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REVIEW ARTICLE GOLDARACENA, GORGEN, AND SAPISOCHIN Current Status of Transplantation for Cholangiocarcinoma

Nicolas Goldaracena, Andre Gorgen, and Gonzalo Sapisochin

Multi-Organ Transplant, Division of General , Department of Surgery, University Health Network, University of Toronto, Toronto, Ontario, Canada

Cholangiocarcinoma (CCA) is the second most common liver , and it is associated with a poor prognosis. CCA can be divided into intrahepatic, hilar, and distal. Despite the subtype, the median survival is 12-24 months without treatment. (LT) is recognized worldwide as a curative option for hepatocellular . On the other hand, the initial results for LT for CCA were very poor mainly due to a lack of adequate patient selection. In the last 2 decades, improvements have been made in the management of unresectable hilar CCA, and the results of LT after neoadjuvant chemoradiation have been shown to be promising. This has prompted a consideration of hilar CCA as an indication for LT in some centers. Furthermore, some recent research has shown promising results after LT for patients with early stages of intrahepatic CCA. A better understanding of the best tools to prognosticate the outcomes of LT for CCA is still needed. Here, we aimed to review the role of LT for the treatment of patients with perihilar and intrahepatic CCA. Also, we will discuss the most recent advances in the field and the future direction of the management of this disease in an era of transplantation . Liver Transplantation 24 294–303 2018 AASLD. Received July 18, 2017; accepted October 1, 2017.

Since the establishment of liver transplantation (LT) stage , its indication to treat tumors con- as the best treatment option for patients with end- fined to the liver has grown substantially.(1,2) (HCC) is the most fre- quent , and LT is the best treatment option in selected patients because it removes both the cancer Abbreviations: BILCAP, Adjuvant for can- cer; CA19-9, carbohydrate antigen 19-9; CCA, cholangiocarcinoma; (with the widest possible margins) and the underlying (3-5) ELITA, European Liver and Intestine Transplant Association; liver disease. However, as the understanding of HCC, hepatocellular carcinoma; hCCA, hilar cholangiocarcinoma; tumor biology and multidisciplinary oncological treat- HCC-CCA, mixed hepato-cholangiocarcinoma; HCV, virus; iCCA, intrahepatic cholangiocarcinoma; iCCA1HCC, concom- ments improve, the indication of LT to treat other itant intrahepatic cholangiocarcinoma and hepatocellular carcinoma in unresectable tumors confined to the liver (ie, cholangio- the explant; iCCA-HCC, mixed hepatocellular cholangiocarcinoma; carcinoma [CCA], metastatic neuroendocrine tumors) LT, liver transplantation; MELD, Model for End-Stage Liver Dis- (6-10) ease; OS, overall survival; PSC, primary sclerosing cholangitis; has expanded. LT has therefore gained momen- TRANSPHILL, Liver Resection Versus Radio-- tum as a treatment for patients with cancer. Because of Transplantation for Hilar Cholangiocarcinoma; UCLA, University organ shortages, the main concern when offering a of California, Los Angeles; UNOS, United Network for Organ Shar- ing; VEGF, vascular endothelial growth factor. transplant to these patients is the impact on other patients on the waiting list.(11) With recent advances in Address reprint requests to Gonzalo Sapisochin, M.D., Multi- Organ Transplant, Division of General Surgery, Department of the treatment of hepatitis C virus (HCV), there seems Surgery, University Health Network, University of Toronto, 585 to be a decrease in the number of patients in need of a University Avenue, 11PMB184, Toronto, M5G 2N2, ON 1 1 LT because of HCV, resulting in a potential increase in Canada. Telephone: 1-416-340-5230; FAX: 1-416-340- (12) 5242; Email: [email protected] the organ pool. However, in some regions (such as North America), the increase in the of Copyright VC 2017 by the American Association for the Study of Liver Diseases. patients with with nonalcoholic steatohepatitis may result in no change in the organ pool.(13) Further- View this article online at wileyonlinelibrary.com. more, living donor LT may be another excellent option DOI 10.1002/lt.24955 to provide access to LT to those patients with cancer. Potential conflict of interest: Nothing to report. In this regard, the use of LT for the treatment of CCA has become a focus of interest around the 294 | REVIEW ARTICLE LIVER TRANSPLANTATION, Vol. 24, No. 2, 2018 GOLDARACENA, GORGEN, AND SAPISOCHIN world.(14-16) This type of tumor arising from the bile  duct is very aggressive, and its prognosis is mainly dependent on its location along the biliary tree and its chance of being completely resected with nega- tive margins.(17) The role of LT to treat patients with CCA has been explored in some centers for those patients presenting with an unresectable tumor confined to the hepatic hilum (ie, perihilar CCA/)(18-21) and more recently for patients with “very early” (single tumor 2 cm) intrahepatic cholangiocarcinomas (iCCAs).(8) So far, only these 2 locations of CCA are the ones where patients can potentially benefit from LT. Here we aimed to review the role of LT for the treat- ment of patients with perihilar CCA and iCCA. Also, FIG. 1. CCA locations. (A) Intrahepatic (iCCA). (B) Hilar we will discuss the most recent advances in the field and (hCCA). (C) Distal. the future direction of the management of this disease. 

