analysis of a complete population of individuals with a defined cancer diagnosis over a prolonged time period is needed to assess whether new therapeutic strategies have affected the whole population 's survival outcome .
cancers arising from the epithelial lining of the intrahepatic , perihilar , and extrahepatic bile ducts are a heterogeneous group of malignancies .
two major diagnoses are identified by location : the intrahepatic cholangiocellular cancer ( ihc ) and the perihilar carcinoma ( phc ) or klatskin tumour at the confluence or bifurcation of the left and right hepatic duct proximal to the cystic duct .
there is not a clear - cut border between an advanced phc and an ihc .
an analysis of netherlands cancer registry record for ihc found a three - year survival rate of 8% , but a steady increase over the past decades .
this change could be the result of developments in surgery , transplantation , and the introduction of new ablative and molecular targeted therapies .
bile duct resection with or without liver resection is the hallmark of potentially curative treatment for patients with phc and 5-year survival is reported among 2040% after surgical resection .
most of these reports describe highly selective materials subjected to surgery in referral centres and it is difficult to assess if these results affect the whole population with the disease [ 35 ] . for
with stringent inclusion criteria liver transplantation according to the mayo protocol has shown impressing long - term results , in phc , even in multi - institutional setting [ 6 , 7 ] .
the combination of gemcitabine and cisplatinum   has demonstrated a survival advantage over treatment with gemcitabine alone , suggesting that certain chemotherapies add to survival .
survival for a complete population of patients with a malignant disease is improving thanks to advancements in diagnostic procedures , patient managements , surgical procedures , and emergence of effective chemotherapeutic agents and molecular target drugs .
the hypothesis of this study was that there is a continuous improvement in survival for the total population of patients with cholangiocellular carcinoma in this millennium .
the study 's goal was further to analyse whether staging and/or therapy options used during the first decade of this century have had an impact on the outcome .
the population studied consisted of all individuals diagnosed as having ihc or phc served by the western regional cancer centre ( rcc ) in sweden .
the hypothesis that there is an improvement in survival for patients with cholangiocarcinoma was formulated before data collection .
the region served by the rcc has a population of 1.6 million . in this region
there is one referral university hospital having a complete liver cancer service , including liver transplantation .
all patients in whom a diagnosis is clinically established are also reported to the register . included in report data
is the stage of the cancer based on clinical and imaging findings , which are translated into tnm criteria ( tnm 6 or higher ) . in this study 's analysis ,
when several therapeutic procedures were described the most important therapy was ranked as the instituted therapy .
data on pre- and postoperative adjuvant therapy was not collected . active palliative treatment ( apt ) included chemotherapy , tace ( transarterial chemotherapy ) , sirolimus , sorafenib , and cox-2 inhibitors .
bile duct drainage and radiation therapy of skeleton metastases were considered as best supportive care ( bsc ) .
all curative and active palliative treatments were handled by the liver surgery service at the university hospital .
cholangiocarcinomas located distally in the bile duct were not included in the analysis . between 2000 and 2011
a total of 627 individuals were reported to the rcc as having cancers originating in the epithelial lining of the bile ducts .
the 49 individuals , where a diagnosis was not established until the postmortem examination , were also excluded .
available information about the clinical staging , treatment , and survival on the remaining 578 individuals was reviewed .
morphologic diagnosis of cholangiocarcinoma was established when an image of adenocarcinoma was present in the specimen , in combination with immunochemical markers typical for cholangiocarcinoma , including cd7 and cd17 .
differentiation between ihc and phc was based on the location of the tumour within the liver .
a number of patients were at an advanced stage when diagnosed with the cancer and in these patients only minor diagnostic procedures were motivated .
these patients were registered under the diagnosis of unspecified primary liver cancer ( n = 65 ) or unspecified bile duct cancer ( n = 117 ) ( table 1 ) .
the diagnosis of unspecified primary liver cancer supposedly cholangiocellular ( mainly icd-10 : c22.9 ) used by the register was based on the following : ( 1 ) no evidence of a previous or concomitant cancer of no hepatic origin , ( 2 ) no underlying liver disease , and ( 3 ) no signs of hepatocellular cancer were found .
the diagnosis of unspecified bile duct cancer ( mainly icd-10 : c24.9 ) was based on the dominant symptom of stricture(s ) in the extra hepatic bile tree above the gallbladder duct that was causing jaundice .
these two diagnoses inevitably included mainly cases of ihc and phc where only best supported care ( bsc ) was administered and median survival was less than two months .
if there was a continuous progress in the outcome , the material was divided into three equal time cohorts : period a 20002003 , period b 20042007 , and period c 20082011 .
no planned changes in the organization of hepatobiliary surgery occurred in the region during 20002012 , but there was an increased awareness of the disease , which led to more referrals ( table 1 ) .
survival time was calculated from the date of the report to the rcc , that is , the date a diagnosis was established histopathologically or clinically .
survival estimates were made using the kaplan - meier method and compared using the log - rank test .
all statistics were calculated using spss 22 statistical software ( spss , chicago , il ) and at a significance level of 5% .
the analyses were done at transplant institute , section for liver surgery , sahlgrenska university hospital , gothenburg , sweden , and regional cancer centre of west sweden , gothenburg , sweden .
overall survival for all individuals with cholangiocarcinoma ( n = 578 ) improved over time ( p = 0.0013 ) . the survival curves for the ihc and phc are shown in figure 1 . the median survival for patients with phc was 6.8 months and for those with ihc 3.0 months ( p = 0.0003 ) .
the age and sex distribution did not change between the three time periods for neither ihc nor phc .
