Patterns of radiotherapy practice for biliary tract cancer in Japan: results of the Japanese radiation oncology study group (JROSG) survey
- Fumiaki Isohashi1,
- Kazuhiko Ogawa1Email author,
- Hirobumi Oikawa2,
- Hiroshi Onishi3,
- Nobue Uchida4, 5,
- Toshiya Maebayashi6,
- Naoto Kanesaka7,
- Tetsuro Tamamoto8,
- Hirofumi Asakura9,
- Takashi Kosugi10,
- Takashi Uno11,
- Yoshinori Ito12,
- Katsuyuki Karasawa13,
- Makoto Takayama14,
- Yoshihiko Manabe15,
- Hideya Yamazaki16,
- Mitsuhiro Takemoto17,
- Yasuo Yoshioka1,
- Kenji Nemoto18 and
- Yasumasa Nishimura19
© Isohashi et al.; licensee BioMed Central Ltd. 2013
Received: 21 December 2012
Accepted: 23 March 2013
Published: 1 April 2013
The patterns of radiotherapy (RT) practice for biliary tract cancer (BTC) in Japan are not clearly established.
A questionnaire-based national survey of RT used for BTC treatment between 2000 and 2011 was conducted by the Japanese Radiation Oncology Study Group. Detailed information was collected for 555 patients from 31 radiation oncology institutions.
The median age of the patients was 69 years old (range, 33–90) and 81% had a good performance status (0–1). Regarding RT treatment, 78% of the patients were treated with external beam RT (EBRT) alone, 17% received intraluminal brachytherapy, and 5% were treated with intraoperative RT. There was no significant difference in the choice of treatment modality among the BTC subsites. Many patients with EBRT were treated with a total dose of 50 or 50.4 Gy (~40%) and only 13% received a total dose ≥60 Gy, even though most institutions (90%) were using CT-based treatment planning. The treatment field consisted of the primary tumor (bed) only in 75% of the patients. Chemotherapy was used for 260 patients (47%) and was most often administered during RT (64%, 167/260), followed by after RT (63%, 163/260). Gemcitabine was the most frequently used drug for chemotherapy.
This study established the general patterns of RT practice for BTC in Japan. Further surveys and comparisons with results from other countries are needed for development and optimization of RT for patients with BTC in Japan.
KeywordsBiliary tract cancer Radiotherapy Chemotherapy Adjuvant Palliative
Biliary tract cancer (BTC) is a rare disease that is curable by surgery in fewer than 10% of all cases. Prognosis depends in part on the anatomic location of the tumor, which affects its resectability. Total resection is possible for 25% to 30% of lesions originating in the distal bile duct, a rate that is clearly better than that for lesions in more proximal sites. However, the rate of relapse is as high as 60-75%, even if clear resection (R0 resection) is possible . In many patients with a tumor that cannot be completely removed by surgery, other treatments such as radiotherapy (RT) or stenting procedures may maintain adequate biliary drainage and improve survival. Optimal management is therefore essential for both postoperative and unresectable BTC.
In Japan, there were an estimated 20,734 new cases of BTC in 2007, with more than a 3-fold increase over the last three decades , while RT has become much more common because new methods and technology for treatment planning are now available. For these reasons, optimal management of RT for BTC has become a major concern in Japan. For the study presented here, the Japanese Radiation Oncology Study Group (JROSG) conducted a nationwide questionnaire-based survey on BTC. The questionnaire elicited detailed information regarding patient characteristics, treatment characteristics, and outcomes of treatment. The primary goal of this study was to determine the patterns of RT practice for BTC in order to provide assistance with development of future randomized clinical trials. Therefore, factors influencing the treatment outcome are analyzed elsewhere (Yoshioka et al.: Factors influencing survival outcome in radiotherapy for biliary tract cancer, submitted). To the best of our knowledge, this is the first report to establish how RT is used nationally to treat BTC in Japan.
The JROSG conducted a nationwide survey of RT used for BTC treatment between 2000 and 2011 using a questionnaire requesting detailed information on patients and treatment characteristics. Patients were included if they met the following criteria: diagnosis of BTC without evidence of distant metastasis; treatment with RT between 2000 and 2011; no diagnosis of any other malignancy; and no previous RT. Diagnosis of BTC without pathologic verification was based on radiographic findings from contrast-enhanced computed tomography (CT), ultrasonography, endoscopic ultrasonography, and endoscopic retrograde/magnetic resonance cholangiopancreatography.
