, etal. Measured versus
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54. Chun YS, Ribero D, Abdalla EK, etal. Comparison of two
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55. Shah A, Goette P, Hubert C, etal. Comparison of dierent
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56. Seyama Y, Kokudo N. Assessment of liver function for safe
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liver cancers. Semin Surg Oncol 1993; 9 (4):298–304.
58. Mihara K, Sugiura T, Okamura Y, etal. A predictive factor of
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59. Shindoh J, Truty MJ, Aloia TA, etal. Kinetic growth rate
aer portal vein embolization predicts posthepatectomy
outcomes:toward zero liver-related mortality in patients with
colorectal liver metastases and small future liver remnant. J Am
Coll Surg 2013; 216 (2):201–209.
60. Denys AL, Abehsera M, Sauvanet A, et al. Failure of right
portal vein ligation to induce le lobe hypertrophy due to
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61. Nagino M, Nimura Y, Kamiya J, Kondo S, Kanai M. Selective
percutaneous transhepatic embolization of the portal vein
in preparation for extensive liver resection:the ipsilateral
approach. Radiology 1996; 200 (2):559–563.
62. Mado DC, Abdalla EK, Gupta S, etal. Transhepatic ipsilateral
right portal vein embolization extended to segment IV:improving
hypertrophy and resection outcomes with spherical particles and
coils. J Vasc Intervent Radiol 2005; 16 (2):215–225.
63. Mado DC, Hicks ME, Abdalla EK, Morris JS, Vauthey JN.
Portal vein embolization with polyvinyl alcohol particles and
coils in preparation for major liver resection for hepatobiliary
malignancy:safety and eectiveness– study in 26 patients.
Radiology 2003; 227 (1):251–260.
64. Mado DC, Hicks ME, Vauthey JN, etal. Transhepatic portal
vein embolization:anatomy, indications, and technical
considerations. Radiographics 2002; 22 (5):1063–1076.
65. Kodama Y, Shimizu T, Endo H, Miyamoto N, Miyasaka K.
Complications of percutaneous transhepatic portal vein
embolization. J Vasc Intervent Radiol 2002; 13 (12):1233–1237.
66. Di Stefano DR, de Baere T, Denys A, etal. Preoperative
percutaneous portal vein embolization:evaluation of adverse
events in 188 patients. Radiology 2005; 234 (2):625–630.
67. Denys A, Mado DC, Doenz F, etal. Indications for and
limitations of portal vein embolization before major hepatic
resection for hepatobiliary malignancy. Surg Oncol Clin N Am
2002; 11 (4):955–968.
68. Azoulay D, Raccuia JS, Castaing D, Bismuth H. Right portal
vein embolization in preparation for major hepatic resection.
J Am Coll Surg 1995; 181 (3):266–269.
189
Section IV:Liver metastases
69. Perarnau JM, Daradkeh S, Johann M, et al. Transjugular
preoperative portal embolization (TJPE) a pilot study.
Hepatogastroenterology 2003; 50 (51):610–613.
70. Gruttadauria S, Luca A, Mandala L, Miraglia R, Gridelli
B. Sequential preoperative ipsilateral portal and arterial
embolization in patients with colorectal liver metastases. Worl d
J Surg 2006; 30 (4):576–578.
71. Nagino M, Kanai M, Morioka A, etal. Portal and arterial
embolization before extensive liver resection in patients with
markedly poor functional reserve. J Vasc Intervent Radiol 2000;
11 (8):1063–1068.
72. Denecke T, Seehofer D, Steen IG, etal. Arterial versus
portal venous embolization for induction of hepatic
hypertrophy before extended right hemihepatectomy in hilar
cholangiocarcinomas:a prospective randomized study. J Vasc
Intervent Radiol 2011; 22 (9):1254–1262.
73. Aoki T, Imamura H, Hasegawa K, etal. Sequential preoperative
arterial and portal venous embolizations in patients with
hepatocellular carcinoma. Arch Surg 2004; 139 (7):766–774.
74. Ogata S, Belghiti J, Farges O, et al. Sequential arterial and portal
vein embolizations before right hepatectomy in patients with
cirrhosis and hepatocellular carcinoma. Br J Surg 2006; 93
(9):1091–1098.
75. Capussotti L, Muratore A, Ferrero A, et al. Extension of right
portal vein embolization to segment IV portal branches. Arch
Surg 2005; 140 (11):1100–1103.
76. van Gulik TM, van den Esschert JW, de Graaf W, etal.
Controversies in the use of portal vein embolization. Digest Surg
2008; 25 (6):436–444.
77. Kishi Y, Mado DC, Abdalla EK, etal. Is embolization of
segment 4 portal veins before extended right hepatectomy
justied? Surgery 2008; 144 (5):744–751.
