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1 CLINICAL STUDY Metaanalysis of Survival, Complications, and Imaging Response following Chemotherapy-based Transarterial Therapy in Patients with Unresectable Intrahepatic Cholangiocarcinoma Charles E. Ray, Jr, MD, PhD, Anthony Edwards, MD, Mitchell T. Smith, MD, MS, Stephen Leong, MD, Kimi Kondo, DO, Matthew Gipson, MD, Paul J. Rochon, MD, Rajan Gupta, MD, Wells Messersmith, MD, Tom Purcell, MD, MBA, and Janette Durham, MD, MBA ABSTRACT Purpose: Unresectable intrahepatic cholangiocarcinoma represents a devastating illness with poor outcomes when treated with standard systemic therapies. Several smaller nonrandomized outcomes studies have been reported for such patients undergoing transarterial therapies. A metaanalysis was performed to assess primary clinical and imaging outcomes, as well as complication rates, following transarterial interventions in this patient population. Materials and Methods: By using standard search techniques and metaanalysis methodology, published reports (published in 2012 and before) evaluating survival, complications, and imaging response following transarterial treatments for patients with unresectable intrahepatic cholangiocarcinoma were identified and evaluated. Results: A total of 16 articles (N ¼ 542 subjects) met the inclusion criteria and are included. Overall survival times were 15.7 months 5.8 and 13.4 months 6.7 from the time of diagnosis and time of first treatment, respectively. The overall weighted 1-year survival rate was 58.0% More than three fourths of all subjects (76.8%) exhibited a response or stable disease on postprocedure imaging; 18.9% of all subjects experienced severe toxicities (National Cancer Institute/World Health Organization grade Z 3), and most experienced some form of postembolization syndrome. Overall 30-day mortality rate was 0.7%. Conclusions: As demonstrated by this metaanalysis, transarterial chemotherapy-based treatments for cholangiocarcinoma appears to confer a survival benefit of 2 7 months compared with systemic therapies, demonstrate a favorable response by imaging criteria, and have an acceptable postprocedural complication profile. Such therapies should be strongly considered in the treatment of patients with this devastating illness. ABBREVIATIONS HCC = hepatocellular carcinoma, RECIST = Response Evaluation Criteria In Solid Tumors From the Departments of Radiology (C.E.R., A.E., M.T.S., K.K., M.G., P.J.R., R.G., J.D.) and Medical Oncology (S.L., W.M., T.P.), University of Colorado School of Medicine, Anschutz Medical Campus, Mail Stop C276, Leprino Office Building, E. 17th Ave., no. 526, Aurora, CO Received February 1, 2013; final revision received and accepted March 15, Address correspondence to C.E.R.; charles.ray@ucdenver.edu From the SIR 2012 Annual Meeting. C.E.R. is a paid consultant for Nordion (Ottawa, Ontario, Canada). None of the other authors have identified a conflict of interest. & SIR, 2013 J Vasc Interv Radiol 2013; 24: Patients diagnosed with unresectable cholangiocarcinoma have a poor prognosis, with 5-year survival rates of approximately 5% and typical survivals times of 5 13 months (1,2). Locoregional therapies, similar to those that have been shown to prolong survival in other unresectable hepatic malignancies, including hepatocellular carcinoma (HCC) (3 5), have also been evaluated in the treatment of cholangiocarcinoma. Historically, it was difficult to differentiate HCC from cholangiocarcinoma, particularly in the absence of advanced imaging techniques or biopsy. Many early studies evaluating outcomes of treatments offered for primary liver cancer likely inadvertently combined data for patients with HCC and cholangiocarcinoma. Now understood to be distinct entities, HCC and cholangiocarcinoma

2 Volume 24 Number 8 August have been shown to respond differently to systemic chemotherapy and radiation therapy, and indeed have different molecular pathways believed to be responsible for their genesis and progression (6). Cholangiocarcinoma is a much less common malignancy, with consequently less robust evidence on the efficacy of chemotherapy-based transarterial therapies, but several smaller nonrandomized studies have been published demonstrating variable efficacy of such treatments (7 22). To resolve questions regarding the survival, response per Response Evaluation Criteria In Solid Tumors (RECIST), and toxicity profile following chemotherapy-based transarterial therapy in patients with unresectable cholangiocarcinoma, a metaanalysis of the literature published during or before 2012 was performed. The hypothesis to be tested was that transarterial therapies may confer improved tumor response and survival benefit with acceptable toxicities compared with standard chemotherapies. MATERIALS AND METHODS Literature searches were performed in PubMed and Embase in August Two search criteria were used: one for disease state, and the other for intervention, linked with the Boolean operator AND ; within those two categories, each term was linked with OR. No limitation terms were placed on the searches; in particular, no study design or dates of publication limitations were used. A medical librarian performed parallel searches. The search was repeated in March 2012, July 2012, and January 2013, just before abstract and manuscript submission, to ensure that the most recent literature citations were being used in the analysis. In addition, a separate search of the Cochrane Library reviews was performed with the single search term cholangiocarcinoma. Initial exclusion criteria included abstracts that were a case report or letter, did not involve treatment, did not involve subjects with cholangiocarcinoma, or could not be translated into English. All abstracts that passed this initial screening process were reviewed. Publications were included in the final analysis if they met all the following criteria (ie, final inclusion criteria): primary data (ie, not a review) presented from a prospective or retrospective study or published abstract, outcomes or complications reported, treatment involved locoregional chemotherapy-based transarterial therapy (ie, transarterial chemotherapeutic infusion or transarterial chemoembolization), data reported specifically reported for subjects with cholangiocarcinoma if the study involved additional subjects; and subjects had unresectable cholangiocarcinoma. Figure 1. Results of literature search.