Of the 71 radiation oncology centers in Japan belonging to the JROSG, 31 (40%) agreed to participate in the survey. The other centers did not participate mostly because too few BTC patients had been treated with RT at the center in the study period. Each participating center provided a database of patients with BTC treated with RT between 2000 and 2011. The study was performed according to guidelines approved by the institutional review board of each institution whenever necessary.
The Mann–Whitney U test and Student’s t-test were used to investigate relationships between variables. A p value of < .05 or a 95% confidence interval not including 1 was considered to be statistically significant. All statistical tests were 2-sided.
Patient and disease characteristics
Patient and disease characteristics (n = 555)
Age (median, 69 y)
< 70 y
≥ 70 y
Pathologic type, verified
Ultrasonography (before RT)
CT (before RT)
MRCP (before RT)
Intrahepatic bile duct
Extrahepatic bile duct
Ampulla of Vater
Maximal tumor size (Median, 4.0 cm)
< 4.0 cm
≥ 4.0 cm
ECOG performance status
No or unknown
Clinical T stage
Clinical N stage
Resectable at diagnosis
Characteristics of surgical procedures
Primary surgery before RT was performed in 242 patients (44%). Curative surgery was performed in 235 patients, but only 63 (26% of those who underwent surgery) had complete (R0) resection. R1 resection (microscopic positive margins) and R2 resection (macroscopic residual tumor) were performed in 142 (59%) and 37 (15%) patients, respectively. Note that surgeries included non-curative (R2) and curative-intent (R0 or R1) resections, because our cohort was based on a RT database. Lymph node dissection was performed on 173 patients (71%) and a positive node was identified pathologically in 85 patients (35%).
Radiation treatment characteristics
The most common treatment modality was external beam radiotherapy (EBRT) alone (78% of the patients), followed by intraluminal brachytherapy (ILBT) with or without EBRT (17%) and intraoperative RT (IORT) with or without EBRT (5%). Chemotherapy before, during, or after RT was used for 260 patients (47%).
Choices of treatment modality according to purpose of RT (n = 529)
Purpose of RT
Treatment modality (%)
median EQD2(range) Gyα/β10
ILBT + EBRT
Curative intent (R0-1)
Non-curative intent (R2)
median EQD2 (range) Gyα/β10
EBRT characteristics (n = 521)
EBRT Radiation portals
≥ 3 portals
EBRT beam energy (MV)
EBRT dose/fraction (Gy)
EBRT total radiation dose (Gy)
40 - < 50
> 50.4 - < 60
primary plus regional LN
CT-based treatment planning
EBRT field according to performance of surgery and N stage (n = 521)
Radiation field (%)
Primary plus LN
ILBT and IORT characteristics
Intraluminal brachytherapy (n = 96)
ILBT single dose/fraction (Gy)
Total dose (Gy)
15 - 25
Prescription point (from the source)
With EBRT (Median EQD2, 60.4 Gy)
Without EBRT (Median EQD2, 35.8 Gy)
IORT was used for only 26 patients (5%) at four institutions (13%, 4/31), 12 (2%) of whom received IORT with EBRT and 14 (3%) received IORT alone. The median dose for IORT was 25 Gy (range, 20–30 Gy), with a median beam energy of 12 mega-electron volts (range, 4–25 mega-electron volts).
Drugs used and timing of chemotherapy (n = 260)
Actual patients (%)
Chemotherapy timing (%)
Actual patients (n)
RT for BTC can be classified into adjuvant therapy after surgery or therapy for inoperable cases. While no randomized control trial has been conducted, a meta-analysis revealed that patients with extrahepatic cholangiocarcinoma treated with adjuvant RT show a significantly lower mortality rate than patients treated with surgery alone . Data in the Surveillance Epidemiology and End Result database also suggest that palliative RT prolongs survival in patients with extrahepatic cholangiocarcinoma . In these reports, the outcomes of the treatment were reported in detail, but detailed information on RT use has not been provided and there are few reports on patterns of RT practice. We therefore decided to evaluate the practice of RT for BTC at Japanese radiation oncology centers, with the goal of assisting with development of randomized clinical trials. JROSG has conducted similar surveys and successfully determined the general patterns of RT practice for several other cancers in Japan [5, 6]. Of the 31 responding institutions, 43% treated fewer than 10 patients over the period covered by the survey. Surprisingly, none of the patients were treated with an investigational protocol, clearly indicating a need for a prospective multicenter study to determine a standard therapeutic approach.