78. Mueller L, Hillert C, Moller L, et al. Major hepatectomy for
colorectal metastases:is preoperative portal occlusion an
oncological risk factor? Ann Surg Oncol 2008; 15 (7):1908–1917.
79. van Lienden KP, van den Esschert JW, de Graaf W, etal. Portal
vein embolization before liver resection:a systematic review.
Cardiovasc Intervent Radiol 2013; 36 (1):25–34.
80. Guiu B, Bize P, Gunthern D, et al. Portal vein embolization
before right hepatectomy:improved results using
n-butyl-cyanoacrylate compared to microparticles plus coils.
Cardiovasc Intervent Radiol 2013; 36 (5):1306–1312.
81. Matsuoka T, Nakatsuka H, Nakamura K, etal. [Long-term
embolization of the portal vein with isobutyl-2-cyanoacrylate
in hepatoma.] Nihon Igaku Hoshasen Gakkai zasshi. Nippon Acta
Radiol 1986; 46 (1):72–74.
82. Bent CL, Low D, Matson MB, Renfrew I, Fotheringham T.
Portal vein embolization using a nitinol plug (Amplatzer
vascular plug) in combination with histoacryl glue and
iodinized oil:adequate hypertrophy with a reduced risk of
nontarget embolization. Cardiovasc Intervent Radiol 2009; 32
(3):471–477.
83. Cazejust J, Bessoud B, Le Bail M, Menu Y. Preoperative portal
vein embolization with a combination of trisacryl microspheres,
gelfoam and coils. Diagn Interv Imaging2013;
84. Geisel D, Malinowski M, Powerski MJ, etal. Improved
hypertrophy of future remnant liver aer portal vein
embolization with plugs, coils and particles. Cardiovasc
Intervent Radiol 2013; 96 (1):57–64.
85. Angle JF, Siddiqi NH, Wallace MJ, etal. Quality improvement
guidelines for percutaneous transcatheter embolization:Society
of Interventional Radiology Standards of Practice Committee. J
Vasc Intervent Radiol 2010; 21 (10):1479–1486.
86. Denys A, Bize P, Demartines N, Deschamps F, De Baere T.
Quality improvement for portal vein embolization. Cardiovasc
Intervent Radiol 2010; 33 (3):452–456.
87. Abulkhir A, Limongelli P, Healey AJ, etal. Preoperative portal
vein embolization for major liver resection:a meta-analysis.
Ann Surg 2008; 247 (1):49–57.
88. akrar PD, Mado DC. Preoperative portal vein
embolization:an approach to improve the safety of major
hepatic resection. Semin Roentgenol 2011; 46 (2):142–153.
89. Abdalla EK, Denys A, Chevalier P, Nemr RA, Vauthey JN.
Total and segmental liver volume variations:implications for
liver surgery. Surgery 2004; 135 (4):404–410.
90. Leelaudomlipi S, Sugawara Y, Kaneko J, et al. Volumetric
analysis of liver segments in 155 living donors. Liver
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91. Nzeako UC, Goodman ZD, Ishak KG. Hepatocellular
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patients. Am J Clin Pathol 1996; 105 (1):65–75.
92. Kishi Y, Abdalla EK, Chun YS, etal. ree hundred and one
consecutive extended right hepatectomies:evaluation of
outcome based on systematic liver volumetry. Ann Surg 2009;
250 (4):540–548.
93. Farges O, Belghiti J, Kianmanesh R, etal. Portal vein
embolization before right hepatectomy:prospective clinical
trial. Ann Surg 2003; 237 (2):208–217.
94. Kooby DA, Fong Y, Suriawinata A, etal. Impact of steatosis
on perioperative outcome following hepatic resection. J
Gastrointest Surg 2003; 7 (8):1034–1044.
95. Azoulay D, Castaing D, Krissat J, etal. Percutaneous portal
vein embolization increases the feasibility and safety of major
liver resection for hepatocellular carcinoma in injured liver.
Ann Surg 2000; 232 (5):665–672.
96. Tanaka H, Hirohashi K, Kubo S, et al. Preoperative portal vein
embolization improves prognosis aer right hepatectomy for
hepatocellular carcinoma in patients with impaired hepatic
function. Br J Surg 2000; 87 (7):879–882.
97. Elias D, De Baere T, Roche A, et al. During liver regeneration
following right portal embolization the growth rate of liver
metastases is more rapid than that of the liver parenchyma. Br
J Surg 1999; 86 (6):784–788.
98. Kokudo N, Tada K, Seki M, etal. Proliferative activity
of intrahepatic colorectal metastases aer preoperative
hemihepatic portal vein embolization. Hepatology 2001; 34
(2):267–272.
