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Trends in the incidence and management of biliary tract cancer: A French population-based study
Research Article
Trends in the incidence and management of biliary tract cancer: A French population-based study Côme Lepage1,2,⇑, Vanessa Cottet1, Marion Chauvenet1,2, Jean-Marc Phelip3, Laurent Bedenne1,2, Jean Faivre1,2, Anne-Marie Bouvier1 1 Registre Bourguignon des Cancers Digestifs; INSERM U866; Université de Bourgogne, Dijon, France; 2Department of Hepato-Gastroenterology, University Hospital Le Bocage, Dijon, France; 3Université Jean Monnet, Saint-Etienne, France
Background & Aims: The trends in incidence and management of biliary tract cancer (BTC) were investigated in a well-defined French population over a 30-year period (1976–2005). Methods: Data were obtained from the Burgundy digestive cancer registry. Age-standardised incidence rates and trends in incidence were determined. Treatment and stage at diagnosis were also investigated. Five-year survival rates were calculated. Results: Six hundred and fifteen cases of BTC were recorded. There was no significant change in BTC incidence over the 30year period. For extrahepatic BTC age-standardised incidence rates were 1.1/100,000 for 1976–80 and 2001–2005. These rates were respectively 0.3 and 0.2/100,000 for intrahepatic BTC. The proportion of patients undergoing resection for cure increased over time from 4.8% to 14.2% (p <0.001). The proportion of stage III cases ranged from 3.2% to 7.1% but did not vary significantly over time (p = 0.55). Most cases were metastatic or unresectable at diagnosis. Five-year relative survival rates were 4.5% for 1976– 85 and 6.7% for 1996–2005, ranging from 35.1% for stages III to 4.3% for advanced BTC. Age and stage at diagnosis were independent prognostic factors. Conclusions: The incidence of BTC has remained stable in Burgundy over the past 30 years. BTC prognosis remains poor and has only improved slightly over time. Ó 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Introduction The epidemiological characteristics of biliary tract cancer (BTC) have received little attention, mainly because these cancers are rare and because histological proof of cancer can be difficult to obtain [1,2]. These cancers originate in the ductal epithelium of the biliary tree, either within the liver (intrahepatic BTC) or more commonly outside the liver including the hilum and main bile duct (extrahepatic BTC). The disease is usually fatal because of
Keywords: Biliary tract cancer; Incidence; Survival rate; Treatment. Received 1 March 2010; received in revised form 4 June 2010; accepted 20 June 2010; available online 7 September 2010 ⇑ Corresponding author. Address: Registre Bourguignon des Cancers Digestifs, INSERM U866, Faculté de Médecine, BP 87900, 21079 Dijon Cedex, France. Tel.: +33 3 80 39 33 40; fax: +33 3 80 66 82 51. E-mail address: [email protected] (C. Lepage).
its late clinical presentation and the lack of effective non-surgical therapeutic modalities [3]. However, interest in this disease is rising because a marked increase in incidence of intrahepatic tumours has been reported in the USA and England [4–7]. There is also a paucity of reports on the management and prognosis of these tumours. Furthermore, most of the available data is provided by specialised centres and thus cannot be used as a reference because of unavoidable selection bias. Population-based studies, recording all cases in a well-defined population, represents the best way to assess the epidemiological characteristics and real management of these cancers. Such studies are rare, however, because they require accurate and detailed data which are seldom collected systematically by cancer registries. The objective of this study was to establish a picture of the trends in incidence, treatment, stage at diagnosis, and prognosis of BTC in a well-defined French population over a 30-year period.
Patients and methods All digestive tract cancers in the resident population of two administrative areas in Burgundy, (France), are recorded in a population-based cancer registry. These areas have a population of 1050,000 according to the 1999 census. Cancer registration began in 1976 in one area and in 1982 in the other. Information is actively collected by the cancer registry staff from multiple sources: pathology laboratories, university hospitals, local hospitals, private specialists (gastroenterologists, surgeons, and oncologists), general practitioners, and monthly reviews of death certificates. Patients, resident in Burgundy and treated outside the area, are identified through the National Health Service. The quality and completeness of the registry is certified every 4 years by an audit conducted by the National Institute for Health and Medical Research (INSERM) and National Public Health Institute (InVS). Due to the involvement of the entire medical profession, and to the multiplicity of data sources, it was assumed that nearly all newly diagnosed cases were recorded. No cases were registered through death certificate alone, given the questionable quality of this source of information. However, they were used to identify missing cases. Patients with BTC were coded according to the International Classification of Diseases for Oncology [8]. The following topography codes were used: C 22.1 (intrahepatic bile duct), C 24.0 (hilum), C 24.1 (main bile duct), C 24.9 (extrahepatic tract not otherwise stated). Cancer of the ampulla of Vater and cancer of the gallbladder were not included in this study. Histological codes included cholangiocarcinoma (8160, 8161) for intrahepatic BTC, and adenocarcinoma (8140, 8260, 8480) and undifferentiated carcinoma (8020, 8021) for extrahepatic BTC. All intrahepatic BTCs were verified histologically. Diagnosis of extrahepatic BTC was based on histological confirmation in 54.3% of cases and on surgical findings or morphological criteria in 45.7%. Adenocarcinoma was the most common histological type (95.5%) among the histologically-verified cases, followed by undifferentiated carcinomas (3.9%).
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JOURNAL OF HEPATOLOGY Patients were categorised into three age groups: 21.6% were aged <65-yearsold, 28.6% were aged 65–74, and 49.8% were aged P75. Cancer extension at the time of diagnosis was classified according to the TNM classification [9]. Three stages were defined: (i) stage III resected cancers without lymph node or visceral metastasis (T1–2 N0 M0); (ii) stage III resected cancers with lymph node metastasis (Any T, N1–2 M0); and (iii) advanced stage cancers with visceral metastasis (M1) and/or for which complete surgical resection was impossible. Surgical treatments included: (i) resection for cure (macroscopic resection of all malignant tissue and no microscopic evidence of surgical marginal spread (n = 71); (ii) palliative resection alone (n = 24); (iii) palliative chemotherapy and/or radiotherapy as the main treatment (n = 86); and (iv) best supportive care alone (including surgical or endoscopic bypass) (n = 434). Survival of patients was ascertained from death certificates recorded by the registrar of the place of residence or from practitioners. Life status was known for 99.5% of the patients in January 2008.
