This study was conducted to evaluate the long-term outcome in patients undergoing pancreaticoduodenectomy (PD) followed by adjuvant chemoradiotherapy for distal cholangiocarcinoma (DCC) in a high-volume center and to identify the prognostic impact of clinicopathologic factors.
A total of 132 consecutive patients who met the inclusion criteria were retrieved from the institutional database from January 1995 to September 2009. All patients received adjuvant treatments at a median of 45 days after the surgery. Median follow-up duration was 57 months (range, 6 to 225 months) for all patients and 105 months for survivors (range, 13 to 225 months).
The 5-year locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS) rates were 70.7%, 55.7%, 49.4%, and 48.1%, respectively. Univariate analysis revealed poorly differentiated (P/D) tumors and lymph node (LN) metastasis were significantly associated with DMFS and OS. Additionally, preoperative carbohydrate antigen 19-9 level was significantly correlated with DFS, LRRFS, and DMFS. Upon multivariate analysis for OS, P/D tumors (p=0.015) and LN metastasis (p=0.003) were significant prognosticators that predicted inferior OS. Grade 3 or higher late gastrointestinal toxicity occurred in only one patient (0.8%).
Adjuvant chemoradiotherapy after PD for DCC is an effective and tolerable strategy without significant side effects. During long-term follow-up, we found that prognosis of DCC was mainly influenced by histologic differentiation and LN metastasis. For patients with these risk factors, further research should focus on improving adjuvant strategies as well as other treatment approaches.
Extrahepatic bile duct (EHBD) cancer is an uncommon disease in Western countries; however, about 5,000 cases are newly diagnosed every year in Korea (crude incidence rate, 10.6 per 100,000 in 2013) [
Tumor location is of clinical importance and may affect survival outcomes. Distal cholangiocarcinoma (DCC) is defined as bile duct tumors between the cystic duct and the ampulla of Vater (except Klatskin tumors and ampulla of Vater cancer), which include mid common bile duct tumors (between the junction with the cystic duct and the junction with the pancreas) and distal (intrapancreatic) bile duct tumors. DCC usually shows improved outcomes compared with perihilar tumors, which may be because of earlier clinical symptoms. Nevertheless, its prognosis remains poor. Moreover, the prognostic factors for these rare tumors have not been widely established because they only comprise about 30% of EHBD cancer occurrences [
In our institution, most patients with resected EHBD cancer received adjuvant CRT (except those who had pT1N0 disease with R0 resection, poor performance status, or refused further treatment). Therefore, we searched for consecutive patients who underwent curative resection (except R2 resection) followed by adjuvant CRT for EHBD cancer from January 1995 to September 2009 in the institutional database of Seoul National University Hospital. Initially, 251 patients were found; however, 89 with Klatskin tumors, 14 with diffuse bile duct tumors, and 16 who only underwent bile duct resection were serially excluded (
Resections included PD or pylorus-preserving PD, each of which were combined with regional lymph node (LN) dissection. TNM stage was re-evaluated during data collection according to the American Joint Committee on Cancer staging, seventh edition.
All patients received adjuvant treatments at a median of 45 days after surgery (range, 24 to 89 days). Preoperative chemotherapy or radiotherapy was not performed. In 103 patients, a total of 40 Gy in daily fractions of 2 Gy was delivered to the tumor bed and regional LNs (pericholedochal, retrocaval, and aortocaval). Patients had 2 weeks of planned rest after 20 Gy. Concomitant 5-fluorouracil (5-FU, 500 mg/m2/day intravenous bolus) was administered for the first 3 days of each 2 weeks of radiotherapy. A continuous course of radiotherapy was administered to 29 patients with a median dose of 50.4 Gy (range, 50 to 55.8 Gy) at 1.8-2.0 Gy per fraction. Concomitant fluoropyrimidine-based chemotherapy (intravenous 5-FU, 500 mg/m2/day or oral capecitabine) was administered during the first 3 days of the first and fifth week of radiotherapy. 5-FU–based maintenance chemotherapy was also administered to 100 patients after the completion of radiotherapy. Of the 100 patients, 60 patients received 5-FU (500 mg/m2/day) for 5 days every 4 weeks, 26 received 5-FU with leucovorin for 5 days every 4 weeks, seven received 5-FU (500 mg/m2) once weekly, four received enteric-coated tegafur/uracil, two were administered had TS-1, and one received oral capecitabine. Maintenance chemotherapy was not offered to 32 patients because of poor performance status after CRT (n=12), patient refusal (n=9), disease progression (n=8), or for unknown reasons (n=3).