99. Hayashi S, Baba Y, Ueno K, etal. Acceleration of primary liver
tumor growth rate in embolized hepatic lobe aer portal vein
embolization. Acta Radiol 2007; 48 (7):721–727.
100. Simoneau E, Aljiry M, Salman A, etal. Portal vein
embolization stimulates tumour growth in patients with
colorectal cancer liver metastases. HPB 2012; 14 (7):461–468.
101. Brouquet A, Abdalla EK, Kopetz S, etal. High survival
rate aer two-stage resection of advanced colorectal liver
metastases:response-based selection and complete resection
dene outcome. J Clin Oncol 2011; 29 (8):1083–1090.
190
Chapter20:Preoperative portal vein embolization
102. Narita M, Oussoultzoglou E, Jaeck D, etal. Two-stage
hepatectomy for multiple bilobar colorectal liver metastases.
Br J Surg 2011; 98 (10):1463–1475.
103. Pawlik TM, Olino K, Gleisner AL, et al. Preoperative
chemotherapy for colorectal liver metastases:impact on
hepatic histology and postoperative outcome. J Gastrointest
Surg 2007; 11 (7):860–868.
104. Vauthey JN, Pawlik TM, Ribero D, etal. Chemotherapy
regimen predicts steatohepatitis and an increase in 90-day
mortality aer surgery for hepatic colorectal metastases. J Clin
Oncol 2006; 24 (13):2065–2072.
105. Shindoh J, Tzeng CW, Aloia TA, etal. Optimal future liver
remnant in patients treated with extensive preoperative
chemotherapy for colorectal liver metastases. Ann Surg Oncol
2013; 20 (8):2493–2500.
106. Zorzi D, Chun YS, Mado DC, Abdalla EK, Vauthey JN.
regeneration aer portal vein embolization in the treatment
of colorectal liver metastases. Ann Surg Oncol 2008; 15
(10):2765–2772.
107. Covey AM, Brown KT, Jarnagin WR, etal. Combined portal
vein embolization and neoadjuvant chemotherapy as a
treatment strategy for resectable hepatic colorectal metastases.
Ann Surg 2008; 247 (3):451–455.
108. Muratore A, Zimmitti G, Ribero D, et al. Chemotherapy
between the rst and second stages of a two-stage hepatectomy
for colorectal liver metastases:should we routinely
recommend it? Ann Surg Oncol 2012; 19 (4):1310–1315.
109. Fischer C, Melstrom LG, Arnaoutakis D, etal. Chemotherapy
aer portal vein embolization to protect against tumor growth
during liver hypertrophy before hepatectomy. JAMA Surg
2013; 148 (12):1103–1108.
Chemotherapy with bevacizumab does not aect liver
191
Section V
Chapter
Organ-specific cancers – extrahepatic biliary cancer
Extrahepatic biliary cancer:Stenting, brachytherapy,
and photodynamic therapy
21
Vlastimil Valek and Tomas Andrasina
Obstruction or stenosis of the extrahepatic bile duct may be
caused by primary tumor, tumors arising from surrounding
organs (gallbladder, pancreas), or compression from lymph
nodes. Bile duct obstruction is a frequent cause of morbidity
and mortality among oncological patients. Failing liver functions due to obstruction in the bile ducts could preclude early
surgical intervention, the application of chemotherapy agents
which metabolize directly in the liver, and, in later stages, therapeutic intervention of any kind due to bleeding complications.
Extrahepatic obstructions may be dierentiated as hilar or
distal according to their locations anatomically. Tumors growing from the epithelium of the biliary tract are most common
in the hilar region (65% of cases), and the complexity of the
perihilar liver region causes curative surgical resection to be
very complicated. Only a small percentage of such tumors are
detected at an early stage. Tumors located in the hilar region
oen inltrate or encase the branches of the common hepatic
artery and portal vein, and cholangiocarcinomas expand longitudinally into the intra- and extrahepatic bile ducts, submucosally and perineurially. As a result, the actual radicality of the
surgery may be debatable. Success in surgical resection is very
low, and the 5-year survival rate is unsatisfactory even aer
curative resection due to a high percentage of local recurrence.
e diculty of resection rises in accordance with the level in
the Bismuth–Corlette classication system. For type I, sometimes only localized resection of the common bile duct with
biliodigestive anastomosis is possible. For types II–IV, liver
resection is usually necessary. Extended le or right hemihepatectomy oen requires presurgical embolization of the portal
vein. Radical procedures include extensive lymphadenectomy,
which is made dicult by the structure of the hepatoduodenal
ligament with respect to the adjoining branches from the portal
vein and the adhesion of aicted lymph nodes on the biliary
tract, portal vein, hepatic artery, or head of the pancreas.