Table 1. Age-standardised incidence rates* of biliary tract tumours by gender, site, and period of diagnosis.
p
Period of diagnosis 1976 1981 1986 1991 1996 80 85 90 95 2000
2001 05
Men
2.4
1.1
0.9
1.5
1.6
1.7
0.910
Women
0.6
0.6
0.5
0.4
0.8
0.9
0.948
Intrahepatic
0.3
0.3
0.4
0.2
0.2
0.2
0.754
Extrahepatic 1.1
0.6
0.5
0.8
0.9
1.1
0.856
1.4
0.9
0.9
1.0
1.1
1.3
0.372
All cases *
World standard population per 100,000 persons-years.
Statistical analysis The data used for calculating incidence rates were based on population estimates by interpolation of the results of four censuses (1975, 1982, 1990, 1999) and then by extrapolation. Incidence rates were calculated by gender, age, site and period of diagnosis. For the purpose of comparison with other countries, rates were standardised by the direct method using the world standard population. Time trends in incidence were analysed using six 5-year periods from 1976 to 2005. Time trends in incidence were assessed by Poisson regression. The association between categorical data was analysed using the Chi2 test. To study the trends in BTC management and prognosis, three time periods were defined: 1976–1985, 1986–1995 and 1996–2005. Relative survival rates were calculated, defined as the ratio of the observed survival rate in the cancer patients under study, to the expected survival rate in a population with similar gender and age distribution, subject only to the mortality rates of the general population. They reflect the excess mortality in the cancer patient group relative to background mortality. Relative survival rates were computed using Stata 10.0 software [10]. A multivariate survival analysis was performed using a relative survival model with proportional hazards, applied to the net survival by intervals [11]. The significance of the covariates was tested using the likelihood ratio test.
Results Incidence by gender, age, and period of diagnosis There were 615 cases of BTC diagnosed between 1976 and 2005, representing 1.8% of digestive tract cancers in men and 2.1% in women. The mean age at diagnosis was 71.7 years in men (SD: 1.2 years) and 75.9 years in women (SD: 1.3 years) (p <0.0001). The overall age-standardised incidence rates were respectively 1.4 and 0.7/100,000. The sex ratio calculated from the age-standardised rates was 2.0. The incidence rate of BTC was low, and was similar in both genders before 55 years of age. Thereafter, incidence rates increased more rapidly in men than in women. Table 1 shows the trends in age-standardised incidence rates of BTC over time by gender, site, and period of diagnosis, standardised to the world population. There was no significant change in incidence of BTC according to site over time. The incidence rates of BTC decreased slightly in men between the first and third study period and then increased slightly. In women, the incidence rates were relatively stable. The incidence of intrahepatic BTC was stable in both sexes. The incidence of extrahepatic BTC decreased slightly from 1976 to 1990 and then increased slightly from 1991 to 2005. Treatment and stage at diagnosis Resection for cure was performed in 12.5% of cases (15.9% of men and 8.0% of women, p = 0.002). Resection for cure was performed
in 21.7% of patients aged <65, 17.7% in the 65–74 age group and 5.6% of those aged P75 years (p <0.0001). The rate of resection for cure varied significantly with the tumour site: 24.7% for intrahepatic localisations, 13.5% for main bile duct cancers, and 4.4% for hilar cancers (p <0.0001). The proportion of patients resected for cure increased from 4.8% during the 1976–85 period, to 14.2% between 1996 and 2005 (p <0.0001) (Table 2). Adjuvant chemotherapy was used only after 1996 and then in only 15.9% of resected cases. Palliative radiotherapy and/or chemotherapy were used in 14.0% of cases. These palliative treatments were administered alone in 29.1% of cases, associated with bypass in 59.3% or with exploratory laparotomy in 11.6%. Palliative radiotherapy and/or chemotherapy, performed without surgical resection, increased from 4.8% of cases between 1976 and 1985, to 21.6% between 1996 and 2005 (p <0.0001) (Table 2). Chemotherapy alone was used in 48.8% of cases, radiotherapy alone in 32.6% and an association of chemo/radiotherapy in 18.6% of cases. Palliative resection was performed in 4.2% of cases. Bypass (either surgical or endoscopic) was performed in 48.9% of cases and exploratory laparotomy in 11.1%. The procedure used to perform the bypass varied over time. There was a dramatic increase in the proportion of endoscopic procedures for bypass, from 11.1% of all bypass cases between 1976 and 1985, to 72.3% between 1996 and 2005. Table 2 shows the distribution of BTCs according to stage at diagnosis and period of diagnosis. There was no significant change in stage at diagnosis over time. The proportion of stage III cancers was 3.2% between 1976–1985, and 7.1% between 1996–2005 (p = 0.550). The corresponding proportions for metastatic and unresectable cases were 93.7% and 89.7%. Symptoms at first diagnosis differed between extrahepatic and intrahepatic bile duct cancers. The proportion of patients with jaundice was respectively 83.0% and 22.8%, with non-specific symptoms (mostly pain) respectively 7.8% and 25.0% and with general state impairment, respectively 9.2% and 52.2% (p <0.0001). Survival The overall 1-, 3- and 5-year relative survival rates were respectively 25.0%, 9.7%, and 6.8%. The 1-, 3- and 5-year relative survival rates for the different variables studied are shown in Table 3. The period of diagnosis did not significantly affect the prognosis.
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Research Article Table 2. Distribution of biliary tract cancers by stage at diagnosis and treatment, according to period of diagnosis and subsite localisation.
Period of diagnosis
Stage, % I-II III Advanced
Localisation of biliary tract cancers
1976 85 (n = 126)
1986 95 (n = 179)
1996 2005 (n = 310)
3.2
6.2
3.2 93.6
4.5 89.3
4.8
p
Intra hepatic (n = 287)
Extra hepatic (n = 328)
7.1
3.5
8.2
3.2 89.7
NS
1.0 95.5
5.8 86.0
11.7
14.2
0.001
9.8
13.1
4.0
3.9
3.9
NS
1.7
5.8
4.7
7.3
21.6
<0.001
17.4
11.3
86.5
77.1
60.3
<0.001
71.1
69.8
p
NS
Treatment, % Resection for cure Palliative resection with or without palliative chemotherapy and/or
0.007
radiotherapy Palliative chemotherapy and/or radiotherapy* Best supportive care *
Palliative chemotherapy and/or radiotherapy without palliative resection.
