Clin Transl Oncol (2015) 17:825–829
DOI 10.1007/s12094-015-1312-0
RESEARCH ARTICLE
Locoregional recurrence after curative intent resection
for intrahepatic cholangiocarcinoma: implications for adjuvant
radiotherapy
S. Song1 • K. Kim1 • E. K. Chie1,3 • S. Kim1 • H. J. Park1
N. J. Yi2 • K.-S. Suh2 • S. W. Ha1,3
Received: 5 April 2015 / Accepted: 26 May 2015 / Published online: 4 June 2015
Ó Federación de Sociedades Españolas de Oncologı́a (FESEO) 2015
Abstract
Backgrounds As for intrahepatic cholangiocarcinoma,
the most frequent site of failure after curative intent
resection is the liver. We identified the risk factors for
locoregional recurrence after curative intent resection for
intrahepatic cholangiocarcinoma.
Methods Medical records of 115 patients treated with
surgical resection alone for intrahepatic cholangiocarci-
noma from November 2000 to December 2010 were ret-
rospectively reviewed. Locoregional failure was defined as
recurrence within 20 mm from resection margin or regio-
nal lymph node. Overall survival and locoregional recur-
rence rates were analyzed using Kaplan–Meier methods,
and the prognostic factors were analyzed using Cox pro-
portional hazards model.
Results Median follow-up duration of surviving patients
was 61 months (range 8–139). Sixty-six patients had
recurrence, and 45 of 66 patients (68 %) had locoregional
recurrence. The 5-year overall survival and locoregional
control rates were 49.1 and 51.6 %, respectively. CT2b
disease and R1 resection were associated with locoregional
recurrence in multivariate analysis. Patients were divided
into two groups whether these risk factors exist or not. The
5-year locoregional control rates of low (no risk factor
& K. Kim
kyubokim@snu.ac.kr
1 18–42 % [5–9]. Unfortunately, the role of adjuvant treat-
Department of Radiation Oncology, Seoul National
University College of Medicine, 101 Daehak-ro, Jongno-gu,
Seoul 110-744, Republic of Korea
2
Department of Surgery, Seoul National University College of
Medicine, Seoul, Republic of Korea
3
Institute of Radiation Medicine, Medical Research Center,
Seoul National University, Seoul, Republic of Korea
•
n = 64) and high (1 or 2 risk factors n = 51) risk groups
were 62.5 and 34.7 %, respectively (P = 0.001).
Conclusions After curative intent resection, locoregional
control and survival of patients with intrahepatic cholan-
giocarcinoma were far from satisfactory. Further studies
are needed to evaluate the potential benefit of adjuvant
locoregional treatment such as radiotherapy for patients
with high-risk factors (CT2b disease or R1 resection).
Keywords Intrahepatic cholangiocarcinoma
Surgery

Locoregional recurrence
Radiotherapy
Introduction
Intrahepatic cholangiocarcinoma (ICC) is the second most
common primary liver cancer, which comprised 10–15 %
of all primary liver malignancies [1]. Recently, global
mortality of ICC is increasing, whereas mortality of
extrahepatic bile duct malignancy is decreasing [2].
Asymptomatic hepatic mass is the common presentation
[3], but abdominal lymph node and/or distant metastasis is
found in more than half of patients at diagnosis [4]. Sur-
gical resection is the only option for cure in patients with
ICC, but recurrence and death are common even after
curative intent resection. Reported 5-year survival rate of
patients treated with surgical resection for ICC is only
ment for ICC remains unclear.
The most frequent site of failure after surgery is the
liver in which more than half of patients experienced
recurrence [10]. If the intrahepatic recurrence frequently
occurred near the resection margin, postoperative radio-
therapy could be beneficial. However, only few studies
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examined intrahepatic recurrences as around resection
margin or not [11].