Even though surgical techniques are continually improving, resectability of hilar cholangiocarcinomas is in the range of
15–20%, the 5-year survival rate is in the range of 10–30%, and
local recurrence occurs in 75% of cases.
1
e eect of systemic chemotherapy alone in the treatment of non-resectable cholangiocarcinomas is very limited.
Fluoropyrimidine derivatives achieve therapeutic response
in only 30% of cases. Gemcitabine as a monotherapy or in
combinations generally achieved a better response rate and
thus has become a widely accepted standard. In particular, a
combination of gemcitabine and cisplatin has shown a response
rate of 53% and median survival in excess of 11months with
only a slight increase in the frequency and severity of side
eects.2 ese results have been further conrmed in a recent
meta-analysis, and thus gemcitabine in combination with platinum agents is widely accepted as the rst-line therapy for
locally advanced biliary tract cancer.3 e addition of biological
therapy to the standard cytotoxic treatment may bring further
improvements in progression-free survival or even increase
overall survival.4 Regional chemotherapy has as its objective to
increase the concentration of chemotherapeutics in the aected
area while decreasing side eects, and that should result in better response rates to the agents. ere are many tested therapeutic regimes combining systemic delivery with intra-arterial
chemotherapy or chemoembolization, which in some cases
with selected patients are able to achieve successful palliation.5
No combination, however, has yet become the standard therapy.
Obstruction of the biliary tract is the rst symptom of
extrahepatic biliary tract tumor. Due to its being less invasive,
endoscopic biliary drainage is the method of choice for stenoses of the distal and central sections of the common bile duct
(i.e., lower biliary obstructions). In this location, it is possible
to resolve obstructions by placing a single stent, the insertion
of which is relatively easy so long as the papilla is readily accessible. In comparison to percutaneous access, endoscopic drainage causes fewer serious complications and is less onerous for
the patient.
Endoscopic drainage of hilar strictures is also technically
possible, although this has a lower success rate and higher risk
of complications. In light of its diculty, percutaneous access is
usually recommended instead.6 An advantage of percutaneous
access is precise choice of drainage lobe, while disadvantages
include local pain and complications at the site of the puncture.
Historical data support the drainage of hilar strictures crossing at the proximal branch of the biliary tree using multiple
stents. According to Deviere, insertion of two or more stents
was associated with signicantly higher survival in patients
(179 vs. 119 days), decreased incidence of cholangitis (17%
vs. 38%), lower 30-day mortality (8 vs. 29%), and decreased
incidence of early death (13% vs. 46%) when compared with
Interventional Oncology, Second Edition, ed. Jean-François H. Geschwind and Michael C. Soulen. Published by Cambridge University Press.
©Cambridge University Press2016
193
Section V:Extrahepatic biliarycancer
the group of patients who underwent unilateral drainage.7 De
Palma etal. arrived at completely opposite conclusions in relation to complications. Alower incidence of early complications
appeared in the group of patients with drainage receiving only
one stent (19% vs. 27%), although the median survival was the
same for both groups (140 vs. 142days). More than one-third
of patients in that group, however, had biliary strictures limited
to common hepatic duct (BismuthI).
8
Even though drainage of merely 25% of liver volume
can successfully relieve symptoms of jaundice, the question
remains whether a single stent can provide for long-term survival, either independently or with the use of other palliative
techniques9 (Figures21.1 and 21.2).
e advantage of plastic temporary stents is their low price,
while their high occlusion rate is a disadvantage.10 Repeated
replacement of endoscopically inserted stents or percutaneous
internal–external biliary drainage means lower quality of life for
the patient in comparison with drainage using self-expandable
metal stents. Percutaneous internal–external drainage necessitates caring for the outer part of the drain, as this constitutes
a direct external pathway for microbial ora into the biliary
ducts. With long-term use of internal–external drainage, there
is a risk of frequent pain at the point of insertion, drain dislocation, or dysfunction. ere commonly is leakage of bile, which
irritates the skin even when the drain is functional, or ascites
may leak if this is present.
is can be resolved by inserting self-expandable metal
stents. e history of applying biliary self-expandable stents
begins in the late 1980s. Stent implantation is an optimal solution for malignant obstructions in patients who are not candidates for surgical intervention and where the expected survival
is longer than 3–6months. Insertion of stents is associated
with shorter patient hospitalization time, a longer period of
duct patency, and lower costs overall in comparison with plastic drains.11 e insertion of metal stents percutaneously and
endoscopically is now a routine procedure. In the case of hilar
stents, the success rate for percutaneous placement is higher
(93% vs. 77%), although the incidences of complications and
survival times in successfully drained patients are similar.