CCA Classification approach was first attempted in the late 1990s and failed to show any promising results because the 5-year CCA is a malignant tumor of the biliary system that survival rate was reported to be approximately 18% stands as the second most common primary liver can- (Table 1).(33) However, this was a retrospective analysis (22) cer after HCC. More than 95% of the time, it con- of a small series where patients did not undergo any sists of an that depending on its type of protocolized neoadjuvant or adjuvant locations on the biliary tree, can be classified as iCCA treatment. or extrahepatic CCA.(23) In turn, the extrahepatic CCA can be subclassified into hilar (Klatskin tumor) or distal CCA (mid third and lower third THE “MAYO CLINIC” PROTOCOL (24) lesions; Fig. 1). In the year 2000, the Mayo Clinic group reported their preliminary experience with a protocol of neoadjuvant therapy followed by LT.(41) The neoadjuvant protocol Hilar CCA consisted of the combination of external beam and The incidence of hilar cholangiocarcinoma (hCCA; transcatheter radiation with intravenous 5-fluorouracil. Klatskin tumor) is approximately 7000 cases per year A total of 11 out of the initial 19 patients who were in North America, representing around two-thirds of found to be eligible for the study completed the proto- all cases of CCA.(25) Unfortunately, the overall survival col and underwent LT, showing encouraging (OS) for patients suffering from an hCCA is detri- results.(18) In 2004, the previous series was updated mental, ranging between 12 and 24 months.(26) and an 82% 5-year survival rate was reported for 24 It is well-known that the most important prognostic patients undergoing the “Mayo protocol.”(35,42) In factor is to achieve a complete resection with negative 2005, the same group published their experience of oncological margins, but unfortunately, this is only neoadjuvant chemoradiation followed by LT. In this achieved in 25%-40% of the patients.(27-29) The cur- study, they compared those patients undergoing a rent 5-year survival rate after surgery, even in select resection approach alone against those who underwent patients, rarely exceeds 40%.(30-32) From this low sur- neoadjuvant therapy in addition to LT.(10) The LT vival after resection derives the concept of treating this group with neoadjuvant chemoradiation (38 patients) patient population with a LT. This concept allows a achieved better OS at 1 year (92% versus 82%), 3 years complete resection with good negative margins in (82% versus 48%), and 5 years (82% versus 21%) when patients who have tumors that are locally unresectable compared with the resection group (26 patients). Also, due to the invasion of major vessels, bilobar tumor the LT group experienced lower posttransplant recur- involvement, or insufficient hepatic reserve. This rence (13% versus 27%).(10) Importantly, all the

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TABLE 1. Patient Survival and Disease-Free Survival of Patients Transplanted With hCCA Neoadjuvant Number of Chemotherapy Total Patients 1- With or Number Who Year 5-Year Without of Underwent OS 3-Year OS Radiation References Center Study Type Patients LT (%) (%) OS (%) (%) Therapy Comments

