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Clinical Study

Chemotherapy 2012;58:134–141 DOI: 10.1159/000337289

Chemotherapy for Inoperable Advanced or Metastatic Cholangiocarcinoma:Retrospective Analysis of 78 Cases in a Single Center over Four Years

Marc Pracht a Guillaume Le Roux c Laurent Sulpice c Habiba Mesbah b

Sylvain Manfredi d Odile Audrain b Karim Boudjema c Jean-Luc Raoul e

Eveline Boucher a

a Medical Oncology Unit and b Medical Information Unit, Comprehensive Cancer Center Eugène Marquis, c Digestive and Hepatobiliary Surgery Division and d Gastroenterology Unit, University Hospital Pontchaillou, Rennes , and e Medical Oncology Unit, Comprehensive Cancer Center Paoli Calmettes, Marseille , France

and 5FU plus cisplatin (n = 9). None of the patients achieved a complete response. The partial response rate was 35.9% (27/78), and the stable disease rate was 26.9% (21/78), giving a disease control rate of 62.8%. At the time of this analysis, with a median follow-up of 18 months, 13 patients were sur-vivors. Median overall survival was 10 months [95% confi-dence interval (CI) 7–12], and median progression-free sur-vival was 7 months (95% CI 6–8). Upon univariate analysis, only the distribution of the disease was significantly linked with prognosis, with a median overall survival of 10 months (95% CI 10–24) for solitary tumors versus 7 months (95% CI 6–11) in the case of infiltrative or multifocal tumors (p = 0.039). Conclusion: The disease control rate, overall survival and progression free-survival in this single-center retrospec-tive study were in agreement with earlier reports. Specific features of this cohort were a large proportion of cholangio-carcinoma with associated cirrhosis (n = 30/78, 38.5%), most-ly intrahepatic (n = 25/30, 83.5%). This confirms the increas-ing incidence of intrahepatic localization and the epidemio-logical link recently reported between intrahepatic biliary tract carcinoma and cirrhosis.

Copyright © 2012 S. Karger AG, Basel

Key Words

Cholangiocarcinoma � Primary hepatic tumors � Palliative chemotherapy � Survival � Cirrhosis

Abstract

Background: Systemic chemotherapy is the treatment of choice for inoperable (advanced or metastatic) cholangio-carcinoma. According to phase II and III trials, regimens com-bining 5-fluorouracil (5FU) or gemcitabine with a platinum salt have provided an overall response rate of 12–50% with a median overall survival of 5–16 months. Methods: This was a retrospective analysis of 78 consecutive cases of inopera-ble cholangiocarcinoma treated by palliative chemotherapy from July 2005 to November 2009 in one center. We firstly aimed to evaluate the impact of palliative chemotherapy in terms of survival and secondly to analyze possible related prognostic factors. Results: This cohort included 25 female and 53 male patients, with a mean age of 60.8 8 11.4 years. Intrahepatic and extrahepatic cholangiocarcinoma were ob-served in 57 and 21 patients, respectively. First-line chemo-therapy regimens were as follows: gemcitabine (n = 7), gem-citabine plus oxaliplatin (with or without cetuximab; n = 62)

Received: August 22, 2011 Accepted after revision: February 16, 2012 Published online: May 10, 2012

Odile Audrain Medical Information, Comprehensive Cancer Center Eugène Marquis CS 44229 FR–35042 Rennes Cedex (France) Tel. +33 2 99 25 32 99, E-Mail o.audrain   @   rennes.unicancer.fr

© 2012 S. Karger AG, Basel0009–3157/12/0582–0134$38.00/0

Accessible online at:www.karger.com/che

Palliative Chemotherapy of Cholangiocarcinoma

Chemotherapy 2012;58:134–141 135

Introduction

Cholangiocarcinoma designates a family of malignant tumors, generally adenocarcinoma, arising from the bili-ary tract epithelium [1, 2] . The anatomic classification distinguishes intrahepatic cholangiocarcinoma from ex-trahepatic cholangiocarcinoma, which includes tumors of the hilus (Klatskin tumors), the main bile duct, the gallbladder and the ampulla of Vater (with biliary differ-entiation) [2] .