Survival was higher for men than for women and for patients aged <65 than for older patients. Survival was not related to the cancer site. Treatment and stage at diagnosis were the most important determinants of survival. After resection for cure, the 5-year relative survival rate was 27.4%, and was 15.4% for palliative resection and 6.4% for other palliative treatments. Prognosis worsened with a more advanced cancer stage. The 5-year relative survival rate varied from 35.1% for stage III to 4.3% for advanced cancer. As treatment and stage at diagnosis were closely correlated, they were not included together in the multivariate analysis. Two successive multivariate survival models were designed based on gender, age, site, and period of diagnosis: one included treatments and the other included stage at diagnosis. The results of the two models were similar so only the second multivariate model is presented (Table 4). For stage at diagnosis, the relative risk of death compared to stage I was 1.2 for stage III and 3.2 for advanced stage. Age and period of diagnosis were also significant prognostic factors and were independent of stage at diagnosis.
Discussion This study is noteworthy in that it describes the incidence and management of BTC at the population level. Its strength was to examine, in an area with a population of over one million people, a series of cases recorded in a long-standing cancer registry, where almost all cases are confirmed, with complete follow-up. All data were collected in a consistent fashion regardless of the time period or place of diagnosis. This study was therefore carried out without selection bias. In this study, 46.7% of extrahepatic bile duct cancers had no histological proof, which is comparable to other population-based studies [12,13]. Although recommended in order to confirm the diagnosis, histological proof is not always possible to obtain. In the absence of histological verification, diagnosis was made from operative findings or by medical imaging [2,14]. In order to avoid bias, epidemiological studies
308
must include all cases whether histologically verified or not and whether treated or not. This study confirms that BTC is still rare, representing about 2% of all digestive cancers in France, which is lower than the proportion reported in England, North America, and North Africa [15]. As in other countries [4–7,16], there was a slight male predominance. The mean age at diagnosis was significantly higher in women than in men. In hospital-based statistics, age at diagnosis is generally lower than in our study, suggesting that older patients are rarely seen in specialised centres [17–20]. Our incidence rates can be compared with those reported in other areas of the world covered by a cancer registry. However, available data on incidence are heterogeneous and for this reason sometimes difficult to compare. Most published articles pool all extrahepatic BTCs including those involving the gallbladder and/or ampulla of Vater, while others deal only with intrahepatic BTCs. Moreover, many articles use the standard American population, which is not an international standard. In spite of these difficulties, it can be concluded that the population of the south-eastern areas of the USA are at high-risk of extrahepatic BTCs: between 2.6 and 1.3/100,000 inhabitants for men and between 1.0 and 0.6/100,000 inhabitants for women [21]. Burgundy (France), other European countries, Australia, other parts of North America, and Caucasian countries have similar risk levels between 1.0 and 0.6/100,000 inhabitants for men, and 0.1 and 0.3/100,000 inhabitants for women. Little is known about the incidence of intrahepatic BTCs across the world as these are very rare tumours. Japan has reported the highest incidence rates, ranging between 0.7 and 0.4/100,000 inhabitants for men, and 0.5 and 0.1/100,000 inhabitants for women [22,23]. Some studies have reported that the trends in incidence of intrahepatic and extrahepatic BTCs have diverged. However, there were no significant changes in incidence of either type of BTC in our area. A similar trend was reported in Denmark [24]. In contrast, recent studies in England and Wales, Scotland [25,26] and the USA [16] have reported an increasing incidence
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JOURNAL OF HEPATOLOGY Table 3. One-, three-, and five-year relative survival rates for patients with biliary tract cancer.
Table 4. Multivariate relative survival analysis for biliary tract cancer.
RR
Survival (%) at:
Overall
1 year
3 years
5 years
25.0
9.7
6.8
p
Male Female
30.0
12.5
7.1
18.5
6.2
6.1
42.4 29.9 15.7
18.1 9.0 7.7
12.2 6.1 5.5
<0.0001
1976 1985 1986 1995
13.7 25.4
5.7 10.6
4.5 10.3
1996 2005
31.1
12.8
6.7
Intrahepatic Hilum
25.8 25.2
11.6 6.4
6.8 4.0
Main bile duct
26.1
10.8
8.3
0.0007
NS
1.0 1.3 1.5
1.02 1.20
1.56 1.78
0.03 <0.0001
1976 1985 1986 1995
1.0 0.7
0.55
0.81
<0.0001
1996 2005
0.6
0.47
0.69
<0.0001
Intrahepatic Hilum
1.0 1.1
0.87
1.40
NS
Main bile duct
1.0
0.75
1.31
NS
1.0 1.2 3.2
0.70 2.18
2.13 4.77
NS <0.0001
69.3 62.2 20.5
54.8 26.1 6.0
35.1 16.0 4.3
NS
67.3
41.9
27.4
23.2
15.4
Palliative chemotherapy and/ or radiotherapy* 56.1
11.5
6.4
7.1
2.5
20.1
I II III Advanced
<0.0001
Treatment Palliative surgery alone 63.2
<65 65-74 75
Stage
Stage
Best supportive care
1.17
Subsite
Subsite
Resection for cure
0.86
Period <0.0001
Period
I II III Advanced
1.0 1.0
Age at diagnosis (years)
Age at diagnosis (years) <65 65-74 75
p
Sex Male Female
Sex
95%CI
<0.0001
*
Palliative chemotherapy and/or radiotherapy without palliative surgery.