12
Upon its release, the stent begins to expand to the calibrated
width due to the shape-memory metal used and its distinctive
lattice design. e stent should extend past the biliary stenosis
by a minimum of 1–2cm at each end and should lead through
the papilla.
13
Percutaneous application of self-expandable metal stents
can be performed as part of initial drainage of the bile ducts
or, most frequently with some time delay, aer temporary
internal–external drainage or external drainage. (Figures 21.3,
21.4, 21.5, and 21.6). Only a minority of patients have dened
histological diagnoses at the time of initial drainage, and therefore biopsy follows internal–external drainage. In case of histologically veried etiology of stenosis in the patient, implantation
Figure 21.1 Magnetic resonance cholangiopancreatography showing
Bismuth 4 cholangiocarcinoma, separately obstructed right anterior and right
posterior sectoral ducts, also branches for segment 1 from left hepatic duct.
Figure 21.2 Contrast-enhanced computed tomography showing insufficient
drainage through one endobiliary drain, and marked dilatation of left and right
sectoral ducts.
Figure 21.3 Percutaneous transluminal forceps biopsy of hilar mass.
Histology confirms cholangiocarcinoma in 2/8 specimens.
194
Chapter21:Stenting, brachytherapy, and photodynamic therapy
Figure 21.4 Three external–internal drains were needed to successfully
relieve jaundice in the patient. After insertion of the last drain, the serum
bilirubin level drops to 15 μmol/L from 70 μmol/L.
Figure 21.6 1. At the time of safety catheter retrieval (10 days after
insertion of stents), angiogram shows no dilatation of bile ducts, although
subsegmental branch for segment 8 is not visualized.
e advantage of uncovered stents is their low migration frequency, while their disadvantages lie in the impossibility of
stent explantation and also earlier occlusions in comparison
with covered stents.16 e use of covered self-expanding stents
does not seem to be an appropriate solution for resolving hilar
strictures due to their obstructing the branches of the bile duct.
eir use in areas of the distal and middle common bile duct is
more frequent, even though there exists a risk for obstruction
of outlets of the cystic and pancreatic ducts.
17
e most frequent complication of self-expandable metal
stents is their closure. e stent gradually becomes covered
with the bile duct mucosa. In some patients, benign obstruction can occur due to its hyperplasia. Frequently, stent occlusion is also associated with migration or closure by detritus
and sludge formation.
18,19
As disease progresses, there can
occur ingrowth or overgrowth of the stent edge by the tumor.
Primary patency of uncovered stents, therefore, has not proven
at all favorable in either small or large study groups. It ranges
Figure 21.5 Insertion of three uncovered self-expandable metal stents.
most frequently from 80 to 120days, and exceptionally reaches
a median of 372days.
20,21,22
e occlusion rate is in the range
of 10–27% of patients (11.8%20; 25.7%21; 27%).22 Some authors
describe higher occlusion rates in cases of hilar tumors, while
others describe lower rates.
13,23,24,25
Despite the fact that covered stents are coated with polyuof the stent with a single-step technique demonstrates no
increased risk of complications. However, patient care in the
early postoperative period must be more intensive.14 Primary
stent patency and patient survival in these groups are also comparable with those for which stents are implanted gradually.
Moreover, Inal etal. judge the performance of initial drainage
with insertion of internal–external drains or balloon predilatation of stenosis to be procedures which do not inuence patient
survival. erefore, these authors regard these as unnecessary
even as they increase procedural costs by 19% per patient.
15
Self-expandable metal stents can today be divided into
three types: fully covered, partially covered, and uncovered.
rethane, silicone or Gore-Tex membrane, the risk of tumor
ingrowth is not precluded. Self-expandable metal stents covered with newer, non-porous materials (expanded polytetrauoroethylene (ePTFE), uorinated ethylene propylene
(FEP)), with new stent design preventing migration, and with
possibilities for safe extraction within 12months have been
studied in multi-institutional randomized trials. In stenoses
of distal and middle common bile duct (tumors of the pancreas and extrahepatic bile ducts), mean patency reached
7.8–8months for covered stents and 5.5–6months for uncovered stents. No stent occlusion from tumorous ingrowth was
observed in the covered stents group, and a lower number of
195
Section V:Extrahepatic biliarycancer
reinterventions was recorded.
covered stents was achieved only within the patient group
having extrahepatic cholangiocarcinoma (244 vs. 181days).
Metal stent occlusion becomes a serious problem for
long-term patient survival in cases of hilar cholangiocarcinoma. According to Lee et al., internal–external drainage is
more advantageous in resolving obstructed stents than is the
addition of another metal stent due to the low expected survival in this patient group.23 Research data regarding local
ablation procedures have been published for smaller patient
groups, but these are frequently associated with early relapse of
stenosis and stent dysfunction.