Histologically, sclerosing cholangiocarcinomas are nodular tumors (mass-like) usually arising from small intrahepatic bile ducts. Periductal extension is seen in ex-trahepatic cholangiocarcinoma which spreads along the large ducts. Intraductal or papillary cholangiocarcino-mas are rare. Mixed forms with mass-like and periductal components have a poor prognosis [2–4] .

The incidence of cholangiocarcinoma in the USA is currently 1–2 new cases per 100,000 persons [4] , while in France biliary tract tumors account for 3% of gastrointes-tinal cancers and 10–20% of primary hepatic tumors [5] . The anatomic distribution is generally considered to be about 20–25% intrahepatic, 50% hilar and 25% nonhilar extrahepatic [4] , although several studies have reported an increase in the incidence of intrahepatic tumors over the last 3 decades, especially in Western countries, this trend being the opposite for extrahepatic localizations [5–7] .

Classical risk factors for cholangiocarcinoma include chronic cholestatic disease (primary biliary cirrhosis) and chronic inflammation of the biliary tract (calculi, malformations, Caroli disease, hamartoma, chronic par-asitic or bacterial infections), but in most cases, no risk factor can be identified. More recent studies show a sta-tistically significant link between the development ofintrahepatic cholangiocarcinoma and the presence of chronic liver disease related to viral hepatitis B or C, al-coholic hepatitis, dysmetabolic disease (nonalcoholic ste-atohepatitis, obesity/diabetes) or inflammatory bowel disease [7–14] .

Palliative medical treatment is generally proposed for inoperable (advanced-stage and metastatic) cholangiocar-cinoma. It is commonly admitted that chemotherapy can be recommended only if compatible with the patient’s gen-eral health status [15, 16] . Evidence from phase II trials, which were generally nonrandomized, and more specifi-cally from three phase III trials, suggests that outcome is superior with 2-drug regimens combining 5-fluorouracil (5FU) or gemcitabine with platinum (cisplatin or oxalipla-tin). Response rates have been higher (20–50%) than with single-drug regimens using gemcitabine (20–30%) or 5FU

(10–20%) [17–22] . Nevertheless, the beneficial effect of these combination regimens (gemcitabine or 5FU + plati-num salt) remains modest, with a median overall survival of less than 1 year, ranging from 5 to 16 months [17, 19–21] . Considering all stages and localizations, the 5-year sur-vival is only 5%, demonstrating the dramatic prognosis of advanced-stage cholangiocarcinoma and the desperate need for improved treatments for biliary tract tumors [9] .

Patients and Methods

Patients This was a retrospective analysis concerning 78 patients who

were given chemotherapy in our center for inoperable advanced-stage or metastatic cancer of the biliary tract from July 2005 to November 2009. All patients had received at least one chemother-apy cycle. We firstly aimed to evaluate the impact of palliative che-motherapy in terms of response rate, overall survival and progres-sion-free survival and secondly to analyze possible related prog-nostic factors. To that purpose, we recorded the following information: (1) patient-related data, i.e. age and gender; (2) tu-mor-related data, i.e. prior and associated treatment(s), tumor lo-calization, tumor size, proportion of diseased liver (more or less than 50% of liver volume), infiltrative, multifocal or unifocal pre-sentation, nodal involvement and metastatic status; (3) histological data, i.e. degree of differentiation and tumor-free liver condition (cirrhosis or not); (4) biological data, i.e. serum markers ( � -feto-protein, cancer antigen 19-9, carcinoembryonic antigen), total bil-irubin and alkaline phosphatases, and (5) therapeutic data, i.e. treatment(s) delivered, duration of treatment, therapeutic inten-sity including dose reduction (25% or more), type and duration of treatment response, hematological and nonhematological toxici-ties of grade 3 or more according to the Common Terminology Criteria for Adverse Events, version 3.0, presence of delayed treat-ments and reasons, reason(s) for treatment withdrawal and best response. Survival time and cause of death were also recorded. Tu-mor response was assessed within the 3 weeks preceding the ini-tiation of treatment and then every 8–12 weeks on triphasic com-puted tomography scans (without contrast, arterial phase and por-tal phase) using the Response Evaluation Criteria in Solid Tumors, version 1.0. All patients had a World Health Organization Perforce Status of ̂ 2, adequate hematologic and renal functions (neutro-phil count 6 1.5 ! 10 9 /l, platelet count 6 100 ! 10 9 /l, hemoglobin level 6 10 g/dl, creatinine ̂ 120 � M) and were able to comply with the scheduled follow-up and management of toxicity. This retro-spective study was approved by the institutional ethics board.