74% of the individuals with ihc were between 50 and 79 years of age when diagnosed , with an equal number younger ( 13% ) and older ( 13% ) than these age groups .
the clinical staging for the 233 individuals with ihc in the three time periods is depicted in table 1(a ) .
one patient was staged as t0 and was transplanted for primary sclerosing cholangitis and ihc was identified in the explanted liver . over time an increasing number of patients were clinically staged ( 63% in period a versus 94% in period c ) . among the staged patients with ihc
overall survival for individuals with ihc was 3.2 months and 6.6% survived more than three years .
a significant improvement in overall survival over time was registered for those diagnosed as having ihc ( p = 0.034 ) ( figure 2 ) .
the one - year survival was significantly higher in the last time period compared to the first period ( p = 0.038 ) .
seventeen of 233 patients ( 7.3% ) had a liver resection and five had a liver transplantation .
the three - year overall survival after liver resection was 29% and after liver transplantation 60% .
there was a nonsignificant increase in the number of liver resections and transplantations between periods a and c ( p = 0.064 ) ( table 1(b ) ) .
a trend towards a more active palliative therapy was seen with more patients being treated with chemotherapy over time among the three cohorts ( p = 0.06 ) . when comparing the impact on survival for those treated with chemotherapy , mainly gemcitabine ( n = 45 ) , the curves for period a + b ( n = 20 ) versus period c ( n = 25 ) were superimposed ( p = 0.96 ) and median survival was six months .
a transcatheter arterial chemoembolization , or tace , was administered during the last period to six patients .
a it was 69% , in b it was 66% , and in c it was 49% ( p = 0.02 ) .
for these three cohorts , the survival curves were worse for period c versus period a + b ( p = 0.04 ) .
the diagnosis of phc was histomorphologically established by brush cytology through an endoscopy or by biopsy in 80% of the patients . in the remaining 20% it was based on radiological findings .
fifteen percent of patients with phc were above 79 years of age and 8% were below 50 years .
no significant stage migration was identified over time in the 163 patients with phc ( table 2(a ) ) .
the use of bismuth criteria for staging the cancers in the confluence of the hepatic ducts increased over time from 49% in period a to 85% in period c ( table 2(a ) ) .
the median survival for the whole phc - population was 6.8 months and 11% survived more than three years .
fifteen percent of the patients had curatively aiming bile duct resection with a concomitant liver resection and 5.5% without liver resection .
three were transplanted according to the mayo protocol , two of them had survived more than 3 years and three were transplanted outside the protocol and the longest survival was 23 months ( table 2(b ) ) . there was no increase in number of patients who received active palliative treatment ( apt ) . in the first two periods
there were 11 who were given miscellaneous palliative therapy ( cox-2 inhibitor n = 9 , sirolimus n = 2 ) .
median survival from date of diagnosis for the 34 patients that received apt was 8.8 months .
the advanced stage of those with phc is evident as approximately 50% were given best supportive care ( bsc ) in all periods .
biliary malignancies or cholangiocarcinomas are most often asymptomatic until late in the course of the disease and in an advanced stage when the diagnosis is established . in this analysis a great number of patients had their first doctor 's consultation when their disease was at such an advanced state that only minor diagnostic procedures were motivated . even in patients with advanced disease efforts to get a diagnosis were improved and , consequently , there was a decline over time in the number of individuals for whom diagnosis was established at a postmortem examination . during the study period ct and magnetic resonance imaging ( mri ) improved differentiation between hepatocellular carcinoma and ihc
. for patients with phc high - resolution magnetic resonance imaging ( mri ) has enabled staging of a cancer in the bile duct confluence according to bismuth 's criteria and is the current preoperative standard to assess phc with an accuracy around 50% .
mri cholangiography is the golden standard used to delineate the localization and extent of a cancer and the possibility of curative surgery .
it has a positive predictive value of 86% , but in a recent meta - analysis , bismuth 's criteria had a lower accuracy rate and were of no prognostic value in cases of phc undergoing resection .
the decreasing number of individuals subjected to bsc over time mirrored the increased active therapeutic strategy for patients with ihc .
the migration of patients to curative and active palliative therapy explains why survival for bsc patients in period c was worse than in period a + b. the improvement in survival over time for patients with icc could be explained by the fourfold increase in number of patients , from 3 to 12 , who had curative surgery ( liver resection and liver transplantation ) from period a to period c contributing in total to 8 patients surviving more than 3 years and 6 to more than five years .