Photodynamic therapy
e principle of photodynamic therapy (PDT) consists in a
cytotoxic eect from a combination of specic chemotherapeutic agents exposed to electromagnetic radiation. e
chemotherapeutic agent (photosensitizer) is administered
systemically into the patient’s body while the application of
radiation is local and therefore location-specic. In addition,
the photosensitizer is preferentially retained in tumorous tissue, so, to a certain degree, the treatment can be considered
tissue-specic. Preferential accumulation of the photosensitizer in malignant tissues probably relates to the chemotherapeutic agent’s anity for proliferating tissues and those tissues’
insucient lymphatic drainage.
Radiation of suitable wave length is applied using an optical
ber with a diuser at the end (Figure 21.7). e photosensitizer is thereby activated, resulting in a release of radicals.
Oxygen radicals have a direct cytotoxic eect (apoptosis or
necrosis of tumorous cells). Another related eect is ischemia
of pathological tissue while damaging the blood vessels and
activating the immune response.
Infrared or red light with wavelength of 630nm is applied
most frequently. It has a possible eective range of up to
26,27
Longer survival in use of
28
5
8–10mm, although the application of PDT neoadjuvantly has
demonstrated a necrosis range of only 4–6mm in explants.
Hematoporphyrin derivatives (e.g., Photofrin, Photosan)
and tetra(m-hydroxyphenyl)chlorine (mTHPC) are the most
frequently used photosensitizers for tumors aecting bile
ducts.29 Despite several dierences in their eects, none of
them has been proven superior to the others.
is treatment involves certain diculties concerning perioperative patient care (including limiting exposure to ambient
light for a period of at least 30days) and the conditions related
to this during hospitalization. Light activation is performed
within a specic time aer administration of photosensitizer
(e.g., the most commonly used agent, Photofrin, is administered 24–48hours prior to the procedure). PDT is delivered
through optical ber with a cylindrical diuser at its distal
end. Various lengths of diuser tips are available. Radiopaque
markers on their proximal and distal ends provide guidance
for precise positioning. e light dose administered is usually
180–200J/cm2.
e reported complications of photodynamic treatment are
mostly not serious. In most studies, the rate of serious complications does not surpass the complication rate associated with
endoscopic or percutaneous drainage (biliary leakage, liver
abscess in fewer than 5% of patients). Based upon data from
2004 to 2010 in a group of 55 patients, Talreja etal. point to a signicant rate of cholangitis requiring stent revision aer PDT in
up to 50% of patients.30 Treatment-specic side eects include
photosensitivity and rash, while 30% of pormer sodium recipients suer 5–7% severe sunburn. Complications that would
require surgical revision in the early period of photosensitization can be problematic, because of the high luminescence
of lamps used in operating rooms. Patients undergoing liver
transplantation more than 6weeks aer administration of the
chemotherapy exhibited no serious complications.
31
Excellent results of PDT were achieved in two randomized
studies carried out in Europe.
32,33
Ortner29 reports an improvement in patients’ survival rate and quality of life along with
decreased cholestasis in a patient group with PDT as contrasted
with patients having implanted plastic stents. Median survival
was 493 vs. 98days (P<0.0001), and the study population was
highly selected to include patients with persistent jaundice
aer stenting. Based upon a randomized study, Zoepf etal.32
also point to an important inuence of the therapy in terms
of improved survival (21 vs. 7 months). Even though they
did not nd similar survival lengths, other (non-randomized
and mostly retrospective) studies conrm the benet of PDT,
as does their meta-analysis. Leggett et al. analyzed six studies encompassing 170 patients who received PDT and 157
patients who had biliary stenting alone.34 ey found a statistically signicant increase in survival length for the PDT group
(advantage of 265days), improvement in Karnofsky scores, and
Figure 21.7 1. Brachytherapy applicator 5F (external–internal drain size of
at least 10F is used for smooth insertion and to allow bile drainage during
radiation therapy). 2. Endoluminal radiofrequency catheter endoHPB (8F,
EMcision, UK). 3. Activated laser quartz fiber (Medlight, Switzerland). It has 400
μm core diameter, 20–50 mm cylindrical diffuser tip, with an X-ray marker on
both ends of the diffuser.
a trend toward decline of serum bilirubin. Because the study
populations are small, however, the quality of the evidence
provided by these data is low. In a retrospective analysis by
Cheon etal., in addition to the benets of longer survival (9.8
vs. 7.3months, P=0.029), longer primary patency of the metal
stent was also recorded in patients undergoing PDT (215 vs.
196
Chapter21:Stenting, brachytherapy, and photodynamic therapy
181days, P=0.018). Most of these patients (71%) had undergone only a single application ofPDT.