The results of the study showed that CT-based treatment planning was used for approximately 90% of the patients. Previous nationwide surveys of the structural characteristics of radiation oncology in Japan found that only 329 (45%) of 726 facilities in 2003 and 407 (57%) of 712 facilities in 2005 used CT-based treatment planning [7, 8]. These results suggest that three-dimensional conformal RT planning became mainstream during the survey period or that patients with BTC received RT more frequently in facilities with advanced equipment.
We examined the variations in RT use (modality, total dose, or RT fields) according to the purpose of RT or BTC subsites. Some analyses have suggested that there is a dose–response relationship for treatment of BTC and have stressed the importance of dose escalation [9, 10]. However, many patients with EBRT included in this survey were treated with a total dose of 50 or 50.4 Gy (~40%) and only 13% of the patients received a total dose ≥60 Gy. These data indicate that use of sufficient doses for EBRT for tumors in the hepatic hilum and liver regions was severely restricted by technical difficulties with the delivery of high doses to these regions while sparing surrounding organs, including the liver, duodenum, stomach, and spinal cord, even though most institutions used CT-based treatment planning. Recently, IMRT has emerged as a sophisticated technique for treatment of tumors, including BTC, in areas at risk of recurrence, while sparing adjacent normal tissue from high-dose irradiation . However, only two patients were treated with IMRT for EBRT during the survey period.
ILBT can also be used for dose escalation in a region at risk [9, 12] since it has the advantage of allowing delivery of a sufficient dosage to a target focus while reducing the effect of irradiation on surrounding tissues. Theoretically, a combination of ILBT and EBRT can enhance the beneficial effects of RT, with fewer adverse effects than those incurred with EBRT alone. In fact, ILBT with EBRT entailed a significantly higher EQD2 dose than EBRT alone in our study cohort. While 42% of the institutions performed ILBT, only 14% of all patients received ILBT combined with EBRT, indicating that this treatment modality was used only in selected cases because the effect of ILBT is limited to the area surrounding the lumen of the biliary tract and improvement in local control can therefore be expected only for small tumors .
The optimal radiation field for BTC remains to be defined. The majority of relapses after resection with curative intent occur at the primary tumor site , which suggests that it may be reasonable to limit RT to the primary tumor (bed). Only 23% of the patients included in this survey received radiation to the tumor (bed) as well as the regional lymph nodes, regardless of the lymph node status. Although limiting the radiation field to the tumor (bed) has tended to become prevalent in Japan, the definition of clinical target volume included regional lymph nodes as well as the tumor (bed) in a recent meta-analysis of 14 selected papers with detailed information on adjuvant RT after surgery , as well as in many reports on unresectable BTC published since 2000 [14–17]. Collectively, these findings indicate that the radiation field for BTC is not yet standardized due to the lack of a large randomized control trial and that additional studies investigating the optimal radiation field should be conducted.
The study presented here showed that chemotherapy is frequently administered in combination with RT (47% of all patients). Chemotherapy was most often administered during RT, followed by after RT. Several trials have examined the efficacy of adjuvant chemoradiation after surgery  or of chemoradiation for unresectable cases . The National Comprehensive Cancer Network (NCCN) reported that most CCRT for BTC involved the use of 5-FU, and that CCRT with gemcitabine is not recommended due to the limited experience with and potential toxicity of this treatment. However, the use of CCRT combined with gemcitabine-containing regimens increased in Japan during the period covered by the current survey, which suggests that additional studies should be undertaken to establish the optimal sequencing of RT and chemotherapy with drugs such as gemcitabine. For chemotherapy for advanced BTC, the recent randomized control phase III ABC-02 study showed that a combination of gemcitabine and cisplatin improved overall and progression-free survival by 30% over gemcitabine alone . Based on these results, the combination of gemcitabine and cisplatin can now be considered to be the standard of care as first-line chemotherapy for patients with advanced or metastatic BTC. In Japan, however, oral anticancer drugs such as TS-1 or UFT also tend to be used as adjuvant chemotherapy after RT, and only two patients in the current study were treated with a combination of gemcitabine and cisplatin after RT.