In the present study, we separately evaluated elsewhere
hepatic recurrence, which occurred far from the resection
site, and locoregional failure was defined as recurrence
within 20 mm from the resection margin or regional lymph
node, which could be targets for adjuvant radiotherapy.
Methods
A total of 165 patients with ICC underwent surgery
between November 2000 and December 2010. Five
patients with double primary cancer and 15 patients who
had operation of palliative aim were excluded from the
analysis. Thirteen patients who underwent postoperative
radiotherapy and 17 who received adjuvant chemotherapy
were additionally excluded to assess the pattern of failure
without adjuvant therapy. Clinicopathologic variables and
survival outcomes were examined in the remaining 115
patients. This study was approved by institutional review
board.
Median age at surgery was 62 years (range 40–80).
Eighty-five patients were male and 30 patients were
female. Data collection was done regarding medical
history, physical examination and serum laboratory tests.
Imaging studies were varied; computed tomography was
performed in 110 (96 %) patients, magnetic resonance
imaging in 69 (60 %), positron emission tomography in
46 (40 %).
Extent of resection was less than hemihepatectomy in 33
patients, hemihepatectomy in 63 and more than hemihep-
atectomy or central hepatectomy in 19. Lymph node (LN)
dissection was performed in 48 (42 %) patients. Median
number of dissected LN was 3 (range 1–31). Pathologic
TNM stage was classified using American Joint Committee
on Cancer (AJCC) staging system Seventh Edition [12].
After surgery, patients were followed with 3–4 months
interval for up to 2 years and then 6 months interval
thereafter.
Overall survival (OS) was defined as the time from the
date of surgery to either death or last follow-up. Failure
sites were divided into four groups; local failure, regional
LN recurrence, elsewhere hepatic recurrence which
excluded local failures, and distant metastasis. Local
failure was defined as the recurrence of which the epi-
center was within 20 mm from the resection margin.
Regional LN was defined according to AJCC Seventh
Edition [12]. All of the failures were counted as the
cumulative event. Univariate analyses were performed
with log rank test. Multivariate analyses were done with
the Cox proportional hazard regression model and for-
ward selection method.
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Clin Transl Oncol (2015) 17:825–829
Results
Median follow-up duration of surviving patients was
61 months (range 8–139). Median OS of all patients was
32 months, and the 5-year OS rate was 49.1 %. Failure
patterns are plotted in Fig. 1. During follow-up, 45 patients
had locoregional recurrence: local recurrence in 34 patients,
regional recurrence in 24, and both local and regional
recurrences in 13. The distance from resection margin to the
epicenter of local recurrence ranged from 0 to 17 mm
(median 4.5 mm). The non-regional LN was the most
common site of distant failure (n = 18), followed by peri-
toneal seeding (n = 11), lung (n = 16), bone (n = 5),
adrenal (n = 3) and other sites (n = 4).
Results of univariate analyses for locoregional control
(LRC) and OS are summarized in Table 1. Advanced T
stage, R1 resection and larger tumor size were significant
risk factors for locoregional recurrence in univariate anal-
yses. Advanced N stage, multiple tumors, vascular invasion
and elevation of preoperative CA19-9 were additional risk
factors for poor 5-year OS in univariate analyses.
In multivariate analysis, CT2b stage and R1 resection
were independently associated with inferior LRC. In terms
of OS, R1 resection, vascular invasion, multiple tumors
were adverse prognostic factors. The relative risk and
confidence interval of each risk factor in multivariate
analysis are summarized in Table 2.
After multivariate analysis, patients with no risk factors
were categorized into low risk group (n = 64), and patients
who had CT2b disease or R1 resection were categorized
into high-risk group (n = 51). Five-year LRC rates of low
and high-risk groups were 62.5 and 34.7 %, respectively
(Fig. 2). The difference between the two groups was sta-
tistically significant (P = 0.001).