35
PDT was compared with the results of surgical resection
in two non-randomized studies.
36,37
Despite the fact that the
patients undergoing palliative procedures had been in a poorer
clinical state, had worse Bismuth grading, and had a tendency
to be older in comparison to patients undergoing the resection procedure with curative intentions, Matull etal. found no
signicant dierence in survival between patients with positive resection margins in comparison to those who underwent
palliative procedures with application of PDT (PDT vs. R1,
P=0.13 and PDT vs. R2, P=0.32; without dierences in survival between R1 and R2 resections, P=0.09). One of the reasons for this result, too, was a 9% rate of 30-day mortality in the
patient group aer the non-radical procedure, while no early
deaths occurred in the patient group withPDT.
36
Survival in patients with PDT can be inuenced by the
number of PDT applications.38 Patients with good performance
status and longer survival could be managed with more PDT
sessions. Better survival and shorter period from disease diagnosis to therapy were recorded in patient groups with lower
bilirubinemia before performance of the PTD. Poorer T stage
has a negative inuence on patient survival, while extrabiliary
spread of the disease (metastases into lymph nodes or distant
organs) did not inuence survival in the study by Cheon etal.
Despite its promising theoretical foundation and results,
PDT has only limited availability. In carcinomas of the intrahepatic and extrahepatic bile ducts, patient survival periods
are reported to have as much as doubled.
32,38
Aproblem is that
most experimental groups are non-randomized and the therapy has been performed on too few patients. Neoadjuvant use
studies, patients treated with IMRT or stereotactic therapy
achieve higher survival, although (despite well-targeted volumes) both acute and late toxicity increases.
40
Intraluminal brachytherapy of the bile ducts is a minimally
invasive method which can overcome the disadvantages of
high-dose external-beam radiation therapy (EBRT). Relative
to EBRT, intraluminal brachytherapy can administer higher
radiation doses in a shorter time. In brachytherapy, either percutaneous access to the bile ducts is used or it can be applied
endoscopically with an implanted drain. Fletcher etal. were
among the rst to use intraluminal brachytherapy with an iridium radiation source (iridium-192) in the late 1970s.41 When
using intraluminal radiation therapy with an iridium radiation source, iridium is formed into a cylindrical, granular, or
liform shape which emits gamma and beta radiation in the
aectedplace.
When applying brachytherapy today, aerloading systems
are used. ese automatically place the radiation source into
an applicator positioned in a pre-established location. e
applicator is a thin catheter (5–6F) which can be temporarily placed into a drain or a metal stent (Figure 21.7). Even
though a metal stent does not signicantly attenuate or scatter radiation,42 when we consider the suboptimal centering
within the lumen of a self-expandable metal stent 8–10mm
35
wide, we recommend performing brachytherapy before
inserting the stent. e extent of malignant bile duct stenosis
relative to the applicators is drawn into the planning examination (image documentation), which is then sent with the
patient to the radiation oncology department (Figures21.8
and 21.9). e patient then undergoes the required number
of brachytherapy fractions.
of PDT has demonstrated eective tumor destruction to a
depth of 4–4.5mm. It is therefore apparent that PDT cannot be
entirely eective for resolving nodular (mass-forming) tumors.
By contrast, its use seems optimal against tumors of papillary
subtypes and sclerosing form.
39
Radiotherapy
Despite the fact that adenocarcinomas of bile ducts are
regarded as tumors with low radiosensitivity, data in the literature support the use of radiotherapy in palliating tumors at
this location. Most cases of palliation failure, however, consist
of locoregional progression, and therefore several authors recommend increasing the dosage in order to improve the results.
Lethal radiation doses against adenocarcinomas are high (up
to 60Gy), and escalating doses increases the risk of damage
to surrounding healthy tissues. Perihilar location of tumors
is risky due to the liver’s radiation sensitivity (the tolerance
dose for liver parenchyma is 30–40Gy), while distal tumors
aecting bile ducts can only be irradiated while considering
the vicinity of the duodenum and small intestine. In contrast
to conventional radiation therapy, modern radiation methods
such as intensity-modulated radiation therapy (IMRT) and stereotactic radiation therapy are able to achieve a higher eective dose intratumorally while applying a markedly lower dose
to tissues outside the planning volume. According to several
Figure 21.8 Patient with hilar involvement of Bismuth 4 (cholangiocellular
carcinoma, grade 2). Atrophy of left hepatic lobe made left-sided drainage
unnecessary.
197
Section V:Extrahepatic biliarycancer
tumor presence visible macroscopically in the biliary ductal
lumen. For those 10patients treated with 90–98Gy, none
had macroscopic presence of tumor in bile ducts and seven
were also without periductal tumor. On the other hand, 34%
(32/93) developed radiation-induced gastroduodenitis and
33% (31/93) had treatment-related biliary complications.