Statistics The database was closed on 30 November 2009, on which date

all data were censored. SAS software was used to determine over-all survival and progression-free survival using the Kaplan-Meier method, starting with treatment onset and taking death or last follow-up and progression, respectively, as the endpoint. The log-rank test was used to examine intergroup differences. Univariate analysis applied the � 2 test, with p ! 0.05 considered statistically significant.

Pracht et al.   Chemotherapy 2012;58:134–141136

Results

Patients Baseline characteristics of the patients are reported in

table 1 . The population included 53 males and 25 females (ratio 2.12), with a mean age of 60.8 8 11.4 years. The disease was symptomatic at diagnosis in 55% of patients, in whom the predominant inaugural sign was pain (42.3%). Diagnosis was fortuitous in the other patients.

Biopsy of the tumor was available for all patients, and biopsy of the tumor-free liver was also available for 75 patients (95.1%). Tumor biopsies showed evidence of ad-enocarcinoma (cytokeratin 7+ and cytokeratin 20– stain-ing) in favor of cholangiocarcinoma (mucosecretion, strong stroma reaction). The liver was healthy in 45 pa-tients (57.6%). In 30 patients (38.5%), there was evidence of cirrhosis or extensive fibrosis which was subsequent to alcohol intake in 19, iron overload in 6 and chronic viral B or C infection in 3.

Tumor characteristics at baseline are shown in table 2 . Tumors were intrahepatic in 57 patients (73%), including

25 (43.8%) with associated cirrhosis. Twenty-one patients (27%) had extrahepatic cholangiocarcinoma, involving the hilus in 16 (20.6%), the main duct in 3 (3.8%) and the gallbladder in 2 (2.6%). Most had multifocal or infiltra-tive disease (n = 54 patients, 69.2%). Mean tumor size was 7.6 8 3.6 cm. Tumor to liver volume was greater than 50% in 21 patients (26.9%). Spread to regional nodes and extrahepatic metastasis were observed in 36 (46.1%) and 24 patients (30.7%), respectively.

The only elevated tumor marker was cancer antigen 19-9, with a mean level of 10 times the normal value (range 1–12,718). Carcinoembryonic antigen and � -feto-protein were mostly in the normal range. Total bilirubin

Table 1. Baseline patient characteristics

Variable n %

Male/female 53/25 67.9/22.1Mean age 8 SD, years 60.8811.4Range 30–78Survival/deceased

(median follow-up of 18 months) 13/65 17.9/82.1Discovery of tumor

Poor general healthJaundicePainFortuitous/screening

9183318

11.523.142.323.1

Liver histologyHealthyCirrhosis/fibrosisMissing data

4526/4

3

57.638.5

3.8Associated liver disease

NoneHBVHCVAlcoholIron overloadPrimary biliary cirrhosisBiliary cirrhosis secondary topancreatic surgeryInflammatory bowel diseaseMissing data

4521

1961

113

57.62.41.2

24.27.61.2

1.21.23.8

HBV = Hepatitis B virus; HCV = hepatitis C virus.