Fig. 1 Patterns of failure
Clin Transl Oncol (2015) 17:825–829 827

Table 1 Univariate analyses Variables N 5-year LRC (%) P value 5-year OS (%) P value
for locoregional control and
overall survival Sex 0.996 0.189
Male 85 51.3 45.2
Female 30 51.6 59.8
T stage 0.038 0.003
T1 51 60.3 62.6
T2a 17 61.6 56.6
T2b 5 30.0 20.0
T3 33 42.6 31.2
T4 9 29.6 44.4
N stage 0.066 0.001
NX 64 59.6 56.0
N0 34 38.0 54.5
N1 17 53.2 12.9
Gross type 0.581 0.270
Mass forming type 81 51.7 43.8
Others 34 52.3 61.3
Histologic differentiation 0.292 0.264
W/D 14 81.8 85.7
M/D 42 51.5 37.4
P/D 17 56.1 58.8
Unknown 42 43.7 45.0
Residual tumor 0.001 \0.001
R0 106 54.9 53.7
R1 9 0 0
Tumor multiplicity 0.060 \0.001
Solitary tumor 102 53.4 55.1
Multiple tumor 13 43.6 0
Tumor size 0.016 \0.001
\4 cm 46 65.4 72.2
C4 cm 65 38.6 32.9
Unknown 4 75.0 50.0
Vascular invasion 0.156 \0.001
No 75 56.9 60.5
Yes 31 38.9 32.6
Unknown 9 37.0 11.1
Preoperative CA19-9 0.180 0.041
B37 U/mL 51 53.4 58.3
[37 U/mL 51 48.0 36.7
Unknown 13 68.8 59.3
LRC locoregional control rate, OS overall survival, W/D well differentiated, M/D moderately differentiated,
P/D poorly differentiated, R0 no residual tumor, R1 microscopic residual tumor

Discussion reported 5-year OS rate of 21 % in prospectively collected

ICC is a rare malignancy with poor prognosis. Standard of
care is surgical resection, although the treatment outcome
is suboptimal. In our surgical series, 5-year OS rate of
49.1 % was comparable with other studies. Farges et al.
reported multicenter data of 212 ICC patients treated with
resection, and the 5-year OS rate was 28 % [9]. Lang et al.
data of 83 patients who underwent resection [13]. Mean-
while, Ercolani and colleagues reported the outcomes of 72
consecutive patients treated with surgery, and the 5-year
OS rate was 48 % [14].
To improve outcome of ICC, treatment intensification
such as adjuvant radiotherapy could be considered.
Locoregional failure sites including resection margin and

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Table 2 Multivariate analyses for locoregional control and overall survival
Variables Locoregional control
Relative risk (95 % CI)
T stage (T1–T2a vs. T2b–T4) 2.458 (1.242–4.865)
Residual tumor (R0 vs. R1) 3.340 (1.124–9.926)
Vascular invasion (no vs. yes)
Tumor multiplicity (solitary vs. multiple)
CI confidence interval
Fig. 2 Locoregional control according to risk group
regional LN could be targets of adjuvant radiotherapy. In
the present study, failure patterns after resection were
assessed for feasibility of adjuvant radiotherapy. Like other
reports [10, 15], the liver was the most frequent site of
failure. We divided hepatic failure into local recurrence
and elsewhere hepatic recurrence. Thirty-four (30 %)
patients experienced relapse near resection margin. These
findings suggest that if we control the failure around
resection site, the incidence of hepatic recurrence could be
significantly reduced. Twenty-four (21 %) patients who
had recurrence at regional LN might also benefit from
adjuvant radiotherapy.
In addition, two subgroups of patients were identified
according to risk of locoregional relapse. More than half of
patients in high-risk group experienced locoregional fail-
ure. These patients would be best candidates of adjuvant
radiotherapy. As these findings are based on the retro-
spectively collected single institutional data, further vali-
dation in multicenter, prospective cohort is needed.