Biliary fistula occurred in three patients and hemobilia in
five patients.
During the administration of brachytherapy, cholangitis
and liver abscess may develop due to cholestasis. Especially
when HDR brachytherapy is combined with external radiotherapy, it is necessary to anticipate acute and late radiation
toxicity. irty-day patient mortality is reported on rare occasions, and biliary and gastrointestinal bleeding occurs occasionally also in other studies. Symptoms of gastrointestinal
toxicity appear in up to 30% of patients, most frequently as very
moderate vomiting and nausea, while in later stages there may
occur gastrointestinal ulceration and erosion.
In treating tumors of the extrahepatic bile ducts, it is fre-
Figure 21.9 Two brachytherapy applicators introduced through 10F
external–internal drainage. Total dose of 21 Gy applied in 3 days.
quently recommended to administer chemotherapy concurrently with radiation therapy. One of the negative aspects of
concomitant radiation and chemotherapy can be disproportionately increased toxicity of the combined treatment in relation to healthy tissues. Indication for combining radiation and
In brachytherapy, high-dose rate (HDR) or low-dose rate
(LDR) techniques are used, which means the application of
> 12 Gy/hour or < 2 Gy/hour, respectively. e advantages
of HDR brachytherapy are shorter hospitalization time and,
according to the literature, lower rates of cholangitis due to
drain blocking. Brachytherapy and EBRT techniques can be
safely combined, the objectives being not only to limit the eect
of radiation therapy to bile ducts but also to irradiate lymphatic
drainage. ere exist local dierences as to the radiation dose
applied in brachytherapy. When combining external radiation
therapy and brachytherapy, the usual dose is in the range of
7–30Gy, prescribed at a distance of 0.5–1.0cm from the center
of the source in 1–6 fractions. Each fraction typically consist of
5.0–7.5Gy and takes several minutes in one HDR brachytherapy session. In the case of standalone brachytherapy, 20–42Gy
is applied.
Studies document a connection between high radiation
dose and longer patient survival. In a publication by Alden
and Mohiuddin, it was reported that by reaching a therapeutic
dose (with EBRT and intraluminal brachytherapy in combination) of more than 55Gy, patients moved into a more favored
group with survival of up to 24months versus a median of
only 6months in patients with lower doses.43 When total doses
exceed 90Gy, on the other hand, patients are subjected to a risk
of increased complication rate with no fundamental inuence
on survival.
44
In a study by Takamura et al., 93 patients underwent
a combination of EBRT and low-dose brachytherapy.
The mean dose of brachytherapy was 40Gy (in the range
20–50 Gy), and a daily dose of 2.0 Gy of external radiotherapy was delivered four times weekly to a total dose of
50Gy. In autopsies performed on 20 patients (with median
10.8months after radiotherapy), 17 patients (85%) had no
chemotherapy must be carefully and individually considered
with a view to the patient’s overall state and his or her intercurrent diseases. We do not utilize standalone brachytherapy in a
concomitant regime.
e eectiveness of brachytherapy has been observed in
mostly small, non-randomized, retrospective studies. In the
case of distal extrahepatic carcinoma, it has contributed to
prolonging median survival to the range of 10–14months.
Evidence of prolonging overall survival in selected patients
has also been established by Shin et al. in a group of 31
patients having inoperable carcinomas of the extrahepatic
bile ducts.45 In 17 patients they administered EBRT alone,
and in 14 patients a combination of EBRT and HDR brachytherapy. EBRT was delivered at a total dose of 36–55 Gy
(median 50.4Gy), and intraluminal brachytherapy was prescribed at 1.5cm from the center of the source with a single
daily dose of 5Gy to a total of 15Gy in 3days. All patients had
implanted metal stent prior to brachytherapy. e 2-year survival rate for patients treated with the combination of EBRT
and brachytherapy was 21% versus 0% for those treated with
EBRT alone (P=0.015). In the case report of Chan etal.,
6-year survival in a patient with Klatskin IV cholangiocarcinoma was achieved with a combination of EBRT (40Gy) and
ILBT (10Gy).46 e largest retrospective study was published
in 2010 by Shinohara et al.,47 who analyzed 193 patients
having cholangiocarcinomas treated with brachytherapy.
Overall median survival in the group was up to 11months,
while in a large control group without radiotherapy (6,859
patients) it reached only 4months. Arandomized study of
brachytherapy and EBRT performed at our institution in a
sample of 42 patients demonstrated a signicant dierence
in survival (12.9 vs. 9.9months). Intraluminal brachytherapy
was performed using the HDR technique and a dose of 30Gy
198