of intrahepatic BTCs in both sexes and a decrease in incidence of extrahepatic bile duct cancer. Improved diagnosis is an unlikely explanation because no screening is available and by the time the tumour becomes symptomatic it is large and relatively easy to diagnose. Another explanation could be that diagnostic procedures, based on contrast radiography and more recently on magnetic resonance imaging, have changed over the past 30 years [27]. However, these kinds of procedures have been available since 1990 in Burgundy and this is also an unlikely explanation. Environmental factors, obesity, diabetes, or smoking habits probably play a role but, due to the rarity of these tumours, they are yet unknown. We describe the management of BTC at the community level. It is widely accepted that surgical resection is always preferable for cure [2]. There was a small but significant increase in the resection rate over the 30 years of our study. Despite this, however,<15% of cases diagnosed during the most recent period could be resected for cure. Resection rates for cure were lower than those reported previously in hospital-based series [18,20]. This
discrepancy is not surprising. Hospital data are provided by specialised units and as such cannot be used as a reference. There is also a wide range in the proportion of advanced cases in hospital-based series. Our study indicates that stage at diagnosis is advanced when the general population is considered. On average, 90.4% of patients had visceral metastasis or unresectable tumours at the time of diagnosis. This study also indicates that there was no significant improvement in the stage at diagnosis of patients with BTC over the 30 years of the study, which is disappointing. Changes in diagnostic strategies have not led to an improvement in the management of BTC. Use of chemotherapy has increased over time and varies according to the age of the patient. Chemotherapy does not have a potent anti-tumour effect [2,14], although most studies are small and only phase II. Meta-analyses have failed to demonstrate a clear benefit of adjuvant [28] or palliative chemotherapy alone or associated with radiotherapy [2,29]. This underlines the need for studies to evaluate new treatments under development. The use of chemotherapy is still limited at the population level. The presentation of patients at diagnosis differs according to cancer site. This can explain the trend towards an earlier diagnosis (not significant) for extrahepatic compared to intrahepatic BTC. The 5-year survival rate of patients with BTC is low and is similar to that observed for pancreatic adenocarcinoma [4,7]. Furthermore, 5-year survival has remained virtually unchanged over the past 30 years. In the EUROCARE study [30], which includes survival data on extrahepatic BTC from 16 European countries, 5-year survival rates varied between 5% (Denmark) and 16% (Germany). Survival rates in Burgundy are somewhere between these two figures. Five-year relative survival rates
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Research Article reported by the SEER programme were higher than in Europe: 20.6% for intrahepatic bile duct cancers and 20.5% for extrahepatic bile duct cancers [31]. There was an improvement in 5-year relative survival over time from 14% (1973–1982) to 24% (1993– 2002). These results suggest that improvements are already being recorded in Europe. Survival rates are generally higher in single institution series [19,21] but these can incur selection bias. The stage at diagnosis is a major determinant of survival. In the absence of an improvement of stage at diagnosis it is not surprising that no improvement in prognosis of BTC has been achieved over time. Because of the lateness of symptoms, earlier diagnosis is difficult to achieve. In the short term, multicentre, cooperative trials are needed to evaluate the benefits of novel adjuvant or palliative chemotherapy. New approaches to the treatment of BTC, such as photodynamic therapy, should also be evaluated. In conclusion, the incidence of intrahepatic and extrahepatic BTCs has remained relatively stable in Burgundy, France, over a 30-year period. The reasons for the different trends over time reported across the world remain unclear. This population-based analysis demonstrates that intrahepatic and extrahepatic BTCs continue to carry a poor prognosis, with no great improvement in either resectability or early stage diagnosis over time.
Conflict of interest The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. References [1] de Groen PC, Gores GJ, LaRusso NF, Gunderson LL, Nagorney DM. Biliary tract cancers. N Engl J Med 1999;341:1368–1378. [2] Khan SA, Davidson BR, Goldin R, Pereira SP, Rosenberg WM, Taylor-Robinson SD, et al. Guidelines for the diagnosis and treatment of cholangiocarcinoma: consensus document. Gut 2002;51:VI1–VI9. [3] Michaud DS. The epidemiology of pancreatic, gallbladder, and other biliary tract cancers. Gastrointest Endosc 2002;56:S195–S200. [4] Khan SA, Taylor-Robinson SD, Toledano MB, Beck A, Elliott P, Thomas HC. Changing international trends in mortality rates for liver, biliary and pancreatic tumours. J Hepatol 2002;37:806–813. [5] Patel T. Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in the United States. Hepatology 2001;33:1353–1357. [6] Patel T. Worldwide trends in mortality from biliary tract malignancies. BMC Cancer 2002;2:10. [7] Taylor-Robinson SD, Toledano MB, Arora S, Keegan TJ, Hargreaves S, Beck A, et al. Increase in mortality rates from intrahepatic cholangiocarcinoma in England and Wales 1968–1998. Gut 2001;48:816–820. [8] ICD-02. International classification of diseases for oncology. Geneva: World Health Organisation; 1992. [9] Ishak K, Anthony P, Sobin L. Histological typing of tumours of the liver. WHO International Histological Classification of Tumours. Berlin: Springer Verlag; 1994. [10] StataCorp. Stata statistical software: release 10. College Station, TX: StataCorp LP; 2007.
310
[11] Esteve J, Benhamou E, Croasdale M, Raymond L. Relative survival and the estimation of net survival: elements for further discussion. Stat Med 1990;9:529–538. [12] De Bellis M, Sherman S, Fogel EL, Cramer H, Chappo J, McHenry Jr L, et al. Tissue sampling at ERCP in suspected malignant biliary strictures (Part 1). Gastrointest Endosc 2002;56:552–561. [13] de Bellis M, Sherman S, Fogel EL, Cramer H, Chappo J, McHenry Jr L, et al. Tissue sampling at ERCP in suspected malignant biliary strictures (Part 2). Gastrointest Endosc 2002;56:720–730. [14] SNFGE. Thésaurus National de Cancérologie Digestive; 2008.. [15] Parkin MD, Whelan SL, Ferlay J, Teppo L, Thomas DB. Cancer incidence in five continents No. 155, vol. VIII. Lyon: IARC Scientific Publication; 2002. [16] Shaib Y, El-Serag HB. The epidemiology of cholangiocarcinoma. Semin Liver Dis 2004;24:115–125. [17] Bismuth H, Nakache R, Diamond T. Management strategies in resection for hilar cholangiocarcinoma. Ann Surg 1992;215:31–38. [18] D’Angelica M, Martin 2nd RC, Jarnagin WR, Fong Y, DeMatteo RP, Blumgart LH. Major hepatectomy with simultaneous pancreatectomy for advanced hepatobiliary cancer. J Am Coll Surg 2004;198:570–576. [19] Jarnagin WR, Fong Y, DeMatteo RP, Gonen M, Burke EC, Bodniewicz BJ, et al. Staging, resectability, and outcome in 225 patients with hilar cholangiocarcinoma. Ann Surg 2001;234:507–517, [discussion 517-9]. [20] Nagino M, Kamiya J, Arai T, Nishio H, Ebata T, Nimura Y. One hundred consecutive hepatobiliary resections for biliary hilar malignancy: preoperative blood donation, blood loss, transfusion, and outcome. Surgery 2005;137:148–155. [21] Miyakawa S, Ishihara S, Horiguchi A, Takada T, Miyazaki M, Nagakawa T. Biliary tract cancer treatment: 5584 results from the biliary tract cancer statistics registry from1998 to 2004 in Japan. J Hepatobiliary