if these patients subjected to curative surgery are excluded , there is no significant impact on the survival curves over time ( p = 0.10 ) .
the three - year survival rate after curative surgery was thus 45% , a figure in agreement with what appears in recent reports .
an explanation could be that in this study we study the whole cohort of patients not only those referred to the surgical clinic .
more patients underwent curative surgery over time but the outcome for ihc patients who had curative surgery did not improve between periods a and b ( n = 10 ) versus period c ( n = 12 ) .
the improvement in survival in the last time period was only observed in those surviving longer than one year .
ihc was considered to be a contraindication for liver transplantation during the whole study period . in the 5 cases where liver transplantation was performed diagnosis
a multi - institutional analysis in the nordic countries reported a 5-year survival rate of 58% among those with ihc staged t1n0 and a ca 19 - 9 of less than 100 who underwent liver transplantation .
based on this figure it has to be asked if there are more patients with ihc who could benefit from liver transplantation . as a recent meta - analysis shows that elevated ca 19 - 9-levels
are associated with a worse prognosis independent of treatment , elevated ca 19 - 9-levels will remain a contraindication to transplantation ; even the criteria were expanded . in this material
, preoperatively discovered lymph node metastases beyond the hepatoduodenal ligament were a contraindication for surgery .
even if lymph node metastases are a strong predictor of survival , the survival of ihc patients with lymph node involvement can be prolonged with hepatectomy and these cases should not be prematurely deemed noncurative . there was a fourfold increase in number of patients with ihc who were treated with chemotherapy , mainly with gemcitabine .
the survival outcome of this therapy did not change over time in this study ; this is consistent with others ' findings [ 17 , 18 ] . among patients selected for tace in the last period of this study the median survival was 18 months . in comparison ,
this difference could be explained by a better clinical stage in patients selected for tace . for those with phc
there was no improvement in the survival over the three time periods studied ( figure 3 ) .
there was no increase in the number treated with curative surgery ( 27% in period a to 30% in period c ) and there was no increase in the number of individuals given active palliative treatment between the first and last periods . despite progress with different treatment options ,
that is , liver transplantation   and chemotherapy , the number of patients who benefitted from these treatments was so small that it did not affect the survival rate of the entire population .
based on the present findings it seems reasonable to speculate that progress in treatment of phc by surgical methods alone is limited .
the mayo protocol with irradiation and chemotherapy and consequent transplantation is reporting a five - year survival of 76% for individuals with phc .
it also raises the question as to whether downsizing phc and also ihc can increase the number of patients who can benefit from curatively aiming surgery .
the role of adjuvant chemotherapy is still debated ; a recent meta - analysis did not show any benefit , while a registry analysis identified that adjuvant chemotherapy was associated with significant survival benefits among patients with positive nodes or positive margins .
a more liberal use of chemotherapy during the last four - year period did not transfer into better outcomes .
the presently used drug combinations that are considered effective   were not fully adopted even in the last time period ; so there may be survival benefit still to be achieved .
new protocols with innovative neoadjuvant and adjuvant therapies are needed to further improve long - term outcome following surgery or transplantation for patient with cholangiocarcinoma . in conclusion , this analysis from a well - defined population in sweden who had ihc or phc has found an improvement in survival for patients with ihc .
more individuals with ihc were over time treated with curative surgery or chemotherapy . despite improvements in different treatment options , no changes in outcome
 
 background . 
 cholangiocarcinoma is a cancer with a poor prognosis . in this millennium 
 there are new diagnostic and therapeutic strategies for these patients . aim . 
 the aim of this study was to find if these changes influenced survival of individuals with proximal cholangiocarcinoma . 
 material . 
 627 individuals with a diagnosis of cholangiocarcinoma ( not including distal common duct cancer ) during the period from 2000 to 2011 were registered in sweden 's western region . 
 the material was divided into three consecutive time periods . 
 results . the overall survival curves for individuals with cholangiocarcinoma improved over the three time periods ( n = 627 )  ( p = 0.0013 ) . 
 median survival increased from 2.6 months in the first period ( 20002003 ) to 3.6 months in the final four years ( 20082011 ) . 
 patients with perihilar cholangiocarcinoma ( phc ) had longer median survival than those with intrahepatic cholangiocarcinoma ( ihc ) : 6.8 versus 3.2 months ( p = 0.0003 ) . 
 an improvement in the survival curves over time was seen for those with ihc ( p = 0.034 ) but not for patients with phc ( p = 0.38 ) . 
 nine percent of the patients with ihc had potential curative surgical therapy . 
 the three - year survival rate after liver resection for patients with ihc was 35% and 60% after liver transplantation . among patients with phc , 
 15.3% had potential curative bile duct resection with a concomitant liver resection and 6.1% bile duct resection alone . 
 the three - year survival rate for these two groups was 32% and 20% , respectively . 
 conclusion . 
 overall survival for individuals with phc was better than for those with ihc . over time survival in ihc patients improved but not in those with phc . 
1. Introduction
2. Material
3. Results
4. Discussion