Iwatsuki et al.(34) University of Retrospective 72 38 (53) 60 32 25 61% 37 (51%) disease free (1998) Pittsburgh comparing of patients at 3 years resection to LT Sudan et al.(18) University of Retrospective 17 11 (65) — — — Yes Median survival (2002) Nebraska 11 months Rea et al.(10) Mayo Clinic Retrospective 71 38 (54) 79 61 58 Yes — (2005) comparing resection to LT Heimbach et al.(35) Mayo Clinic Retrospective 106 65 (61) 91 — 76 Yes Median time (2004) to recurrence 22 months Rosen et al.(36) Mayo Clinic Retrospective 148 90 (61) 82 63 55 Yes — (2008) Kaiser et al.(37) Germany Retrospective 47 47 (100) 61 31 22 No — (2008) Multicenter Darwish et al.(38) United States Retrospective 287 216 (75) — 68 (2 years) 53 Yes 65% 5-year (2012) Multicenter disease-free survival Welling et al.(20) University of Retrospective 12 6 (50) 83 — — Yes — (2014) Michigan Marchan et al.(39) Emory Retrospective 10 8 (80) 80 67% (2 years) — Yes — (2016) Mantel et al.(40) ELITA database Retrospective 173 28 (16)* — — 59* Yes This article compared (2016) Multicenter 77 (45)† 21† patient selection within “Mayo protocol” to beyond that protocol.

*Within Mayo protocol. †Beyond Mayo protocol. patients who underwent LT were deemed to be .(44) In 2012, a multicenter study of 12 US centers unresectable. including patients with hCCA who were treated with On the basis of their experience, the Mayo clinic neoadjuvant therapy followed up by LT reported a group described the risk factors for dropout of the LT 65% 5-year recurrence-free survival and an 11.5% waiting list due to disease progression.(43) These were dropout rate after 3.5 months of therapy.(38) This found to be as follows: carbohydrate antigen 19-9 study validated the hypothesis that it is appropriate for (CA19-9)  500 U/mL, a mass  3 cm, malignant selected patients with hCCA to receive the proposed brushing or , and a Model for End-Stage Liver MELD exception points and therefore have a faster Disease (MELD) score  20. Likewise, factors found access to transplant. to be predictors of recurrence after LT were as follows: an elevated CA19-9, the presence of an encased portal LIVER RESECTION VERSUS LT vein, and the evidence of a residual tumor on FOR hCCA explant.(43) Since the establishment of the Mayo protocol, sev- Other groups have also assessed the role of resection eral other groups reported their experience with the versus transplantation for hCCA.(34,45) In 2011, Hong same or similar protocols. In 2006, based on the expe- et al. found in a 24-year experience that surgical resec- riences of the Mayo Clinic and the University of tion was a predictor of worse survival outcome when Nebraska, Gores et al. proposed that patients with compared with transplantation.(9,46) However, data of unresectable hilar CCA arising in the setting of pri- this study might be misleading because it included mary sclerosing cholangitis (PSC) should receive a iCCA and hCCA as well as patients with and without MELD score exception points for better allocation of liver cirrhosis. Also, numbers in the hCCA group were