Pancreat Surg 2009;16:1–7. [22] Parkin MD, Whelan SL, Ferlay J, Teppo L, Thomas DB. Cancer incidence in five continents No. 88, vol. V. Lyon: IARC Scientific Publication; 1987. [23] Parkin MD, Whelan SL, Ferlay J, Teppo L, Thomas DB. Cancer incidence in five continents No. 120, vol. VI. Lyon: IARC Scientific Publication; 1992. [24] Jepsen P, Vilstrup H, Tarone RE, Friis S, Sorensen HT. Incidence rates of intraand extrahepatic cholangiocarcinomas in Denmark from 1978 to 2002. J Natl Cancer Inst 2007;99:895–897. [25] West J, Wood H, Logan RF, Quinn M, Aithal GP. Trends in the incidence of primary liver and biliary tract cancers in England and Wales 1971–2001. Br J Cancer 2006;94:1751–1758. [26] Wood R, Brewster DH, Fraser LA, Brown H, Hayes PC, Garden OJ. Do increases in mortality from intrahepatic cholangiocarcinoma reflect a genuine increase in risk? Insights from cancer registry data in Scotland. Eur J Cancer 2003;39:2087–2092. [27] Malhi H, Gores GJ. Review article: the modern diagnosis and therapy of cholangiocarcinoma. Aliment Pharmacol Ther 2006;23:1287–1296. [28] Takada T, Amano H, Yasuda H, Nimura Y, Matsushiro T, Kato H, et al. Is postoperative adjuvant chemotherapy useful for gallbladder carcinoma? A phase III multicenter prospective randomized controlled trial in patients with resected pancreaticobiliary carcinoma. Cancer 2002;95: 1685–1695. [29] Robertson JM, Lawrence TS, Dworzanin LM, Andrews JC, Walker SK, DuRoss DJ, et al. Treatment of primary hepatobiliary cancers with conformal radiation therapy and regional chemotherapy. J Clin Oncol 1993;11: 1286–1293. [30] Sant M, Aareleid T, Berrino F, Bielska Lasota M, Carli PM, Faivre J, et al. EUROCARE-3: survival of cancer patients diagnosed 1990–94-results and commentary. Ann Oncol 2003;14:v61–v118. [31] SEER. Liver and Intrahepatic Bile Duct Cancers; 2009.
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Trends in the incidence and management of biliary tract cancer: A French population-based study Côme Lepage1,2,⇑, Vanessa Cottet1, Marion Chauvenet1,2, Jean-Marc Phelip3, Laurent Bedenne1,2, Jean Faivre1,2, Anne-Marie Bouvier1 1 Registre Bourguignon des Cancers Digestifs; INSERM U866; Université de Bourgogne, Dijon, France; 2Department of Hepato-Gastroenterology, University Hospital Le Bocage, Dijon, France; 3Université Jean Monnet, Saint-Etienne, France
Background & Aims: The trends in incidence and management of biliary tract cancer (BTC) were investigated in a well-defined French population over a 30-year period (1976–2005). Methods: Data were obtained from the Burgundy digestive cancer registry. Age-standardised incidence rates and trends in incidence were determined. Treatment and stage at diagnosis were also investigated. Five-year survival rates were calculated. Results: Six hundred and fifteen cases of BTC were recorded. There was no significant change in BTC incidence over the 30year period. For extrahepatic BTC age-standardised incidence rates were 1.1/100,000 for 1976–80 and 2001–2005. These rates were respectively 0.3 and 0.2/100,000 for intrahepatic BTC. The proportion of patients undergoing resection for cure increased over time from 4.8% to 14.2% (p <0.001). The proportion of stage III cases ranged from 3.2% to 7.1% but did not vary significantly over time (p = 0.55). Most cases were metastatic or unresectable at diagnosis. Five-year relative survival rates were 4.5% for 1976– 85 and 6.7% for 1996–2005, ranging from 35.1% for stages III to 4.3% for advanced BTC. Age and stage at diagnosis were independent prognostic factors. Conclusions: The incidence of BTC has remained stable in Burgundy over the past 30 years. BTC prognosis remains poor and has only improved slightly over time. Ó 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Introduction The epidemiological characteristics of biliary tract cancer (BTC) have received little attention, mainly because these cancers are rare and because histological proof of cancer can be difficult to obtain [1,2]. These cancers originate in the ductal epithelium of the biliary tree, either within the liver (intrahepatic BTC) or more commonly outside the liver including the hilum and main bile duct (extrahepatic BTC). The disease is usually fatal because of
Keywords: Biliary tract cancer; Incidence; Survival rate; Treatment. Received 1 March 2010; received in revised form 4 June 2010; accepted 20 June 2010; available online 7 September 2010 ⇑ Corresponding author. Address: Registre Bourguignon des Cancers Digestifs, INSERM U866, Faculté de Médecine, BP 87900, 21079 Dijon Cedex, France. Tel.: +33 3 80 39 33 40; fax: +33 3 80 66 82 51. E-mail address: [email protected] (C. Lepage).
its late clinical presentation and the lack of effective non-surgical therapeutic modalities [3]. However, interest in this disease is rising because a marked increase in incidence of intrahepatic tumours has been reported in the USA and England [4–7]. There is also a paucity of reports on the management and prognosis of these tumours. Furthermore, most of the available data is provided by specialised centres and thus cannot be used as a reference because of unavoidable selection bias. Population-based studies, recording all cases in a well-defined population, represents the best way to assess the epidemiological characteristics and real management of these cancers. Such studies are rare, however, because they require accurate and detailed data which are seldom collected systematically by cancer registries. The objective of this study was to establish a picture of the trends in incidence, treatment, stage at diagnosis, and prognosis of BTC in a well-defined French population over a 30-year period.
Patients and methods All digestive tract cancers in the resident population of two administrative areas in Burgundy, (France), are recorded in a population-based cancer registry. These areas have a population of 1050,000 according to the 1999 census. Cancer registration began in 1976 in one area and in 1982 in the other. Information is actively collected by the cancer registry staff from multiple sources: pathology laboratories, university hospitals, local hospitals, private specialists (gastroenterologists, surgeons, and oncologists), general practitioners, and monthly reviews of death certificates. Patients, resident in Burgundy and treated outside the area, are identified through the National Health Service. The quality and completeness of the registry is certified every 4 years by an audit conducted by the National Institute for Health and Medical Research (INSERM) and National Public Health Institute (InVS). Due to the involvement of the entire medical profession, and to the multiplicity of data sources, it was assumed that nearly all newly diagnosed cases were recorded. No cases were registered through death certificate alone, given the questionable quality of this source of information. However, they were used to identify missing cases. Patients with BTC were coded according to the International Classification of Diseases for Oncology [8]. The following topography codes were used: C 22.1 (intrahepatic bile duct), C 24.0 (hilum), C 24.1 (main bile duct), C 24.9 (extrahepatic tract not otherwise stated). Cancer of the ampulla of Vater and cancer of the gallbladder were not included in this study. Histological codes included cholangiocarcinoma (8160, 8161) for intrahepatic BTC, and adenocarcinoma (8140, 8260, 8480) and undifferentiated carcinoma (8020, 8021) for extrahepatic BTC. All intrahepatic BTCs were verified histologically. Diagnosis of extrahepatic BTC was based on histological confirmation in 54.3% of cases and on surgical findings or morphological criteria in 45.7%. Adenocarcinoma was the most common histological type (95.5%) among the histologically-verified cases, followed by undifferentiated carcinomas (3.9%).