All patients were regularly followed up for surveillance for recurrence. Patient follow-up was completed by May 2014. Routine exams including appropriate imaging methods (abdomino-pelvic computed tomography [CT], ultrasonography, or magnetic resonance imaging) and serum tumor marker (carbohydrate antigen 19-9 [CA 19-9]) assessment were performed at prespecified intervals (typically every 3 months up to 2 years, followed by every 6 months) or when there were any suspicious findings suggestive of recurrence. Most recurrences were clinically diagnosed by imaging studies such as CT on a region of interest and/or positron emission tomography without pathologic confirmation. Recurrence patterns were classified as locoregional recurrence (LRR), distant metastasis (DM), or both. LRR was defined as recurrence in the tumor bed, anastomosis sites, or regional LN area. DM was defined as recurrence in the nonregional LN area or in other organs. Peritoneal seeding was determined by expert radiologists based on the results of CT analysis of ascites, thickening of the peritoneum (either smooth or nodular), or scalloping of the liver or splenic surface. Treatment toxicities caused by primary surgery or adjuvant CRT were also evaluated retrospectively through medical records. Gastrointestinal radiation toxicity was evaluated using the Radiation Therapy Oncology Group (RTOG) criteria.
Locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS) were measured from the day of surgery to the time of LRR, DM, any failure or death from any causes, respectively, during the follow-up period. Patients who were alive or free of recurrence were censored at the time of the last follow-up. The actual survival rates were determined by the Kaplan-Meier method and compared using the log-rank test. The Cox proportional hazards model was used for multivariate analysis to estimate the hazard ratio and to adjust for potential confounding factors. Factors found to be significant upon univariate analysis or thought to be clinically relevant were subjected to both forward and backward stepwise selection multivariate analysis. A p-value of < 0.05 was considered statistically significant. The differences in characteristics between groups were compared using a chi-square test. Data were analyzed using the SPSS ver. 18.0.1 (SPSS Inc., Chicago, IL).
Overall patient and tumor characteristics are shown in
Median follow-up duration was 57 months (range, 6 to 225 months) for all patients and 105 months for survivors (range, 13 to 225 months). Overall, 66 patients (50.0%) experienced recurrences. LRR occurred in 34 patients (25.8%) and DM occurred in 58 patients (43.9%). Time to recurrence was similar between patients with LRR (median, 13 months) and DM (median, 12 months). Only 13 patients (9.8%) had an initial isolated local recurrence. In patients with DM, the most common site was the liver (30 patients, 51.7%), followed by peritoneal seeding (18 patients, 31.0%), nonregional LNs (three patients, 5.2%), and others.
Of the 57 patients who did not develop recurrence during the first 5 years after surgery, only one developed late recurrence at 121 months after surgery. After a pylorus-preserving PD for mid common bile duct tumor (pT3N1M0-R1), she was disease-free for 121 months before LRR (hepaticojejunostomy site) and DM (liver and nonregional LN) were detected simultaneously. She refused further treatments and died 5 months later.
During the follow-up period, 89 patients (67.4%) died. The 5-year LRRFS, DMFS, DFS, and OS rates were 70.7%, 55.7%, 49.4%, and 48.1%, respectively (
The results of the univariate analyses of LRRFS, DMFS, DFS, and OS are shown in
Multivariate analysis incorporating residual disease, LN metastasis, and histologic differentiation demonstrated that P/D tumors (hazard ratio [HR], 2.015; p=0.015; backward selection) and LN metastasis (HR, 1.933; p=0.003; backward selection) were significant prognosticators that predicted inferior OS (
Treatment toxicities were also comprehensively evaluated using retrospective medical records. Following PD, the most common complication was delayed wound healing (seven patients, 5.3%), although stomy site leakage (four patients), fluid collection (three patients), postoperative cholangitis (two patients), intra-abdominal abscess (two patients), postoperative bleeding (one patient), and postoperative pancreatitis (one patient) were also observed.
During CRT, acute gastrointestinal toxicity occurred in 88 patients (66.7%), with RTOG grade 1 being observed in 37 (28.0%) and grade 2 in 51 (38.6%) patients. The most common acute symptoms were nausea and abdominal pain, which were tolerable and alleviated after supportive treatments. Grade 3 or higher toxicity did not occur during CRT. During follow-up, only one patient (0.8%) experienced grade 3 late gastrointestinal toxicity. This patient underwent small bowel resection because of an adhesive ileus at 43 months after the end of a radiotherapy session, without evidence of LRR.
This retrospective study was conducted to evaluate the long-term outcome of DCC in patients who underwent PD followed by adjuvant CRT. Although our study only analyzed a selected group of patients, the results suggest that adjuvant CRT for DCC following PD is an effective and tolerable treatment strategy without significant side effects.