Patients with BTC should continue to be enrolled in prospective studies of RT with radiosensitizing agents or of RT with dose escalation methods using techniques such as IMRT. Further surveys and comparisons with results from other countries are needed for development and optimization of RT for patients with BTC in Japan.
Written informed consent was obtained from the patient for publication of this report and any accompanying images.
Biliary tract cancer
External beam radiotherapy
The Japanese radiation oncology study group
The biologically equivalent dose in 2-Gy fractions
National comprehensive cancer network.
- Park SW, Park YS, Chung JB, Kang JK, Kim KS, Choi JS, Lee WJ, Kim BR, Song SY: Patterns and relevant factors of tumor recurrence for extrahepatic bile duct carcinoma after radical resection. Hepatogastroentelogy 2004, 51: 1612-1618.
- Matsuda T, Marugame T, Kamo K, Katanoda K, Ajiki W, Sobue T, Japan Cancer Surveillance Research Group: Cancer incidence and incidence rates in Japan in 2006: based on data from 15 population-based cancer registries in the monitoring of cancer incidence in Japan (MCIJ) project. Jpn J Clin Oncol 2012, 42: 139-147. 10.1093/jjco/hyr184View ArticlePubMed
- Bonet Beltràn M, Allal AS, Gich I, Solé JM, Carrió I: Is adjuvant radiotherapy needed after curative resection of extrahepatic biliary tract cancers? A systematic review with a meta-analysis of observational studies. Cancer Treat Rev 2012, 38: 111-119. 10.1016/j.ctrv.2011.05.003View ArticlePubMed
- Shinohara ET, Mitra N, Guo M, Metz JM: Radiotherapy is associated with improved survival in adjuvant and palliative treatment of extrahepatic cholangiocarcinomas. Int J Radiat Oncol Biol Phys 2009, 74: 1191-1198. 10.1016/j.ijrobp.2008.09.017View ArticlePubMed
- Nishimura Y, Koike R, Ogawa K, Sasamoto R, Murakami Y, Itoh Y, Negoro Y, Itasaka S, Sakayauchi T, Tamamoto T: Clinical practice and outcome of radiotherapy for esophageal cancer between 1999 and 2003: the Japanese radiation oncology study group (JROSG) survey. Int J Clin Oncol 2012, 17: 48-54. 10.1007/s10147-011-0254-yView ArticlePubMed
- Ogawa K, Ito Y, Karasawa K, Ogawa Y, Onishi H, Kazumoto T, Shibuya K, Shibuya H, Okuno Y, Nishino S, Ogo E, Uchida N, Karasawa K, Nemoto K, Nishimura Y, JROSG Working Subgroup of Gastrointestinal Cancers: Patterns of radiotherapy practice for pancreatic cancer in Japan: results of the Japanese radiation oncology study group (JROSG) survey. Int J Radiat Oncol Biol Phys 2010, 77: 743-750. 10.1016/j.ijrobp.2009.05.063View ArticlePubMed
- Shibuya H, Tsujii H: The structural characteristics of radiation oncology in Japan in 2003. Int J Radiat Oncol Biol Phys 2005, 62: 1472-1476. 10.1016/j.ijrobp.2004.12.082View ArticlePubMed
- Teshima T, Numasaki H, Shibuya H, Nishio M, Ikeda H, Ito H, Sekiguchi K, Kamikonya N, Koizumi M, Tago M, Nagata Y, Masaki H, Nishimura T, Yamada S, Japanese Society of Therapeutic Radiology and Oncology Database Committee: Japanese structure of radiation oncology in 2005 based on institutional stratification of patterns of care study. Int J Radiat Oncol Biol Phys 2008, 72: 144-152. 10.1016/j.ijrobp.2007.12.047View ArticlePubMed
- Alden ME, Mohiuddin M: The impact of radiation dose in combined external beam and intraluminal Ir-192 brachytherapy for bile duct cancer. Int J Radiat Oncol Biol Phys 1994, 28: 945-951. 10.1016/0360-3016(94)90115-5View ArticlePubMed