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JOURNAL OF HEPATOLOGY Patients were categorised into three age groups: 21.6% were aged <65-yearsold, 28.6% were aged 65–74, and 49.8% were aged P75. Cancer extension at the time of diagnosis was classified according to the TNM classification [9]. Three stages were defined: (i) stage III resected cancers without lymph node or visceral metastasis (T1–2 N0 M0); (ii) stage III resected cancers with lymph node metastasis (Any T, N1–2 M0); and (iii) advanced stage cancers with visceral metastasis (M1) and/or for which complete surgical resection was impossible. Surgical treatments included: (i) resection for cure (macroscopic resection of all malignant tissue and no microscopic evidence of surgical marginal spread (n = 71); (ii) palliative resection alone (n = 24); (iii) palliative chemotherapy and/or radiotherapy as the main treatment (n = 86); and (iv) best supportive care alone (including surgical or endoscopic bypass) (n = 434). Survival of patients was ascertained from death certificates recorded by the registrar of the place of residence or from practitioners. Life status was known for 99.5% of the patients in January 2008.
Table 1. Age-standardised incidence rates* of biliary tract tumours by gender, site, and period of diagnosis.
p
Period of diagnosis 1976 1981 1986 1991 1996 80 85 90 95 2000
2001 05
Men
2.4
1.1
0.9
1.5
1.6
1.7
0.910
Women
0.6
0.6
0.5
0.4
0.8
0.9
0.948
Intrahepatic
0.3
0.3
0.4
0.2
0.2
0.2
0.754
Extrahepatic 1.1
0.6
0.5
0.8
0.9
1.1
0.856
1.4
0.9
0.9
1.0
1.1
1.3
0.372
All cases *
World standard population per 100,000 persons-years.
Statistical analysis The data used for calculating incidence rates were based on population estimates by interpolation of the results of four censuses (1975, 1982, 1990, 1999) and then by extrapolation. Incidence rates were calculated by gender, age, site and period of diagnosis. For the purpose of comparison with other countries, rates were standardised by the direct method using the world standard population. Time trends in incidence were analysed using six 5-year periods from 1976 to 2005. Time trends in incidence were assessed by Poisson regression. The association between categorical data was analysed using the Chi2 test. To study the trends in BTC management and prognosis, three time periods were defined: 1976–1985, 1986–1995 and 1996–2005. Relative survival rates were calculated, defined as the ratio of the observed survival rate in the cancer patients under study, to the expected survival rate in a population with similar gender and age distribution, subject only to the mortality rates of the general population. They reflect the excess mortality in the cancer patient group relative to background mortality. Relative survival rates were computed using Stata 10.0 software [10]. A multivariate survival analysis was performed using a relative survival model with proportional hazards, applied to the net survival by intervals [11]. The significance of the covariates was tested using the likelihood ratio test.
Results Incidence by gender, age, and period of diagnosis There were 615 cases of BTC diagnosed between 1976 and 2005, representing 1.8% of digestive tract cancers in men and 2.1% in women. The mean age at diagnosis was 71.7 years in men (SD: 1.2 years) and 75.9 years in women (SD: 1.3 years) (p <0.0001). The overall age-standardised incidence rates were respectively 1.4 and 0.7/100,000. The sex ratio calculated from the age-standardised rates was 2.0. The incidence rate of BTC was low, and was similar in both genders before 55 years of age. Thereafter, incidence rates increased more rapidly in men than in women. Table 1 shows the trends in age-standardised incidence rates of BTC over time by gender, site, and period of diagnosis, standardised to the world population. There was no significant change in incidence of BTC according to site over time. The incidence rates of BTC decreased slightly in men between the first and third study period and then increased slightly. In women, the incidence rates were relatively stable. The incidence of intrahepatic BTC was stable in both sexes. The incidence of extrahepatic BTC decreased slightly from 1976 to 1990 and then increased slightly from 1991 to 2005. Treatment and stage at diagnosis Resection for cure was performed in 12.5% of cases (15.9% of men and 8.0% of women, p = 0.002). Resection for cure was performed
in 21.7% of patients aged <65, 17.7% in the 65–74 age group and 5.6% of those aged P75 years (p <0.0001). The rate of resection for cure varied significantly with the tumour site: 24.7% for intrahepatic localisations, 13.5% for main bile duct cancers, and 4.4% for hilar cancers (p <0.0001). The proportion of patients resected for cure increased from 4.8% during the 1976–85 period, to 14.2% between 1996 and 2005 (p <0.0001) (Table 2). Adjuvant chemotherapy was used only after 1996 and then in only 15.9% of resected cases. Palliative radiotherapy and/or chemotherapy were used in 14.0% of cases. These palliative treatments were administered alone in 29.1% of cases, associated with bypass in 59.3% or with exploratory laparotomy in 11.6%. Palliative radiotherapy and/or chemotherapy, performed without surgical resection, increased from 4.8% of cases between 1976 and 1985, to 21.6% between 1996 and 2005 (p <0.0001) (Table 2). Chemotherapy alone was used in 48.8% of cases, radiotherapy alone in 32.6% and an association of chemo/radiotherapy in 18.6% of cases. Palliative resection was performed in 4.2% of cases. Bypass (either surgical or endoscopic) was performed in 48.9% of cases and exploratory laparotomy in 11.1%. The procedure used to perform the bypass varied over time. There was a dramatic increase in the proportion of endoscopic procedures for bypass, from 11.1% of all bypass cases between 1976 and 1985, to 72.3% between 1996 and 2005. Table 2 shows the distribution of BTCs according to stage at diagnosis and period of diagnosis. There was no significant change in stage at diagnosis over time. The proportion of stage III cancers was 3.2% between 1976–1985, and 7.1% between 1996–2005 (p = 0.550). The corresponding proportions for metastatic and unresectable cases were 93.7% and 89.7%. Symptoms at first diagnosis differed between extrahepatic and intrahepatic bile duct cancers. The proportion of patients with jaundice was respectively 83.0% and 22.8%, with non-specific symptoms (mostly pain) respectively 7.8% and 25.0% and with general state impairment, respectively 9.2% and 52.2% (p <0.0001). Survival The overall 1-, 3- and 5-year relative survival rates were respectively 25.0%, 9.7%, and 6.8%. The 1-, 3- and 5-year relative survival rates for the different variables studied are shown in Table 3. The period of diagnosis did not significantly affect the prognosis.
