Extrahepatic bile duct adenocarcinoma is an uncommon disorder with a grim prognosis, and unfortunately, the ultimate goal of treatment is often no more than palliation of pain and obstructive jaundice symptoms. This article examines the results of treating primary bile duct neoplasms with Ir-192 brachytherapy versus radical surgery, based on the authors' experience at the University of Virginia Medical Center.
are in the Department of Radiation Oncology at Massachusetts
General Hospital, Harvard Medical School in Boston, MA.
is with the United States Army Reserves.
are with the Department of Therapeutic Radiology and Oncology at
the University of Virginia Health Sciences Center in
was with the Department of Radiology at the University of
Virginia Health Sciences Center.
xtrahepatic bile duct cancer is uncommon, with an annual incidence
of approximately 2500 cases in the United States. Ninety-eight
percent of these tumors are adenocarcinomas, with squamous cell
carcinomas representing the remainder.
The prognosis in patients with this type of cancer is often grim:
5-year survival ranges from 0% to 31%. Distant metastases are less
frequently reported with this tumor. Instead, this tumor behaves
very aggressively in a local manner, often involving such organs as
the liver, pancreas, gallbladder, and duodenum. Unfortunately, the
ultimate goal of treatment is often no more than palliation of pain
and obstructive jaundice symptoms.
It has been widely believed that surgery is the only treatment
that may offer a cure. However, only 20 to 40% of these tumors are
resectable for cure, and locoregional recurrences occur in 60 to
80% of cases.
Distal duct lesions traditionally have been managed with a
pancreaticoduodenal resection (Whipple procedure). Proximal lesions
involving the region extending from the right and left hepatic
ducts to the common hepatic duct inferiorly to the level of the
cystic duct are referred to as Klatskin tumors. Fifty to 70% of
Klatskin tumors are unresectable; the remainder is managed by
surgical resection and Roux-en-Y hepaticojejunostomy bypass.
Radiation therapy traditionally has been considered to be a
palliative option in treating bile duct cancers in cases of
unresectable disease. It also has been used as an adjuvant for
microscopic residual disease after surgery. Radiation therapy
options currently available include external beam radiotherapy,
intraoperative radiotherapy using orthovoltage equipment or
electrons, and intracavitary irradiation using Ir-192 applied
through a carefully placed "decompression" tube. Recent studies
have shown a survival benefit in patients with bile duct cancers
treated with brachytherapy and stenting compared to patients
treated with stents alone.
Studies also have shown improved survival in patients treated with
radiotherapy following either complete or incomplete surgical
resection of bile duct tumors.
Our purpose in this study is to examine retrospectively the
results of treating primary bile duct neoplasms with Ir-192
brachytherapy versus radical surgery, based on our experience
between 1981 and 1994 at the University of Virginia Medical
Materials and methods
Forty-six patients were diagnosed with primary extrahepatic bile
duct carcinoma at the University of Virginia Hospital from 1981 to
1994. Of these, 21 received radiotherapy only, 14 were treated
surgically with curative intent, 3 were treated palliatively with
stent placement, and 8 patients either expired prior to treatment
or refused treatment. Preoperative staging evaluations included
physical examination, laboratory tests, and imaging studies
percutaneous cholangiography (PTC)
and, in some cases, angiography. The histopathologic diagnosis of
bile duct adenocarcinoma was made by cytological brushings, needle
biopsy, or by tissue obtained at surgery.
Three of the 21 radiotherapy patients were treated by external
beam irradiation (EBRT) alone and were excluded from further
analysis. Eighteen of the 21 radio-
therapy patients were treated by either brachytherapy alone or in
combination with EBRT and constituted Group I in this study.
Table 1 presents demographic data, modality of treatment, and
follow-up information on all Group I radiotherapy patients. There
were 9 females (50%) and 9 males (50%) in this group. The mean age
of Group I patients at the time of diagnosis was 66.2 years
(SD±12.0 years). The mean total radiation dose delivered to this
group was 3997 cGy (SD±1185 cGy). The mean brachytherapy dose rate
was 45 cGy/hour (SD±6.2 cGy/hour) at 0.5 cm from the linear source.
All patients in this group had percutaneously placed stents. Two
patients received external beam irradiation in addition to Ir-192.
Patient 1 received 30 Gy of EBRT and 30 Gy
Ir-192. Patient 18 received 20 Gy EBRT plus 20 Gy Ir-192.