Table 2. T umor characteristics

Variable

TypeIntrahepatic

ExtrahepaticGallbladderMain bile ductHilus

57 (25 withcirrhosis)21

23 (1 with

cirrhosis)16 (4 withcirrhosis)

73.0% (43.8%)

27.0%2.6%3.8% (33.3%)

20.6% (25.0%)

DiffusionMultifocal/infiltrativeSolitary tumor (nodular)Missing data

5422

2

69.2%28.2%

2.6%Mean tumor size, cm (n = 45/78) 7.683.6Tumor/liver volume >50% 21 26.9%Differentiation

Well-differentiatedIntermediatePoorly differentiatedMissing data

12121044

15.4%15.4%12.8%56.4%

Nodal spread (N+) 36 46.1%Metastasis (M+) 24 30.7%Serum markers1

CEA (n = 52/78)CA19-9 (n = 60/78)AFP (n = 29/78)Total bilirubin (n = 55/78)Alkaline phosphatases (n = 53/78)

110

123

1–1181–12,7181–6001–121–11

Surgery or biliary drainage prior to orconcomitant with CT treatment 27 34.6%

Values represent numbers of patients, except where indicated otherwise. CEA = Carcinoembryonic antigen; CA19-9 = cancer antigen 19-9; AFP = �-fetoprotein.

1 Values represent the mean factor by which each marker was greater than the normal value, with the range in the final column.

Palliative Chemotherapy of Cholangiocarcinoma

Chemotherapy 2012;58:134–141 137

and alkaline phosphatases mostly showed a minor in-crease (2–3 times the normal values).

Treatments, Efficacy and Safety Treatments delivered and responses to treatments are

summarized in table 3 . First-line chemotherapy protocols were gemcitabine-oxaliplatin (GEMOX; gemcitabine 1,000 mg/m 2 on day 1, oxaliplatin 100 mg/m 2 on day 2, every 2 weeks) for 62 patients (79.4%), in combination with cetuximab (500 mg/m 2 on day 1) for 6 of them, mod-ified de Gramont 5FU-cisplatin (5FU bolus 400 mg/m 2 on day 1 then 2,400 mg/m 2 during 46 h, cisplatin 50mg/m 2 on day 1, every 2 weeks) for 9 patients (11.7%) and gemcitabine alone (1,000 mg/m 2 on days 1, 8 and 15, every 4 weeks) for 7 patients (8.9%). Patients received a mean of 4.7 8 3.8 full-dose treatments and 5.2 8 10.2 reduced-dose treatments. The mean duration of first-line treat-ment was 4.3 months (range 0–33 months).

In the intent-to-treat analysis, there were no complete responses, but a partial response was noted in 28 patients (35.9%) and stable disease in 21 (26.9%). The disease con-trol rate was 62.8%. The mean duration of disease control was 6.3 8 7.3 months (range 1–35 months). During first-line chemotherapy, grade 3 or 4 hematological toxicities (Common Terminology Criteria for Adverse Events, ver-sion 3.0) were observed in 30 patients (38.5%) and grade 3 or 4 nonhematological toxicities in 35 (44.9%).

Second-line chemotherapy was delivered to 25 pa-tients (32.0%), using 5FU plus a platinum salt (oxaliplatin or cisplatin) in 14 patients and gemcitabine combined with oxaliplatin or capecitabine in 11, depending on the first-line regimen. A partial response was observed in 5 patients (20%) and stable disease in 9 (36%), giving a dis-ease control rate of 56% (14/25). The 5FU-cisplatin regi-men was the preferred regimen in second-line treatment after GEMOX. Third-line chemotherapy could be deliv-ered to 6 patients (7.7%).

Treatment prior to or concomitant with chemotherapy was delivered to 27 patients (34.6%). For 21 of them, this treatment was a biliary duct drainage, for 18 before the beginning of the chemotherapy and for 3 during the che-motherapy course (progressive disease). These drainages were mostly endoscopic. For the 6 other patients, this treatment was primitive surgery. The indication for pal-liative chemotherapy in this setting was a relapse occur-ring either before the beginning of an adjuvant chemo-therapy or later, after the end of an adjuvant treatment.

Median overall survival was 10 months [95% confi-dence interval (CI) 7–12], and median progression-free survival was 7 months (95% CI 6–8). The 1- and 2-year survival rates were 34.5 and 19%, respectively ( table 4 ).