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Research Article Table 2. Distribution of biliary tract cancers by stage at diagnosis and treatment, according to period of diagnosis and subsite localisation.
Period of diagnosis
Stage, % I-II III Advanced
Localisation of biliary tract cancers
1976 85 (n = 126)
1986 95 (n = 179)
1996 2005 (n = 310)
3.2
6.2
3.2 93.6
4.5 89.3
4.8
p
Intra hepatic (n = 287)
Extra hepatic (n = 328)
7.1
3.5
8.2
3.2 89.7
NS
1.0 95.5
5.8 86.0
11.7
14.2
0.001
9.8
13.1
4.0
3.9
3.9
NS
1.7
5.8
4.7
7.3
21.6
<0.001
17.4
11.3
86.5
77.1
60.3
<0.001
71.1
69.8
p
NS
Treatment, % Resection for cure Palliative resection with or without palliative chemotherapy and/or
0.007
radiotherapy Palliative chemotherapy and/or radiotherapy* Best supportive care *
Palliative chemotherapy and/or radiotherapy without palliative resection.
Survival was higher for men than for women and for patients aged <65 than for older patients. Survival was not related to the cancer site. Treatment and stage at diagnosis were the most important determinants of survival. After resection for cure, the 5-year relative survival rate was 27.4%, and was 15.4% for palliative resection and 6.4% for other palliative treatments. Prognosis worsened with a more advanced cancer stage. The 5-year relative survival rate varied from 35.1% for stage III to 4.3% for advanced cancer. As treatment and stage at diagnosis were closely correlated, they were not included together in the multivariate analysis. Two successive multivariate survival models were designed based on gender, age, site, and period of diagnosis: one included treatments and the other included stage at diagnosis. The results of the two models were similar so only the second multivariate model is presented (Table 4). For stage at diagnosis, the relative risk of death compared to stage I was 1.2 for stage III and 3.2 for advanced stage. Age and period of diagnosis were also significant prognostic factors and were independent of stage at diagnosis.
Discussion This study is noteworthy in that it describes the incidence and management of BTC at the population level. Its strength was to examine, in an area with a population of over one million people, a series of cases recorded in a long-standing cancer registry, where almost all cases are confirmed, with complete follow-up. All data were collected in a consistent fashion regardless of the time period or place of diagnosis. This study was therefore carried out without selection bias. In this study, 46.7% of extrahepatic bile duct cancers had no histological proof, which is comparable to other population-based studies [12,13]. Although recommended in order to confirm the diagnosis, histological proof is not always possible to obtain. In the absence of histological verification, diagnosis was made from operative findings or by medical imaging [2,14]. In order to avoid bias, epidemiological studies
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must include all cases whether histologically verified or not and whether treated or not. This study confirms that BTC is still rare, representing about 2% of all digestive cancers in France, which is lower than the proportion reported in England, North America, and North Africa [15]. As in other countries [4–7,16], there was a slight male predominance. The mean age at diagnosis was significantly higher in women than in men. In hospital-based statistics, age at diagnosis is generally lower than in our study, suggesting that older patients are rarely seen in specialised centres [17–20]. Our incidence rates can be compared with those reported in other areas of the world covered by a cancer registry. However, available data on incidence are heterogeneous and for this reason sometimes difficult to compare. Most published articles pool all extrahepatic BTCs including those involving the gallbladder and/or ampulla of Vater, while others deal only with intrahepatic BTCs. Moreover, many articles use the standard American population, which is not an international standard. In spite of these difficulties, it can be concluded that the population of the south-eastern areas of the USA are at high-risk of extrahepatic BTCs: between 2.6 and 1.3/100,000 inhabitants for men and between 1.0 and 0.6/100,000 inhabitants for women [21]. Burgundy (France), other European countries, Australia, other parts of North America, and Caucasian countries have similar risk levels between 1.0 and 0.6/100,000 inhabitants for men, and 0.1 and 0.3/100,000 inhabitants for women. Little is known about the incidence of intrahepatic BTCs across the world as these are very rare tumours. Japan has reported the highest incidence rates, ranging between 0.7 and 0.4/100,000 inhabitants for men, and 0.5 and 0.1/100,000 inhabitants for women [22,23]. Some studies have reported that the trends in incidence of intrahepatic and extrahepatic BTCs have diverged. However, there were no significant changes in incidence of either type of BTC in our area. A similar trend was reported in Denmark [24]. In contrast, recent studies in England and Wales, Scotland [25,26] and the USA [16] have reported an increasing incidence
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JOURNAL OF HEPATOLOGY Table 3. One-, three-, and five-year relative survival rates for patients with biliary tract cancer.
Table 4. Multivariate relative survival analysis for biliary tract cancer.
RR
Survival (%) at:
Overall
1 year
3 years
5 years
25.0
9.7
6.8
p
Male Female
30.0
12.5
7.1
18.5
6.2
6.1
42.4 29.9 15.7
18.1 9.0 7.7
12.2 6.1 5.5
<0.0001
1976 1985 1986 1995
13.7 25.4
5.7 10.6
4.5 10.3
1996 2005
31.1
12.8
6.7
Intrahepatic Hilum
25.8 25.2
11.6 6.4
6.8 4.0
Main bile duct
26.1
10.8
8.3
0.0007
NS
1.0 1.3 1.5
1.02 1.20
1.56 1.78
0.03 <0.0001
1976 1985 1986 1995
1.0 0.7
0.55
0.81
<0.0001
1996 2005
0.6
0.47
0.69
<0.0001
Intrahepatic Hilum
1.0 1.1
0.87
1.40
NS
Main bile duct
1.0
0.75
1.31
NS
1.0 1.2 3.2
0.70 2.18
2.13 4.77
NS <0.0001
69.3 62.2 20.5
54.8 26.1 6.0
35.1 16.0 4.3
NS
67.3
41.9
27.4
23.2
15.4
Palliative chemotherapy and/ or radiotherapy* 56.1
11.5
6.4
7.1
2.5
20.1
I II III Advanced
<0.0001
Treatment Palliative surgery alone 63.2
<65 65-74 75
Stage
Stage
Best supportive care
1.17
Subsite
Subsite
Resection for cure
0.86
Period <0.0001
Period
I II III Advanced
1.0 1.0
Age at diagnosis (years)
Age at diagnosis (years) <65 65-74 75
p
Sex Male Female
Sex
95%CI
<0.0001
*
Palliative chemotherapy and/or radiotherapy without palliative surgery.