296 | REVIEW ARTICLE LIVER TRANSPLANTATION, Vol. 24, No. 2, 2018 GOLDARACENA, GORGEN, AND SAPISOCHIN low (13 patients in the LT group versus 7 in the resec- (HCC-CCA) in the explant pathology.(62) Moreover, tion group). It is important to note that this was not a a German series of 10 patients who underwent LT randomized controlled trial and therefore patients in with a preoperative diagnosis of iCCA demonstrated a the LT group were unresectable and likely had more 5-year survival of 33%.(63) The results of these studies advanced disease. Therefore, there is a need for ran- showed a poor and likely unacceptable 5-year survival domized controlled trials that can better compare the for LT in the current era of organ shortage. outcome of resectable (with similar disease stage) In 2011, the University of California, Los Angeles hCCA between LT and resection. (UCLA) group published a series comparing LT and To date, until randomized controlled trials show resection using neoadjuvant chemotherapy associating otherwise, LT after aggressive neoadjuvant therapy radiotherapy in some patients.(9) In this 24-year expe- including external beam and transluminal radiation, as rience with a total of 132 CCAs, they performed LT well as systemic chemotherapy, seems like an adequate in 38 patients (25 of those were iCCA). The 5-year treatment for both unresectable hCCA, as well as survival after LT was 32%. Unfortunately, the OS was hCCA arising in the setting of PSC.(25) However, calculated for both iCCA and hCCA, and the data on these transplants should be conducted in large aca- each type of cancer were not available.(9) In a subse- demic centers with both a transplant and surgical quent publication, the same group reported a multivar- oncology expertise. iate analysis identifying predictors of tumor recurrence. Multifocal tumors, perineural invasion, infiltrative sub- type, and lack of neoadjuvant and adjuvant therapies Intrahepatic CCA were found to be associated with a poor prognosis.(46) Intrahepatic cholangiocarcinoma (iCCA) corresponds On the other hand, tumor size failed to be found as a to 5%-10% of all CCAs.(47) The incidence of iCCA is predictor of tumor recurrence. However, this study was 0.6-1.0/100,000 new cases per year in the United a retrospective analysis where only 13 patients had States and its incidence is increasing.(48) This increase received neoadjuvant treatment with chemotherapy plus , making the results difficult to seems to be greater in groups with risk factors for (46) HCC as cirrhosis, chronic viral hepatitis, and nonalco- interpret. holic steatohepatitis.(49,50) Several retrospective series were conducted to review the outcomes after LT for patients with incidental LT FOR iCCA iCCA. A Canadian multicenter study found 10 patients who underwent LT for other indications and Currently, iCCA is a contraindication for LT in most were found to have CCA features in the explant. The LT centers around the world.(15,51) This is probably 3-year OS in this series was 30%.(60) Also, Facciuto related to the very poor outcomes in the early experi- et al. studied the explanted specimens and found 32 ence of LT for this disease.(52-54) The results of initial patients with intrahepatic biliary differentiation and experiences were difficult to interpret as most series cirrhosis. Interestingly, they conducted a matched included patients with both iCCA and hCCA as well analysis of this CCA population with HCC control as patients with and without liver cirrhosis. It is well- patients. When patients were stratified by Milan crite- known that iCCA and hCCA are different entities ria, those within Milan had similar OS between groups that may present with different outcomes, and we also (78% for CCA versus 79% for only HCC; P 5 0.61). know from the HCC literature that tumors arising In the same way, patients outside Milan criteria had a from healthy versus cirrhotic livers may also present lower 5-year OS compared with those within Milan with different outcomes.(55) criteria, but it was not different between CCA and In 2004, Robles et al. published a retrospective anal- HCC groups (48% for CCA versus 53% for only ysis of a multicenter experience with 23 patients who HCC; P 5 0.12).(64) In 2016, Vilchez et al. conducted underwent LT for iCCA (Table 2).(56) Notably, in 10 a retrospective analysis using the United Network for of their patients, the tumor was diagnosed incidentally Organ Sharing (UNOS) database. They analyzed 4049 after LT. The overall 5-year survival was reported to patients, of whom 440 had an iCCA diagnosis. The 5- be 42%. Likewise, in 2011, Sapisochin et al. reported a year OS for patients with iCCA in the explant was 47% 5-year survival for patients who underwent trans- 47%, but no subgroup analysis according to the size of plantation with preoperative diagnosis of HCC but the tumor was conducted. A population-based study had either iCCA or mixed hepato-cholangiocarcinoma from the United States found a worse OS when

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TABLE 2. Patient Survival and Disease-Free Survival From Studies Including Patients Transplanted for Both iCCA and hCCA Neoadjuvant Chemotherapy With or Total Without Number 1-Year 3-Year 5-Year Radiation References Center Study Type of Patients OS (%) OS (%) OS (%) Therapy Comments