Group II in our study was comprised of 14 patients treated
surgically with curative intent. Of these patients, nine underwent
the Whipple procedure (pancreaticoduodenectomy) and five underwent
surgical excision of tumor with
an accompanying bypass procedure (hepaticojejunostomy). All
patients in this group initially had percutaneous stents placed to
relieve obstruction. Table 2 presents demographic and treatment
information on all Group II patients. There were eight males (57%)
and six females (43%) in this group. The mean age of Group II
patients at the time of diagnosis was 64.6 years (SD±12.9
The criteria for unresectability included findings of encasement
or occlusion of the common hepatic artery or main portal vein on CT
or angiography. Extensive invasion of adjacent structures such as
the liver, stomach, colon, or gallbladder, or findings of
peritoneal metastases on laparoscopy also deemed patients
unresectable. All patients in Group I were judged to have
clinically staged, unresectable, locally advanced disease. All
Group II patients, based on preoperative evaluation, were deemed to
have resectable disease. Operative and pathologic findings,
however, revealed that five patients (#2, 5, 7, 10, and 14) had
tumors with invasion into adjacent structures. Hence, 64% of
patients in Group II had localized disease, and 36% had locally
advanced disease based on operative and pathologic findings.
Tables 1 and 2 present follow-up information for patients in
Groups I and II, respectively. Of the 18 Group I patients treated
with brachytherapy alone or in combination with external beam
radiotherapy, three were alive at their latest follow-ups, ranging
from 5 to 24 months after treatment. One patient in Group I
(patient #17 in table 1) died of myocardial infarction but was free
of disease at latest follow-up. Fourteen patients in Group I
ultimately died of disease. All of these patients had progressive
local disease with invasion into critical adjacent structures and
of resulting complications, including infection/sepsis.
Life table survival probabilities are shown in figure 1 for both
groups. Actuarial analysis of survival reveals a median survival of
13 months with a standard error (SE) of ±6.09 months. The
Brookmeyer-Crowley 95th percent confidence interval for median
survival ranged from 9 to 15 months. The 1- and 2-year life table
survivals were 53% and 20%, respectively, for Group I patients
(table 3). There appeared to be no dose-response effect. Of the
nine patients receiving 30 Gy, three were alive at their latest
follow-up. None of the nine patients receiving doses of greater
than 30 Gy were alive at their latest follow-up.
Of the 14 patients treated with radical surgical resection
(Group II), four were alive at their latest available follow-ups,
ranging from 7 to 86 months. Three of these four patients had no
evidence of disease (NED); one of these patients had a local
recurrence and is presently being treated with salvage
chemotherapy. Nine of the remaining 10 patients died of
complications arising from recurrent local disease or hepatic
metastases. One patient died of postoperative sepsis. Actuarial
analysis of survival reveals a median survival of 14 months
(SE±2.48 months). The Brookmeyer-Crowley 95th percent confidence
interval for median survival ranged from 12 to 18 months. The 1-
and 2-year life table survivals for Group II patients were 70% and
31%, respectively (table 3).
Any differences in median survival between the two groups were
relatively minor and were not statistically significant (p=0.32).
The mean age of the Group I patients was slightly higher than that
of Group II patients; however, this was not found to be
statistically significant (p>0.05). Mean age, therefore, does
not appear to have been a confounding factor in this study.
With the exception of minor infections around the immediate
catheter site, there were no reports of serious complications
resulting from treatment in Group I patients. However, there were
three reported cases of serious postoperative infection/sepsis in
Group II patients. As previously mentioned, one of these patients
died of post-surgical complications after a procedure involving
surgical resection and bypass. The other two patients recovered
fully from their infections with intensive IV antibiotic therapy.
Although they were not analyzed, out of the three patients
receiving only external beam therapy, one died of complications
from a liver abscess and sepsis one year following treatment.
All patients in Groups I and II received palliation of their
obstructive symptoms (jaundice and pain) after treatment. Table 4
summarizes complication rates and palliative benefits by treatment
Primary bile duct adenocarcinomas are aggressive tumors with
very poor long-term prognoses. It is widely believed that the only
means of cure is radical surgery. Resectability in these cases
should meet three major criteria for optimal success: 1) there
should be an absence of extensive vascular invasion, in which tumor
invades the main portal vein and/or both the right and left hepatic
veins and arteries; 2) there should be a complete absence of
metastatic disease, growth into surrounding structures, and
peritoneal metastases; and 3) there should be a complete absence of
tumor within the second-order biliary radicles. The patient also
must be medically stable to tolerate radical surgery.
Only 30 to 40% of all extrahepatic biliary tumors meet all three
aforementioned criteria and are considered resectable. Recurrences
after resection have been found in up to 81% of cases,
and the survival prognosis is still grim after treatment, with some
reports suggesting 5-year survival averages close to 5%.
Radical surgery for bile duct tumors commonly entails one of two
procedures: 1) resection of tumor and Roux-en-Y hepaticojejunostomy
as a bypass, which is more often used for proximal bile duct
lesions (e.g. Klatskin tumors); 2) pancreaticoduodenectomy (Whipple
procedure), which is preferred for malignant lesions involving the
middle and lower thirds of the common bile duct.
Most patients with hilar bile duct carcinoma are technically
unresectable, but a significant number of these patients undergo
radical resection regardless and ultimately do very poorly.
Both surgical procedures can produce substantial morbidity. The
average operative mortality rate is reported to range from 5% to as
high as 20%.