As expected, long-term survival was still unsatisfactory; nevertheless, our finding of a 5-year OS rate of 48.1% was comparable or slightly better than the results of previously reported studies [
A positive resection margin has been considered as an adverse prognostic factor in some studies [
Our study had a LRR rate of 25.8%, lower than the reported range from 35% to 74% even after complete resection in the previous studies [
To the best of our knowledge, no randomized controlled trials have evaluated the role of adjuvant CRT in EHBD cancer and in DCC. Given the lack of evidence supporting the application of adjuvant CRT, our favorable long-term results could help researchers establish the application of adjuvant CRT. A recent multicenter study in Korea also demonstrated that adjuvant CRT was associated with significantly improved relapse-free survival and OS in patients with R0-resected DCC [
For a median follow-up of 57 months, about three-fifths of our patients had a recurrence but recurrence 5 years after surgery was rarely observed. These results were somewhat different from those of a previous study by Jang et al. [
It should be noted that there are several limitations to this study. Specifically, its retrospective nature might be a significant weakness; however, we thought that it would be difficult to conduct a prospective study because of the rarity of DCC. Moreover, although our institution offered adjuvant CRT to almost all patients who underwent PD, the patients evaluated in this study were selected ones who both underwent surgery and received adjuvant therapy. In addition, treatment-related toxicity might be underestimated because it was not considered prospectively. Finally, heterogeneous details of adjuvant CRT during a relatively long study period (for example, radiotherapy dose or type of maintenance chemotherapy) might also influence clinical outcomes.
In conclusion, we reported the actual long-term outcome of DCC in patients who underwent PD followed by adjuvant CRT. During long-term follow-up, we found that prognosis of DCC after PD was mainly influenced by histologic differentiation and LN metastasis. For patients with these risk factors, further research should focus on improving adjuvant strategies as well as other treatment approaches.
Supplementary materials are available at Cancer Research and Treatment website (
Conflict of interest relevant to this article was not reported.
Byoung Hyuck Kim was supported by an institutional R&D project funded by the Armed Forces Medical Research Institute (2015-AFMRI-02). Kyubo Kim was supported by the Ewha Womans University Research Grant of 2016.
CONSORT diagram of study patients. 5-FU, 5-fluorouracil; FL, 5-fluorouracil+leucovorin; UFT-E, enteric-coated tegafur/uracil.
Locoregional recurrence-free survival (A), distant metastasis-free survival (B), disease-free survival (C), and overall survival (D) in patients treated with pancreaticoduodenectomy followed by adjuvant chemoradiotherapy for distal cholangiocarcinoma.
Overall survival curves according to histologic differentiation (A) and N stage (B). W/D, well-differentiated; M/D, moderately differentiated; P/D, poorly differentiated.
Distant metastasis-free survival curves according to N stage.
Summary of patient characteristics
Characteristic | No. (%) (n=132) |
---|---|
≥ 60 | 82 (62.1) |
< 60 | 50 (37.9) |
Male | 92 (69.7) |
Female | 40 (30.3) |
0-1 | 111 (84.1) |
2 | 21 (15.9) |
Mid common bile duct | 65 (49.2) |
Distal (intrapancreatic) bile duct | 67 (50.8) |
Pancreaticoduodenectomy | 46 (34.8) |
Pylorus-preserving pancreaticoduodenectomy | 86 (65.2) |
R0 | 118 (89.4) |
R1 | 14 (10.6) |
W/D, M/D | 109 (82.6) |
P/D | 19 (14.4) |
Unknown | 4 (3.0) |
≥ 2 | 90 (68.2) |
< 2 | 41 (31.1) |
Unknown | 1 (0.7) |
T1-2 | 51 (38.6) |
T3 | 81 (61.4) |
Yes | 43 (32.6) |
No | 89 (67.4) |
T1N0 | 2 (1.5) |
T1N1 | 2 (1.5) |
T2N0 | 34 (25.8) |
T2N1 | 13 (9.8) |
T3N0 | 53 (40.1) |
T3N1 | 28 (21.2) |
Yes | 103 (78.0) |
No | 28 (21.2) |
Unknown | 1 (0.7) |
≥ 37 | 71 (53.8) |
< 37 | 35 (26.5) |
Unknown | 26 (19.7) |
ECOG, eastern cooperative oncology group; W/D, welldifferentiated; M/D, moderately-differentiated; P/D, poorly-differentiated; CA19-9, carbohydrate antigen 19-9.