Upon univariate analysis, overall survival for a soli-tary tumor was 11 months (95% CI 10–24), versus 7 months (95% CI 6–11) for infiltrative or multifocal dis-ease (p = 0.039). There was a trend to better progression-free survival for extrahepatic tumors (8 months, 95% CI 5–7) compared with intrahepatic tumors (5 months, 95% CI 4–13; p = 0.056). Other analyzed variables (age, gender, tumor volume, cirrhotic/healthy liver, type of first- or second-line chemotherapy, tumor differentiation) were not correlated with survival (p 1 0.05).

Discussion

There is a large body of literature on the beneficial ef-fects of chemotherapy for palliative treatment of biliary tract carcinoma [15, 16, 18, 22, 23] . Based on the results of

Table 3. T reatments delivered

Variable

First-line chemotherapy (CT1)GEMOX (+ cetuximab)GemcitabineLV5FU2-CDDP

62 (6)79

79.48.9

11.7Number of CT1 treatments

Full doseReduced dose

4.783.85.2810.2

0–180–81

Duration of CT1, months 4.384.3 0–33Best response to CT1

Partial responseStable diseaseDisease progression

282129

35.9%26.9%37.2%

Duration of best response to CT1, months 6.387.3 1–35Grade 3–4 hematological toxicities (CT1) 30 38.5%Grade 3–4 nonhematological toxicities (CT1) 35 44.9%Second-line chemotherapy (CT2)

5FU 8 platinum salt (cisplatin, oxaliplatin)Gemcitabine 8 oxaliplatin or capecitabine

1411

56%44%

Number of CT2 treatmentsFull doseReduced dose

3.183.14.087.2

0–120–26

Best response to CT2Partial responseStable diseaseDisease progression

59

11

20%36%44%

Third-line chemotherapy (CT3) 6 7.7%

Values represent numbers of patients and percentages or means 8 SD and ranges, as appropriate. LV5FU2-CDDP = Com-bination 5-fluorouracil, folinic acid and cisplatin.

Pracht et al.   Chemotherapy 2012;58:134–141138

a phase III trial (Advanced Biliary Cancer-02) [21] , the ev-idence is now clear that combined regimens using gem-citabine and platinum salts are more beneficial than sin-gle-drug gemcitabine-based regimens. In France, since the publication in 2008 by André et al. [17] of a phase II trial, the GEMOX combination has been used for first-intention treatment of advanced-stage biliary tract carcinoma.

In the present study, we reviewed our data on patients who had received at least one chemotherapy cycle; we identified 78 patients treated over a 4-year period. This population had several specific features: (1) our patients were relatively young (mean age 68 years) and very pre-dominantly male (male to female ratio 2.12) compared with classical data (mean age about 70 years and less marked male predominance) [7] ; (2) disease stage was ad-vanced at diagnosis, i.e. diffuse disease with nodal in-volvement (46.7%) or metastasis (30.7%); (3) intrahepatic forms of cholangiocarcinoma predominated (73%), and (4) the percentage of patients with associated cirrhosis was high (n = 30/78, 38.5%), particularly among those with intrahepatic cholangiocarcinoma (43.8%, 25/57). These data are in line with the trend observed over the last 3 de-cades showing an increase in the incidence of intrahepat-ic cholangiocarcinoma [1, 14] and also the more recently noted trend of a link between hepatic cirrhosis and biliary tract carcinoma, particularly intrahepatic cholangiocar-cinoma [8, 11, 12] . Indeed, in our cohort, 25 of the 30 (83.5%) cholangiocarcinomas arising on cirrhotic liver were intrahepatic. These specific features could probably be explained by the fact that we perform a liver biopsy sys-tematically for all liver tumors on a cirrhotic liver, even if an hepatocarcinoma is suspected on the basis of the Bar-celona Liver Clinic criteria [24] . This high prevalence of intrahepatic cholangiocarcinoma with cirrhosis is an ar-gument in favor of a systematic biopsy for all cases of primitive liver tumor with cirrhosis, even if the pattern of the contrast uptake is typical of hepatocarcinoma [25] (7.1% of a cohort of 28 patients with intrahepatic cholan-giocarcinoma treated in our center had a contrast uptake typical of hepatocarcinoma; unpublished data).