O’Grady et al.(52) King’s College Retrospective 13 hCCA 38 10 10 No — (1988) 13 iCCA Yokoyama et al.(57) University of Retrospective 19 hCCA 24 24 0 No — (1990) Pittsburgh 2 iCCA 50 0 — Meyer et al.(58) Cincinnati Retrospective 207 72 48 23 No 10% had . (2000) Transplant Multicenter 84% disease-free survival Tumor Registry in 25 months Shimoda et al.(59) UCLA Retrospective 9 hCCA 86 31 — 4 patients 8 patients with iCCA-HCC (2001) 16 iCCA 62 39 5-year disease-free survival 57% for patients with hCCA and 35% for those with iCCA Robles et al.(56) Spain Retrospective 36 hCCA 82 53 30 No 2-year disease-free survival (2004) Multicenter 23 iCCA 77 65 42 52% for hCCA and 35% for iCCA Ghali et al.(60) Canada Retrospective 10 — 30 — No 1 patient had iCCA-HCC (2005) Multicenter Hong et al.(9) UCLA Retrospective 132 — 38 32 Yes LT for 25 iCCA (2011) comparing LT for 13 hCCA resection 3 LT 29% patients underwent LT Panjala et al.(61) Mayo Retrospective 22 90 63 — Yes — (2012) Duignan et al.(19) Dublin Retrospective 27 73 73 61 (4 years) Yes 74% patients underwent LT. (2014) Median time to recurrence 37 months compared with HCC (hazard ratio, 1.1; 95% confi- series, patients with “very early” iCCA (2 cm) did dence interval, 1.1-1.2) for patients with iCCA. not present tumor recurrence, and their longterm sur- Unfortunately, only 2.2% of iCCA patients were vival at 5 years was 73%. Instead, patients with tumors treated with LT, so it is difficult to extrapolate these >2 cm or with multifocal disease did much worse with worse results to the transplant field.(65) a 40% 5-year survival. These promising results sug- gested that patients with “very early” iCCA should NEW INSIGHTS maybe be considered as a formal indication for LT. However, the number of patients on that study was In the last few years, efforts have been made to analyze limited, and their conclusions needed validation.(69) homogeneous cohorts (Table 3). A multicenter study Hence, in 2016, Sapisochin et al. conducted a multi- of LT centers in Spain published in 2014 their experi- center international study with the aim of validating ence with LT for patients found to have iCCA and the previous findings. A total of 48 (59%) out of 81 mixed HCC-CCA in the explant pathology.(67) These patients with iCCA features at the explant pathology results were compared with a control group of patients were found have only iCCA. Among them, 31% (15 transplanted for HCC. The OS was 50% at 5 years for patients) constituted the “very early” iCCA group. those patients with exclusively iCCA. Interestingly, This group of patients was then compared with 33 this large series found tumor size (>2 cm) and multi- (69%) patients with “advanced” disease (single tumor nodularity as risk factors for tumor recurrence and >2 cm or multifocal disease). The 5-year actuarial sur- worse outcomes when compared with similar HCCs. vival rates were 65% in the “very early” iCCA group On the other hand, patients with small single tumors versus 45% in the advanced group. The cumulative risk had similar results to those of patients with HCC. Fol- of recurrence at 5 years was 18% versus 61%, respec- lowing that study, the same Spanish consortium tively. These data support the previous findings that reported a series of 29 patients who were found to have “very early” iCCA (2 cm) should formally be consid- exclusively iCCA in their explant pathology. In this ered as candidates for LT.(8) Notably, all of these

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TABLE 3. Survival and Disease-Free Survival of Patients Transplanted With iCCA Total 5-Year Number of 1-Year 3-Year 5-Year Disease-Free References Center Study Type Patients OS (%) OS (%) OS (%) Survival (%)

Sotiropoulos et al.(63) Mainz Retrospective 10 70 50 33 — (2008) Vallin et al.(66) France Retrospective 10 80 60 24 — (2013) Multicenter Sapisochin et al.(67) Spain Retrospective 27 78 66 51 36 (2014) Multicenter Facciuto et al.(64) Mont Sinai Retrospective 7 iCCA 71 — 57 44 (2015) Medical Center 9 iCCA1HCC 16 iCCA-HCC Vilchez et al.(68) UNOS database Retrospective 440 79 58 47 — (2016) Multicenter Sapisochin et al.(8) Canada Retrospective 15 iCCA single  2cm 93 84 65 18 (2016) Multicenter 33 iCCA multiple or > 2cm 79 50 45 61