- Lu JJ, Bains YS, Abdel-Wahab M, Brandon AH, Wolfson AH, Raub WA, Wilkinson CM, Markoe AM: High-dose-rate remote afterloading intracavitary brachytherapy for the treatment of extrahepatic biliary duct carcinoma. Cancer J 2002, 8: 74-78. 10.1097/00130404-200201000-00013View ArticlePubMed
- Milano MT, Chmura SJ, Garofalo MC, Rash C, Roeske JC, Connell PP, Kwon OH, Jani AB, Heimann R: Intensity-modulated radiotherapy in treatment of pancreatic and bile duct malignancies: toxicity and clinical outcome. Int J Radiat Oncol Biol Phys 2004, 59: 445-453. 10.1016/j.ijrobp.2003.11.003View ArticlePubMed
- Takamura A, Saito H, Kamada T, Hiramatsu K, Takeuchi S, Hasegawa M, Miyamoto N: Intraluminal low-dose-rate 192Ir brachytherapy combined with external beam radiotherapy and biliary stenting for unresectable extrahepatic bile duct carcinoma. Int J Radiat Oncol Biol Phys 2003, 57: 1357-1365. 10.1016/S0360-3016(03)00770-3View ArticlePubMed
- Jarnagin WR, Ruo L, Little SA, Klimstra D, D’Angelica M, DeMatteo RP, Wagman R, Blumgart LH, Fong Y: Patterns of initial disease recurrence after resection of gallbladder carcinoma and hilar cholangiocarcinoma: implications for adjuvant therapeutic strategies. Cancer 2003, 98: 1689-1700. 10.1002/cncr.11699View ArticlePubMed
- Crane CH, Macdonald KO, Vauthey JN, Yehuda P, Brown T, Curley S, Wong A, Delclos M, Charnsangavej C, Janjan NA: Limitations of conventional doses of chemoradiation for unresectable biliary cancer. Int J Radiat Oncol Biol Phys 2002, 53: 969-974. 10.1016/S0360-3016(02)02845-6View ArticlePubMed
- Brunner TB, Schwab D, Meyer T, Sauer R: Chemoradiation may prolong survival of patients with non-bulky unresectable extrahepatic biliary carcinoma. A retrospective analysis. Strahlenther Onkol 2004, 180: 751-757. 10.1007/s00066-004-1315-1View ArticlePubMed
- Shin HS, Seong J, Kim WC, Lee HS, Moon SR, Lee IJ, Lee KK, Park KR, Suh CO, Kim GE: Combination of external beam irradiation and high-dose-rate intraluminal brachytherapy for inoperable carcinoma of the extrahepatic bile ducts. Int J Radiat Oncol Biol Phys 2003, 57: 105-112. 10.1016/S0360-3016(03)00410-3View ArticlePubMed
- Chen YX, Zeng ZC, Tang ZY, Fan J, Zhou J, Jiang W, Zeng MS, Tan YS: Determining the role of external beam radiotherapy in unresectable intrahepatic cholangiocarcinoma: a retrospective analysis of 84 patients. BMC Cancer 2010, 10: 492. 10.1186/1471-2407-10-492View ArticlePubMedPubMed Central
- Nelson JW, Ghafoori AP, Willett CG, Tyler DS, Pappas TN, Clary BM, Hurwitz HI, Bendell JC, Morse MA, Clough RW, Czito BG: Concurrent chemoradiotherapy in resected extrahepatic cholangiocarcinoma. Int J Radiat Oncol Biol Phys 2009, 73: 148-153. 10.1016/j.ijrobp.2008.07.008View ArticlePubMedPubMed Central
- Czito BG, Anscher MS, Willett CG: Radiation therapy in the treatment of cholangiocarcinoma. Oncology (Williston Park) 2006, 20: 873-884.
- Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, Madhusudan S, Iveson T, Hughes S, Pereira SP, Roughton M, Bridgewater J, ABC-02 Trial Investigators: Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 2010, 362: 1273-1281. 10.1056/NEJMoa0908721View ArticlePubMed
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.