The first- and second-line regimens were either a com-bination of gemcitabine and a platinum salt (oxaliplatin) or 5FU and a platinum salt (cisplatin). These drugs have been widely used in published phase II and III trials [17, 18, 21, 23, 26] . Response rates (objective response 36%, disease control 62%) in our series were similar to those in earlier reports [17, 18, 21–23] , although more than half of the patients needed a dose reduction of 25% or more. The GEMOX combination was preferred as first-line treat-ment (n = 62, 79.4%) in our center because it appears to

be less toxic in the case of liver dysfunction than the gem-citabine-cisplatin regimen [21] , because it avoids hyper-hydration and the risk of renal failure observed with cis-platin, as reported by Hollebecque et al. [26] , and because it shows benefits even if a patient’s performance status is poor [27] . Cetuximab was used concomitantly with the GEMOX combination for 6 patients on first-line treat-ment. Those patients were all treated according to the BINGO trial, an international randomized phase II trial which aimed to compare the GEMOX combination alone versus this regimen associated with cetuximab [28] ac-cording to overexpression of epidermal growth factor re-ceptor (EGFR) in more than 67% of biliary tract cancers [29] . The 5FU-cisplatin regimen was preferred as second-line treatment according to the efficacy of this combina-

Table 4. S urvival

Variable n Median survival months

p

Overall survivalProgression-free survival

78 10 (7 –12)7 (6–8)

Overall survival by genderMaleFemale

5325

9.5 (6.0–11.0)11 (6.0–12.0)

0.344

Overall survival by first-line chemotherapyGEMOX + GemzarLV5FU2-CDDP

699

9.0 (6.0–11.0)16.0 (8.0–27.0)

0.359

Overall survival by second-line chemotherapyGemcitabine-based

LV5FU2-based 1411

21.5 (8.0–37.0)12.0 (9.0–18.0)

0.276

Overall survival by liver histologyHealthy/fibrosisCirrhosis

5226

10.0 (7.0–12.0)9.0 (5.0–14.0)

0.430

Overall survival by tumor volume>50%<50%

2157

10.0 (6.0–14.0)9.0 (7.0–12.0)

0.256

Overall survival by type of CCKExtrahepaticIntrahepatic

5721

9.5 (6.0–29.0)9.0 (7.0–11.0)

0.453

Overall survival by patient age≤50 years>50 to ≤65 years>65 years

123630

14.0 (7.0–15.0)7.0 (6.0–10.0)9.5 (5.0–14.0)

0.583

Overall survival by tumor distributionInfiltrative/multifocalSolitary

5422

7.0 (6.0–11.0)11.0 (10.0–24.0)

0.039*

Progression-free survival by tumor localizationIntrahepaticExtrahepatic

5721

5.0 (5.0–7.0)8.0 (4.0–13.0)

0.056

Values in parentheses represent 95% CIs. LV5FU2 = Fluoro-uracil and leucovorin; CDDP = cisplatin; CCK = cholangiocarci-noma.

Palliative Chemotherapy of Cholangiocarcinoma

Chemotherapy 2012;58:134–141 139

tion assessed in numerous phase II trials, as reported by Ducreux et al. [23] , who showed (in chemo-naive pa-tients) an overall response rate of 19% and 44% of patients with stable disease.

Our patients showed a high rate of grade 3–4 toxicities (38.5 and 44.9% for hematological and nonhematological events, respectively), but this was not very different from earlier reports [17, 18, 21] . Comparing the new first-line standard gemcitabine-cisplatin regimen reported by Val-le et al. [21] , we had more grade 3–4 hematological tox-icities (38.5 vs. 32.3%) but fewer grade 3–4 nonhemato-logical toxicities (44.9 vs. 54.5%).

Median overall and progression-free survival was 10 and 7 months, respectively, in line with data in the litera-ture on advanced-stage or metastatic cholangiocarcino-ma. Verslype et al. [22] , who summarized 120 studies, reported on nearly 3,000 patients and found that the over-all survival varied from 5 to 16 months with chemother-apy regimens analogous to our treatments. Valle et al. [21] reported 11.7 and 8.1 months for overall and progression-free survival, respectively, with the gemcitabine-cisplatin combination, a new standard in inoperable biliary tract cancers.