of intrahepatic BTCs in both sexes and a decrease in incidence of extrahepatic bile duct cancer. Improved diagnosis is an unlikely explanation because no screening is available and by the time the tumour becomes symptomatic it is large and relatively easy to diagnose. Another explanation could be that diagnostic procedures, based on contrast radiography and more recently on magnetic resonance imaging, have changed over the past 30 years [27]. However, these kinds of procedures have been available since 1990 in Burgundy and this is also an unlikely explanation. Environmental factors, obesity, diabetes, or smoking habits probably play a role but, due to the rarity of these tumours, they are yet unknown. We describe the management of BTC at the community level. It is widely accepted that surgical resection is always preferable for cure [2]. There was a small but significant increase in the resection rate over the 30 years of our study. Despite this, however,<15% of cases diagnosed during the most recent period could be resected for cure. Resection rates for cure were lower than those reported previously in hospital-based series [18,20]. This
discrepancy is not surprising. Hospital data are provided by specialised units and as such cannot be used as a reference. There is also a wide range in the proportion of advanced cases in hospital-based series. Our study indicates that stage at diagnosis is advanced when the general population is considered. On average, 90.4% of patients had visceral metastasis or unresectable tumours at the time of diagnosis. This study also indicates that there was no significant improvement in the stage at diagnosis of patients with BTC over the 30 years of the study, which is disappointing. Changes in diagnostic strategies have not led to an improvement in the management of BTC. Use of chemotherapy has increased over time and varies according to the age of the patient. Chemotherapy does not have a potent anti-tumour effect [2,14], although most studies are small and only phase II. Meta-analyses have failed to demonstrate a clear benefit of adjuvant [28] or palliative chemotherapy alone or associated with radiotherapy [2,29]. This underlines the need for studies to evaluate new treatments under development. The use of chemotherapy is still limited at the population level. The presentation of patients at diagnosis differs according to cancer site. This can explain the trend towards an earlier diagnosis (not significant) for extrahepatic compared to intrahepatic BTC. The 5-year survival rate of patients with BTC is low and is similar to that observed for pancreatic adenocarcinoma [4,7]. Furthermore, 5-year survival has remained virtually unchanged over the past 30 years. In the EUROCARE study [30], which includes survival data on extrahepatic BTC from 16 European countries, 5-year survival rates varied between 5% (Denmark) and 16% (Germany). Survival rates in Burgundy are somewhere between these two figures. Five-year relative survival rates
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Research Article reported by the SEER programme were higher than in Europe: 20.6% for intrahepatic bile duct cancers and 20.5% for extrahepatic bile duct cancers [31]. There was an improvement in 5-year relative survival over time from 14% (1973–1982) to 24% (1993– 2002). These results suggest that improvements are already being recorded in Europe. Survival rates are generally higher in single institution series [19,21] but these can incur selection bias. The stage at diagnosis is a major determinant of survival. In the absence of an improvement of stage at diagnosis it is not surprising that no improvement in prognosis of BTC has been achieved over time. Because of the lateness of symptoms, earlier diagnosis is difficult to achieve. In the short term, multicentre, cooperative trials are needed to evaluate the benefits of novel adjuvant or palliative chemotherapy. New approaches to the treatment of BTC, such as photodynamic therapy, should also be evaluated. In conclusion, the incidence of intrahepatic and extrahepatic BTCs has remained relatively stable in Burgundy, France, over a 30-year period. The reasons for the different trends over time reported across the world remain unclear. This population-based analysis demonstrates that intrahepatic and extrahepatic BTCs continue to carry a poor prognosis, with no great improvement in either resectability or early stage diagnosis over time.
Conflict of interest The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. References [1] de Groen PC, Gores GJ, LaRusso NF, Gunderson LL, Nagorney DM. Biliary tract cancers. N Engl J Med 1999;341:1368–1378. [2] Khan SA, Davidson BR, Goldin R, Pereira SP, Rosenberg WM, Taylor-Robinson SD, et al. Guidelines for the diagnosis and treatment of cholangiocarcinoma: consensus document. Gut 2002;51:VI1–VI9. [3] Michaud DS. The epidemiology of pancreatic, gallbladder, and other biliary tract cancers. Gastrointest Endosc 2002;56:S195–S200. [4] Khan SA, Taylor-Robinson SD, Toledano MB, Beck A, Elliott P, Thomas HC. Changing international trends in mortality rates for liver, biliary and pancreatic tumours. J Hepatol 2002;37:806–813. [5] Patel T. Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in the United States. Hepatology 2001;33:1353–1357. [6] Patel T. Worldwide trends in mortality from biliary tract malignancies. BMC Cancer 2002;2:10. [7] Taylor-Robinson SD, Toledano MB, Arora S, Keegan TJ, Hargreaves S, Beck A, et al. Increase in mortality rates from intrahepatic cholangiocarcinoma in England and Wales 1968–1998. Gut 2001;48:816–820. [8] ICD-02. International classification of diseases for oncology. Geneva: World Health Organisation; 1992. [9] Ishak K, Anthony P, Sobin L. Histological typing of tumours of the liver. WHO International Histological Classification of Tumours. Berlin: Springer Verlag; 1994. [10] StataCorp. Stata statistical software: release 10. College Station, TX: StataCorp LP; 2007.
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[11] Esteve J, Benhamou E, Croasdale M, Raymond L. Relative survival and the estimation of net survival: elements for further discussion. Stat Med 1990;9:529–538. [12] De Bellis M, Sherman S, Fogel EL, Cramer H, Chappo J, McHenry Jr L, et al. Tissue sampling at ERCP in suspected malignant biliary strictures (Part 1). Gastrointest Endosc 2002;56:552–561. [13] de Bellis M, Sherman S, Fogel EL, Cramer H, Chappo J, McHenry Jr L, et al. Tissue sampling at ERCP in suspected malignant biliary strictures (Part 2). Gastrointest Endosc 2002;56:720–730. [14] SNFGE. Thésaurus National de Cancérologie Digestive; 2008.
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