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Siu-Yin Chan,
Ronnie T. Poon, Kelvin K. Ng, Chi-Leung Liu, Sheung-Tat Fan,
Centre for the Study of Liver Disease and Department of Surgery, The
University of Hong Kong, Pokfulam, Hong Kong, China
Raymond T. Chan, Department of Clinical Oncology, The
University of Hong Kong, Pokfulam, Hong Kong, China
Correspondence to: Dr. Ronnie T. Poon, Department of Surgery,
The University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road,
Hong Kong, China. poontp@hkucc.hku.hk
Telephone: +852-285-53641
Fax: +852-281-75475
Received: 2004-07-12
Accepted: 2004-09-19
Abstract
Surgical resection with a tumor-free margin is the only curative
treatment for hilar cholangiocarcinoma (Klatskin tumor). However,
over half of the patients present late with unresectable tumors.
Radiotherapy using external beam irradiation or intraluminal
brachytherapy (ILBT) has been used to treat unresectable hilar
cholangiocarcinoma with satisfactory outcome. We reported a patient
with unresectable hilar cholangiocarcinoma surviving more than 6
years after combined external beam irradiation and ILBT.
© 2005 The WJG Press and Elsevier Inc. All rights reserved.
Key words: Brachytherapy; Hilar cholangiocarcinoma
Chan SY, Poon RT, Ng KK, Liu CL, Chan RT, Fan ST. Long-term survival
after intraluminal brachytherapy for inoperable hilar
cholangiocarcinoma: A case report. World J Gastroenterol
2005; 11(20): 3161-3164
http://www.wjgnet.com/1007-9327/11/3161.asp
INTRODUCTION
Cholangiocarcinoma is a malignant tumor arising from either the
extra-or intra-hepatic bile duct. The histological types include
adenocarcinoma, carcinoma in situ, papillary adenocarcinoma,
mucinous adenocarcinoma, and squamous cell carcinoma[1].
Hilar cholangiocarcinoma (Klatskin tumor) is a specific disease
entity involving malignant tumors that locate in the biliary
confluence at the liver hilum. Surgical resection with an adequate
tumor-free margin is the only curative treatment[2].
The reported medium survival after surgical resection ranges from 16
to 46 mo[3-5].
A 5-year survival rate ranging from 21% to 25% after curative
hepatectomy for hilar cholangiocarcinoma has been reported[6,7].
However, the prognosis of most patients with hilar
cholangiocarcinoma is usually poor because of the low resectability
rate, ranging from 28% to 37%[3,4,6,8].
This can be related to their locally advanced disease with extensive
biliary and/or vascular involvement, presence of distant metastases,
and poor pre-morbid conditions precluding a major operation. The
median survival for patients with unresectable hilar
cholangiocarcinoma has been reported to be 6-12 mo[3,4,6,9].
Among the palliative therapies for unresectable
hilar cholangiocarcinoma, radiotherapy can achieve satisfactory
local tumor control and possible survival benefit. It can be given
in the form of external beam radiotherapy (EBRT), intraluminal
brachytherapy (ILBT), or a combination of both. With the advancement
in computerized 3D treatment planning system, the accuracy of the
delivery of EBRT to the targeted tumor has been much improved. This
technique leads to tumor shrinkage and improves bile drainage, thus
reducing the incidence of septic complications. Likewise, ILBT
imposes a high radiation dose to the tumor volume, bypasses the
radiosensitive skin and superficial structures, and therefore spares
the surrounding normal structures from radiation toxicity. The
reported medium survival for unresectable hilar cholangiocarcinoma
is 11 mo with ILBT alone[10]
and 14.5 mo with combined EBRT and ILBT[11].
Both techniques offer satisfactory symptom palliation with minimal
toxicity and are technically feasible for most patients. However,
long-term survival beyond 5 years is very rare after radiotherapy
for unresectable cholangiocarcinoma. We reported a patient with
unresectable hilar cholangiocarcinoma surviving more than 6 years
after combined treatment by EBRT and ILBT, and briefly reviewed the
literatures of this treatment modality.
CASE REPORT
A 49-year-old gentleman presented with painless obstructive
jaundice and significant weight loss in May 1998. Liver biochemistry
showed elevated bilirubin (185 mmol/L)
and alkaline phosphatase (285 IU/L) concentration. His carcino-embryonic
antigen concentration was normal. Endoscopic retrograde
cholangiopancreatography (Figure 1) showed a Bismuth type IV
stricture[12].
Contrast computed tomography (CT) scan of the abdomen revealed
enlarged lymph nodes along the hepatoduodenal ligament (Figure 2).
Subsequent hepatic and superior mesenteric angiogram showed
encasement of the common hepatic artery and main portal vein by the
tumor. The tumor was considered unresectable and ultrasound-guided
fine needle aspiration cytology of the hilar mass confirmed the
diagnosis of hilar cholangiocarcinoma.