We also looked for prognostic factors. On univariate analysis, the only significant variable was disease distri-bution (p = 0.035); we found median overall survival of 7.0 months for infiltrative or multifocal tumors versus 11.0 months for solitary tumors. This could be explained by considering solitary tumors as an early form of tumor and infiltrative or multifocal tumors as more advanced tumors. Other variables reported in earlier studies to be correlated with poor prognosis, such as tumor size, cell differentiation, nodal involvement or metastatic spread, were not linked with prognosis in this study [9, 12] . Tu-mor localization (intra- versus extrahepatic disease) did not affect overall survival (p = 0.43) but did appear to in-fluence progression-free survival, particularly in the ex-trahepatic forms, where the difference of 8.0 versus 5.0 months almost reached significance (p = 0.056). This finding disagrees with previous data, where the progno-sis was more favorable in distal tumors compared with proximal tumors, but this could be explained by the fact that intrahepatic tumors are often diagnosed at a more advanced stage than extrahepatic tumors because of mild or nonspecific symptoms. In contrast, extrahepatic tu-mors are often symptomatic at an early stage, mostly with cholestasis and jaundice [1, 2] . The presence of cirrhosis was not found to be linked with prognosis, although this factor has been described as having a negative impact on intrahepatic cholangiocarcinoma [1] .

In the future, indications for liver transplantation will undoubtedly include an increasing number of patients with inoperable hilar cholangiocarcinoma. A multidisci-plinary management scheme combining laparoscopy and staging will be proposed, confirming the indication for surgery followed by concomitant neoadjuvant radiation-chemotherapy as in the strategy proposed by the Mayo Clinic team for a series of patients with initially inoperable hilar cholangiocarcinoma who achieved an overall 5-year survival of 82% [30] . The role of intra-arterial treatments such as transcatheter chemoembolization protocols [31, 32] or radioembolization [33, 34] needs to be explored. We have therefore initiated a phase I study at our center to in-vestigate the feasibility of radioembolization using yttri-um-90 in inoperable intrahepatic cholangiocarcinoma. Also, the role of biotherapies remains to be defined, since recent phase II trials have provided interesting data [28, 35–42] . For example, EGFR tyrosine kinase inhibition with cetuximab led to an objective response rate of 63% in a phase II study that enrolled 30 patients [43] .

The results of this study are in accordance with previ-ously published data in terms of survival and tolerance. The efficacy and the acceptable tolerance profile of the GEMOX regimen in comparison to the new standard gemcitabine-cisplatin regimen [21] is confirmed, even if the rate of grade 3–4 toxicities observed in our cohort ap-peared to be higher than those of previous studies [26] . The GEMOX regimen appears to be an interesting option in the case of contraindication to cisplatin. The opti-mized gemcitabine-based combination remains to be ex-plored in order to discover the best partner of gemcitabi-ne (oxaliplatin?, irinotecan? [44] , other?) and the best gemcitabine perfusion duration [26] . Together with re-cent epidemiological data and recent developments in targeted molecular therapeutics, this study shows the need to revisit the therapeutic options proposed for inop-erable cholangiocarcinoma, examined not only as a unique anatomic and clinical entity but also as a hetero-geneous family of tumors with different anatomic (intra- vs. extrahepatic cholangiocarcinoma), biological (e.g. overexpression of EGFR or met) bioepidemiological (aris-ing on liver cirrhosis or not) and prognostic (infiltrative/multifocal tumors vs. solitary tumors) patterns and as a consequence different therapeutic solutions. It also illus-trates the epidemiological link between cirrhosis and in-trahepatic cholangiocarcinoma and the absolute need to perform a tumor biopsy of all primitive liver tumors even if they arise on cirrhotic liver and if they correspond to the definition of an hepatocellular carcinoma according to the Barcelona Liver Clinic criteria [24] .

Pracht et al.   Chemotherapy 2012;58:134–141140

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