NOTE: All articles included patients without neoadjuvant chemoradiation. studies were conducted in patients who were either Asian centers, arterial resection and reconstruction in transplanted with the suspicion of HCC and were some cases of bilateral arterial involvement may be found to have iCCA in the explant (misdiagnosis) or considered as an alternative to LT, and this treatment underwent transplantation due to decompensated cir- strategy should be further investigated in the rhosis and were incidentally diagnosed with an iCCA. future.(71) Certainly, this is the main caveat of these encourag- For iCCA, the encouraging results from retrospec- ing results, and the outcomes of patients with known tive studies opens a new door when considering LT iCCA before transplant is still to be investigated and for patients with “very early” iCCA. Indeed, given will need to be evaluated prospectively. Also, it is that the radiological features of iCCA (especially in important to mention that the first treatment option cirrhosis) have yet to be established, a tumor biopsy in for patients with iCCA should be liver resection if pos- patients considered for LT with a nodule without typ- sible.(51) As with HCC, LT for early stages of iCCA ical HCC features will need to be performed. In this (72) should be reserved for patients where liver resection is regard, a prospective trial (NCT02878473) aiming not an option (ie, portal hypertension). All patients to transplant patients with “very early” iCCA will be evaluated in previous studies analyzing LT for “very recruiting in the near future to prospectively confirm early” iCCA only included patients who were not can- that these patients can benefit from this treatment didates for liver resection.(8,56,69) and to open a new indication for LT. The main caveat for such a protocol will be the difficulty of precisely diagnosing these tumors in patients where a tumor Future Perspectives biopsy cannot be performed. One of the unanswered questions is if as with hCCA and the Mayo protocol, Prospective trials should allow the identification of these patients will require neoadjuvant chemoradia- hCCA patients who would benefit from either LT or tion. Also, it is unclear if by using chemoradiation surgical resection. To answer this question, there is protocols LT could be offered to patients with a currently 1 prospective, randomized, multicenter >2 cm iCCA. These unanswered questions will need study (Liver Resection Versus Radio-Chemotherapy- to be studied in the near future to better understand Transplantation for Hilar Cholangiocarcinoma and improve the management of patients with cirrho- [TRANSPHILL] study NCT02232932) comparing sis diagnosed with CCA. LT preceded by neoadjuvant radiochemotherapy ver- To date, available data on systemic therapy for sus standard of care liver and bile duct resection. The CCA have demonstrated limited therapeutic efficacy. primary outcome for this study is OS.(70) Hopefully Data from the Adjuvant capecitabine for biliary tract in the future, we will have some insights if LT is a cancer (BILCAP) randomized trial, presented recently better treatment than LR in resectable patients. On at the American Society of Clinical Oncology, showed the other hand, due to encouraging results from some encouraging results of capecitabine as adjuvant therapy

REVIEW ARTICLE | 299 GOLDARACENA, GORGEN, AND SAPISOCHIN LIVER TRANSPLANTATION, February 2018 after resection of biliary . The OS in the capeci- these genomic classes will predict the outcomes of tabine group was 15 months longer compared with iCCA after LT. observation.(73) The applicability of this in the trans- plant setting is unknown and probably difficult to extrapolate, but it should be explored in the future Conclusion under research protocols aiming to increase the survival The era of “Transplant Oncology”(6) is happening now of transplant recipients with CCA. and is likely to advance further in the next decade. Certainly, target therapies in the context of LT for Selected patients with CCA can benefit from a radical CCA will also need to be better assessed. Genetic treatment such as LT to achieve a cure. However, fur- aberrations such as KRAS mutation, fibroblast growth ther research to better define inclusion criteria and factor receptor 2 gene fusions, and somatic mutations neoadjuvant and adjuvant treatments is needed. The in IDH1/2 are common in CAA and potentially can- (74,75) hCCA should be an indication for LT under a strict didates to targeted therapies. In the same way, neoadjuvant chemoradiation protocol, and patients vascular endothelial growth factor (VEGF) expression (76) must be carefully followed while listed to identify is reported in up to 40% of CCA. However, the tumor progression and avoid posttransplant recurrence. results with VEGF blockers in CCA are disappoint- Posttransplant analysis suggests patients with cirrhosis ing. Although sorafenib failed to prove beneficial in with very early iCCA may achieve excellent OS. In phase 2 studies, bevacizumab associated with gemcita- this regard, it is possible that patients diagnosed preop- bine and oxaliplatin has shown a median progression- eratively of a “very early” iCCA may achieve the same free survival of 7 months in a single-arm phase 2 (77,78) results after LT. Further prospective research is needed study. Immune checkpoints have also been to confirm these encouraging results. proven to be dysregulated in CCA resected tissue.(79) However, the clinical experience in immunotherapy for CCA is incipient with 2 phase 2 trials that are ongoing REFERENCES (80,81) (NCT02628067 and NCT02268825). The 1) Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, results of these trials will hopefully provide a better Bozzetti F, et al. Liver transplantation for the treatment of small understanding of the role of these new therapies in hepatocellular in patients with cirrhosis. N Engl J Med 1996;334:693-699. patients with CCA. 2) Eghtesad B, Aucejo F. 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