Bile duct decompression was performed by
percutaneous transhepatic biliary drainage (PTBD), and the patient
received combined EBRT and ILBT. A total of 40 Gy EBRT was given to
the tumor bed in 20 divided fractions, which was followed by 10 Gy
ILBT using iridium 192 (Ir192)
wire. These radio-therapeutic procedures were not associated with
any complication. A self-expandable metallic stent (Wallstent,
Boston Scientific Ltd, USA) (Figure 3) was then inserted via the
PTBD tract to bypass the stricture site, and the patency of the
metallic stent lasted for 14 mo. Subsequently he required PTBD again
when the metallic stent was blocked.
There was evidence of tumor regression on
reassessment by CT scan in the first 2 years following the treatment
(Figure 4). Subsequently there was slow disease progression with
bile duct segregation and tumor infiltration to the second part of
the duodenum. The patient relied on long-term PTBD for symptomatic
control. Nevertheless, he has survived for more than 6 years since
the initial diagnosis was made, and enjoyed a reasonable quality of
life. He was able to work after the radiotherapy until the most
recent 2 years of his disease course. At the time of writing the
manuscript, the patient was still alive with satisfactory general
condition.
Figure
1 Endoscopic
retrograde cholangiopancreatography showing bile duct stricture at
liver hilum suggesting hilar cholangiocarcinoma.
Figure
2 Contrast CT
scan showing lymph node enlargement at hepatoduodenal ligament
(black arrow).
Figure
3 Metallic
stent (black arrow) inside common duct on endoscopic retrograde
cholangiopancreatography.
Figure
4 Contrast CT
scan showing tumor regression after combined ILBT and external beam
irradiation.
DISCUSSION
In spite of its low incidence, hilar cholangiocarcinoma is a
deadly tumor because the diagnosis is commonly not made until the
disease progresses to its advanced stage which is not amenable to
curative resection. The median survival is less than 1 year if the
tumor is unresectable[3,4,6,9].
The treatment options for unresectable advanced hilar
cholangiocarcinoma are limited. Orthotopic liver transplantation has
been proposed to be a curative treatment modality for locally
advanced hilar tumors with no evidence of extrahepatic tumors.
However, it could be offered only to patients with locally advanced
unres-ectable tumors without widespread metastases. The reported
medial survival is 25 mo[13]
and 5-year survival ranges from 30% to 87%[6,14,15].
Hassoun et al.[14],
achieved a high 5-year survival of 87% by very careful patient
selection including staging laparotomy. Nonetheless, the practice of
this treatment option is largely limited by the lack of organ donors
and the potential risk of tumor recurrence following
immunosup-pressive therapy. For most patients with unresectable
hilar cholangiocarcinoma, therapeutic efforts are mainly confined to
palliation, which primarily involves relief and treatment of
cholestasis. However, no palliative treatment is of proven value in
prolonging survival.
Mortality of patients with hilar
cholangiocarcinoma is usually caused by locoregional phenomena, as a
result of liver failure secondary to bile duct obstruction,
cholangitis, and sepsis. Bile duct decompression by endoscopic or
radiological techniques is of paramount importance. This not only
relieves patients’ symptoms such as itching and cholangitis, but
also facilitates biliary access and recovery of hepatic parenchymal
function. In addition, it makes further oncological treatments of
the tumor possible[9].
In fact, ILBT is regarded to be beneficial as it improves bile
drainage in patients with hilar cholangiocarcinoma[10].
In case of significant biliary obstruction, prior establishment of
patency of the common duct is important for a successful delivery of
ILBT. This can be achieved by self-expandable metallic stent
insertion, either percutaneously or endoscopically via the duodenum[16,17].
ILBT prolongs the patency of the metallic stent, which has been
reported to range from 6 to 8 mo[9,17].
This minimizes the chance of stent occlusion, and delays the use of
external biliary drain, which is associated with significant
psychological problems and physiological disturbances such as
dehydration and electrolyte imbalance[17].
Our patient received ILBT before metallic stent insertion, and the
patency of the stent lasted for 14 mo after brachytherapy.
With regard to ILBT, there is no randomized
controlled study to prove its effectiveness in patients with hilar
cholangi-ocarcinoma[18].
The number of patients studied was small in most of the series in
the literature[10,11,19-23].
The medium survival after ILBT for extrahepatic cholangiocarcinoma
has been reported to range from 4 to 13 mo[19-23].
With respect to hilar cholangiocarcinoma per se, the reported
medium survival ranges from 11 to 14.5 mo[10,11]
(Table 1). ILBT was initially planned as a boost, as part of a
treatment regimen for patients with inoperable tumors. This
treatment modality was first reported in 1979 by Zimmon et al.[24].