Univariate analysis for LRRFS, DMFS, DFS, and OS
Variable | No. of patients | 5-Yr LRRFS (%) | p-value | 5-Yr DMFS (%) | p-value | 5-Yr DFS (%) | p-value | 5-Yr OS (%) | p-value |
---|---|---|---|---|---|---|---|---|---|
< 60 | 50 | 67.4 | 0.552 | 49.9 | 0.275 | 44.1 | 0.387 | 44.0 | 0.775 |
≥ 60 | 82 | 72.8 | 59.1 | 52.6 | 50.7 | ||||
0-1 | 111 | 67.0 | 0.190 | 52.6 | 0.219 | 45.4 | 0.107 | 44.6 | 0.108 |
2 | 21 | 80.5 | 71.4 | 71.4 | 66.7 | ||||
Mid | 65 | 72.3 | 0.905 | 52.7 | 0.657 | 45.5 | 0.455 | 43.1 | 0.094 |
Distal | 67 | 69.5 | 58.5 | 53.1 | 53.2 | ||||
R0 | 118 | 72.6 | 0.077 | 57.0 | 0.312 | 51.7 | 0.104 | 51.3 | 0.067 |
R1 | 14 | 50.0 | 41.3 | 26.8 | 21.4 | ||||
T1-2 | 51 | 67.1 | 0.606 | 52.7 | 0.675 | 43.6 | 0.286 | 45.1 | 0.563 |
T3 | 81 | 72.8 | 57.5 | 53.1 | 50.1 | ||||
≥ 2 | 90 | 71.6 | 0.926 | 51.4 | 0.306 | 47.7 | 0.657 | 47.8 | 0.526 |
< 2 | 41 | 68.1 | 64.1 | 52.0 | 47.7 | ||||
No | 89 | 72.1 | 0.344 | 66.2 | < 0.001 | 58.7 | 0.001 | 53.9 | 0.001 |
Yes | 43 | 68.0 | 33.2 | 29.9 | 36.0 | ||||
W/D, M/D | 109 | 72.5 | 0.240 | 59.1 | 0.025 | 51.6 | 0.090 | 51.0 | 0.007 |
P/D | 19 | 57.3 | 31.3 | 31.3 | 31.6 | ||||
Yes | 103 | 68.8 | 0.768 | 52.1 | 0.143 | 45.0 | 0.106 | 42.7 | 0.191 |
No | 28 | 74.1 | 66.8 | 63.6 | 67.0 | ||||
≥ 37 | 71 | 57.5 | 0.006 | 49.7 | 0.032 | 41.8 | 0.014 | 45.1 | 0.097 |
< 37 | 35 | 87.0 | 70.8 | 68.1 | 64.8 | ||||
≥ 56 | 24 | 72.0 | 0.991 | 53.6 | 0.842 | 50.0 | 0.877 | 52.3 | 0.685 |
< 56 | 108 | 70.4 | 56.1 | 49.3 | 47.2 | ||||
Yes | 100 | 72.4 | 0.122 | 56.0 | 0.341 | 49.8 | 0.266 | 48.5 | 0.185 |
No | 29 | 61.5 | 50.4 | 44.1 | 44.8 |
LRRFS, loco-regional relapse-free survival; DMFS, distant metastasis-free survival; DFS, disease-free survival; OS, overall survival; ECOG, Eastern Cooperative Oncology Group; W/D, well-differentiated; M/D, moderately-differentiated; P/D, poorly-differentiated; CA19-9, carbohydrate antigen 19-9.
Results of multivariate analysis of prognostic factors for the overall survival
Variable | Backward selection |
Forward selection |
||||
---|---|---|---|---|---|---|
Hazard ratio | 95% CI | p-value | Hazard ratio | 95% CI | p-value | |
W/D, M/D | 1 | 1 | ||||
P/D | 2.015 | 1.148-3.535 | 0.015 | 1.865 | 1.073-3.241 | 0.027 |
No | 1 | 1 | ||||
Yes | 1.933 | 1.245-3.001 | 0.003 | 1.951 | 1.257-3.031 | 0.003 |
R0 | 1 | - | ||||
R1 | 1.824 | 0.955-3.482 | 0.069 | - | - | - |
CI, confidence interval; W/D, well-differentiated; M/D, moderately-differentiated; P/D, poorly-differentiated.
Results of the multivariate analysis of prognostic factors of distant metastasis-free survival
Variable | Backward selection |
Forward selection |
||||
---|---|---|---|---|---|---|
Hazard ratio | 95% CI | p-value | Hazard ratio | 95% CI | p-value | |
W/D, M/D | 1 | - | ||||
P/D | 1.839 | 0.921-3.671 | 0.084 | - | - | - |
No | 1 | 1 | ||||
Yes | 2.345 | 1.289-4.267 | 0.005 | 2.730 | 1.517-4.914 | 0.001 |
< 37 | 1 | - | ||||
≥ 37 | 1.913 | 0.944-3.875 | 0.072 | - | - | - |
CI, confidence interval; W/D, well-differentiated; M/D, moderately-differentiated; P/D, poorly-differentiated; CA19-9, carbohydrate antigen 19-9.