Several studies reported risk factors for recurrence after
surgical resection in ICC. Hyder et al. reported the surgical
outcomes of 12 major hepatobiliary centers in United
States and Europe [16]. Vascular invasion, tumor size, and
LN status were independently associated with recurrence.
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Clin Transl Oncol (2015) 17:825–829
Overall survival
P value Relative risk (95 % CI) P value
0.010
0.030 5.113 (1.913–13.664) 0.001
2.080 (1.133–3.820) 0.018
4.224 (2.039–8.750) \0.001
Saiura et al. reported a single institutional data of consec-
utive resected cases [17]. Multiple tumors and poor dif-
ferentiated histology were adverse risk factors for
recurrence. Saxena et al. reported that elevated CA 19-9
and R1 resection were correlated with recurrence [18].
Shirabe et al. also reported that lymphatic invasion index
and histologic grade were independent risk factors for
recurrence [19]. Prognostic factors found in our study were
also reported in other studies. While other studies evaluated
recurrences regardless of the location, however, our study
is the first to assess risk factors for ‘‘locoregional’’ recur-
rence to the best of our knowledge.
Despite frequent locoregional recurrence of ICC, the
role of adjuvant radiotherapy has not yet been proven.
However, several studies suggested a potential benefit of
radiation therapy. Shinohara et al. analyzed 3839 ICC
patients from the Surveillance, Epidemiology, and End
Results (SEER) database [20]. Although only one-fourth of
patients had localized disease, patients treated with surgery
and adjuvant radiation therapy survived longer than those
treated with surgery alone (11.0 vs. 6.0 months). Ben-Josef
and colleagues reported the result of phase II trial of con-
formal radiation therapy with intraarterial chemotherapy
for unresectable intrahepatic tumors [21]. Forty-six patients
with ICC were included and their median survival was
13.3 months, which was a favorable outcome compared to
that of historical control. Although these studies included
advanced or unresectable cases, these data might suggest
that radiation therapy could be beneficial for selected
patients with ICC.
In terms of therapeutic tolerance, adjuvant radiotherapy
to resection margin and regional lymphatics could affect
the liver function after partial hepatectomy. In extrahepatic
biliary tract cancers, Choi et al. reported the influence of
adjuvant radiotherapy on the liver regeneration and func-
tion after partial hepatectomy [22]. While one-third of liver
was irradiated with more than 30 Gy, no significant
adverse effect on liver function was observed after 1 year.
Although the radiation field for ICC would cover more
liver than for extrahepatic biliary tract cancer, adjuvant
radiotherapy could be delivered safely if secure dose-vol-
umetric constraints were reached.
Clin Transl Oncol (2015) 17:825–829
There are a number of limitations in our study: the
retrospective data from small number of patients, the
arbitrary definition of local recurrence and so on. More-
over, the proportion of locoregional recurrence was smaller
than distant metastasis, and one might argue that this
proportion implicates the smaller benefit of adjuvant
radiotherapy. However, this is mainly because the inci-
dence was counted as the cumulative event. As the first site
of failure, the incidence of locoregional recurrence only
was 33 %, which was the dominant pattern of failure (data
not shown). Since a significant proportion of patients with
locoregional recurrence eventually experience distant
metastasis, the overall outcome might be improved if
adjuvant radiotherapy can decrease the locoregional
recurrence. However, the correlation between locoregional
recurrence and distant metastasis is still unknown; this
hypothesis is beyond the scope of our study, and not sup-
ported by our data. Therefore, the authors reported the
locoregional recurrence as the cumulative event, and
intended to avoid overestimating the potential benefit of
adjuvant radiotherapy.
In conclusion, our study showed that locoregional
recurrence after curative intent resection for ICC was not
uncommon. Incidence of locoregional recurrence was even
higher for patients with high-risk factors (CT2b disease or
R1 resection). Further studies are needed to evaluate the
potential benefit of adjuvant radiotherapy for these patients.
Conflict of interest The authors declare that they have no conflicts
of interest.
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