In that study, the iridium wire source was placed through PTBD in
four patients. The treatment duration lasted for 24-72 h. It
provides symptomatic palliation and significant tumor control
without exacerbation of cholestasis or infective complication. It is
suggested that early ILBT after PTBD might extend palliation of
jaundice due to its effect on the limitation of tumor extension. Ir192,
with a half-life of 7 d, is the usual irradiation source for ILBT.
The wire source can be put through PTBD or a nasobiliary catheter to
reach the site of neoplastic stricture under fluoroscopic guidance.
The wire can be placed across, parallel to or inside a stent. Au198
grains, with a shorter half-life of 2.7 d, have also been used for
ILBT. It was found that the medical staff is better protected from
radioactivity when the Au198
sources are withdrawn after brachytherapy[25].
Table 1 Survival
after radiotherapy for extrahepatic cholangiocarcinoma
| Study |
No.
of patients |
Pathology |
Mode
of radiotherapy |
Medium
survival (mo) |
| Fletcher
et al. (1983)[10] |
18 |
Hilar
cholangiocarcinoma |
ILBT |
11 |
| Kuvshinoff
et al. (1995)[11] |
12 |
Hilar
cholangiocarcinoma |
ILBT+EBRT |
14.5 |
| Levitt
et al. (1988)[19] |
20 |
Cholangiocarcinoma |
ILBT |
10 |
| Ede
et al. (1989)[20] |
14 |
Cholangiocarcinoma |
ILBT |
10.5 |
| Veeze-Kuijpers
et al. (1990)[21] |
31 |
Cholangiocarcinoma |
ILBT+EBRT |
8 |
| Morganti
et al. (2000)[22] |
20 |
Cholangiocarcinoma |
ILBT+EBRT |
13 |
| Gonzalez
et al. (2002)[23] |
38 |
Cholangiocarcinoma |
ILBT+EBRT |
10.4 |
ILBT,
intraluminal brachytherapy; EBRT, external beam radiotherapy.
The optimal irradiation dose and duration of brachyt-herapy are
unknown. Our patient received a combination of 50-Gy external
irradiation. The relationship between irradiation dosage and
survival has been studied by Alden and Mohiuddin[26].
The patients with cholangiocarcinoma receiving high-dose combined
brachytherapy and external beam radiation of more than 55 Gy showed
significantly better survival than those who received smaller doses
in unresectable cases. Among patients who received high-dose
radiation, 48% of them experienced an extended 2-year survival. In
another study, brachytherapy was given to five patients with
Klatskin tumor for up to 5 d[27].
Two ribbons containing Ir192
seeds were threaded into the right and left percutaneous biliary
drainage catheters in a “Y-shaped” configuration that
corresponded well to the “Y-shaped” volume of the Klatskin
tumor. Despite all these survival results, long-term survivors after
radiation therapy for hilar cholangiocarcinoma, as in our case, have
rarely been reported.
The procedure itself is not without risk. In the
absence of any standardized protocol for brachytherapy, it is
meaningless to compare the overall morbidity in different studies.
The reported complication rate for cholangitis, which can be fatal,
ranges from 6% to 30%[11,28,29].
Complications can be classified as those related to catheter
introduction and those resulting from irradiation. There is an
increased risk of bactobilia and bile duct perforation with either
endoscopic or percutaneous biliary tract instrumentation. The wire
source is introduced to the stricture site commonly via PTBD
catheters, thus the potential risks are hemobilia, catheter
dislodgement, superficial wound infection, liver abscess, and bile
leakage. The complications related to ILBT itself are cholangitis
and pancreatitis, as a result of blocked stent with biliary
obstruction, as well as gastrointestinal tract upset with peptic
ulcer or diarrhea[11,28].
There has been no report on the benefits of
offering EBRT in advance to ILBT or vice versa. However, EBRT is
given first in the majority of centers. This may be attributed to
its effect on tumor shrinkage that prevents cholangitis during
brachytherapy treatment. It is also questionable whether the
addition of chemotherapy is beneficial to patients with inoperable
Klatskin tumors. Basically, the use of chemotherapy is mainly
limited to clinical trials. Nomura et al.[30],
reported a survival benefit in patients with unresectable
extrahepatic bile duct cancer receiving brachytherapy combined with
EBRT and repeated hepatic arterial infusion chemotherapy when
compared with those receiving brachytherapy alone.
ILBT was intensely investigated 10 years ago, but
it is still not commonly practiced nowadays. This case report showed
that palliative combined EBRT and ILBT could be associated with
long-term survival. Hence, it is worthwhile to reconsider its
potential effect on local tumor control and possible survival
benefits by proper randomized controlled trials. Hilar
cholangiocarcinoma, once labeled as a dismal disease with poor
outcome, can be associated with long-term survival as shown in our
patient. In addition to improvement of life expectancy, the
prolonging of symptom-free survival is an important target of the
treatment as well.
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