The most serious complication resulting from the Whipple procedure
is disruption of the pancreaticojejunostomy, which occurs in 10% of
This may result in an upper abdominal abscess and/or external
pancreatic fistula. In the worst case, necrotizing retroperitoneal
infection may result in the erosion of the major vessels of the
upper abdomen, including the exposed portal vein or the remnant of
the gastroduodenal artery, ultimately leading to death.
Additionally, following surgical resection, recurrences are common
and often involve peritoneal implants, malignant ascites, and
malignant pleural effusions due to hematogenous spread. In the many
series in the literature, 2-year survival following surgical
resection approaches 25%, and 5-year survival is reported to be
close to 5%.
As the mean age of onset is 60 years of age, surgical complications
in many cases contribute to the high mortality rates in this
Nonsurgical palliative stenting and brachytherapy traditionally
has been reserved for those patients with unresectable disease.
Stents can be placed through the obstructing tumor either during
endoscopic retrograde cholangiopancreatography (ERCP), or they can
be implanted by the percutaneous transhepatic approach.
The latter approach was used initially to relieve obstructive
symptoms in all Group I and II patients in our study.
The types of ensuing complications from stent placement are
classified according to when they occur. Early complications
generally occur within a week or two after placement.
Sepsis and bleeding represent the majority of early complications
and ultimately cause death in 1.5% of all external stent
placements; that rate is somewhat lower with endoscopic catheters.
Late complications generally are much less severe and primarily
involve local infection around the catheter site. These can be
treated with simple catheter exchanges in the majority of
Recently it has been reported that combined external beam
radiotherapy and intramural Ir-192 brachytherapy significantly
increased 2-year survival in patients who received this combined
modality of treatment, compared to those patients who did not
receive radiation in the course of their treatment. Alden et al
hypothesize that the effectiveness of brachytherapy resides in its
ability to maintain ductal stent patency, delaying the onset of
severe complications from biliary obstruction.
Equivalent survival rates have been reported
in a study comparing brachytherapy
with more radical surgical procedures.
Veeze-Kuijpers et al have reported that the most accurate
prognostic factors in bile duct cancers are the status of lymph
nodes and of hepatic involvement.
These researchers demonstrated higher survival rates in those
patients treated with a combination of surgical resection and
postoperative radiotherapy compared to those patients who received
radiotherapy alone. Fletcher et al, in the early 1980s, found
equivalent survival rates in those patients treated with Ir-192
brachytherapy compared to other treatment modalities.
Our data suggests that a significant difference in median
survival does not exist between those patients treated
surgically and those treated with brachytherapy (p=0.32). With
either treatment modality the prognosis appears grim, with few
long-term survivors. In our series, the 3-year survival rate for
the brachytherapy patients was 12%, compared to 22% for patients
treated with surgical resection. There was no significant survival
difference between the two groups despite the presence of more
advanced tumors in the radiotherapy group.
It is unclear whether surgery is the only modality that offers
curative potential. The patient in our study who has lived out to
86 months in the surgical arm and is presently alive and free of
disease may represent a curative success. Brachytherapy appears to
prolong survival; however, it remains unclear whether it offers
hope of definitive cure (one patient in Group I of our study did
live out to 81 months, though the patient ultimately died of
An important consideration is effectiveness of the treatment
modality in palliating pain and obstructive jaundice symptoms while
minimizing the rate of serious complications. All patients treated
with brachytherapy and surgery received palliation of their
obstructive symptoms. However, the rates of serious complications
differed significantly. With the exception of minor infections
around the immediate catheter site, there were no reports of
serious complications in the group of patients in our study treated
with brachytherapy. In the surgical group, there were three
reported cases of serious postoperative sepsis, and in one of these
cases a patient died of post-surgical complications. Radical
surgical procedures such as the Whipple procedure are known to
carry significant risks, with mortality rates between 5 and 20%.
The procedure itself is long and technically complicated for the
surgeon, and it is often not well tolerated in the age group
commonly presenting with primary extrahepatic bile duct tumors.
Surgery may offer curative potential for a very limited number
of cases of bile duct tumors, as evidenced by one patient in our
series who has lived out
to 86 months disease free. Although brachytherapy with stent
placement appears to result in comparable median survival, it
remains to be seen if lasting cures can result from this treatment
approach. It must be emphasized that the probability of long-term
survival with either surgery or brachytherapy appears to be
minimal, with 2-year survivals of 31% and 20%, respectively, in our
series. We would therefore recommend surgery with curative intent
for those younger patients with resectable tumors who are medically
fit to tolerate surgery.
With high palliation rates and what appears to be a far lower
rate of serious complications than radical surgery, brachytherapy
may be better suited for older patients, especially in view of the
general medical condition of this patient population. Future
prospective randomized studies comparing brachytherapy with radical
surgical resection in the management of primary extrahepatic bile
duct tumors may be needed to better resolve this issue.