3 Table 1. Compilation of Articles Included in Metaanalysis (7 22) No. of Procedures per Median Survival (mo) 1-y Survival Severe Study, Year Pts. Chemotherapeutic Dose per Treatment Embolization Agent Patient* (%) Toxicities From Diagnosis From Procedure Kuhlmann et al (7), Irinotecan 200 mg; mitomycin C 15 mg DEBs; Gelfoam 1.5 NA Vogl et al (8), Mitomycin C 8 mg/m 2, gemcitabine 1,000 mg/m 2, cisplatin 35 mg/m 2 DEBs 7.1 NA Park et al (9), Cisplatin 2 mg/kg Gelfoam NA Schiffman et al (10), Irinotecan 75 mg, doxorubicin 150 mg DEBs NA 68 4 (median doses) Andrasina et al (11), Cisplatin 45 mg/m 2, 5-FU 450 mg/m 2 None NA NA Chaiteerakij et al (12), NA Yes; NS NA NA 46.9 NA Kiefer et al (13), Mitomycin C 10 mg, doxorubicin 50 mg, cisplatin 100 mg PVA Harder et al (14), Irinotecan 200 mg DEBs 1.6 NA NA NA 4 Poggi et al (15), Oxaliplatin 50 mg DEBs 3.3 NA Aliberti et al (16), Doxorubicin mg DEBs 2.6 NA Gusani et al (17), Gemcitabine 1,250 2,250 mg/m 2, cisplatin Embosphere 3.5 NA 9.1 NA mg/m 2, oxaliplatin mg/m 2 Kim et al (18), Cisplatin 2 mg/kg Gelfoam NA Shitara et al (19), Mitomycin C 2 8 mg Degradable starch 8 NA microspheres Herber et al (20), Mitomycin C 10 mg None y 16.3 y Burger et al (21), Cisplatin 100 mg, doxorubicin 50 mg, PVA or Embosphere NA 23 NA NA 1 mitomycin C 10 mg Kirchhoff et al (22), Cisplatin 50 mg/m 2, doxorubicin 50 mg/m 2 Degradable starch microspheres 2 12 y 12 y NA 0 DEB ¼ drug-eluting bead, 5-FU ¼ 5-fluorouracil, NA ¼ not applicable, NCI ¼ National Cancer Institute, NS ¼ not specified, PVA ¼ polyvinyl alcohol, WHO ¼ World Health Organization. n Median or mean. Total NCI/WHO grade 4 3 toxicities from any cause. Study published only in abstract form. y Does not specifically state if survival from time of diagnosis or time of procedure Metaanalysis: Transarterial Therapy for Cholangiocarcinoma Ray et al JVIR

4 Volume 24 Number 8 August The following data were recorded from each included study: subject demographic data, study design, median survival from the time of diagnosis and time of therapy, Kaplan Meier 1-year survival data, response categorized per RECIST, length of time between therapy and posttherapy imaging evaluation, number and type of toxicities of treatment, and type of locoregional therapy, including dose, embolization agent, and number of treatments per subject. By using standard metaanalysis methodology, data were pooled and analyzed. Because of a lack of comparative arms in the published reports, tests for heterogeneity (I 2 or Cochran Q) were not performed. Based on the nature of the present study, institutional review board review was not sought. RESULTS The search criteria resulted in an initial 369 citations; 16 of these studies, which included 542 subjects, fulfilled the inclusion/exclusion criteria and are included in the metaanalysis (Fig 1, Table 1) (7 22). Direct comparisons between studies were limited by differences in reporting survival (from time of diagnosis vs from time of procedure) and differences in chemotherapeutic and embolization agents used. Across the 16 studies, subjects had similar Child Pugh disease class (0% with class C disease) and Eastern Cooperative Oncology Group performance status (4 95% with performance status o 2). For studies presenting such data, the weighted cumulative median overall survival from the date of diagnosis was 15.7 months 5.8 (Fig 2) (9 13,18,21); from the dates of initiation of transarterial therapy, the weighted median overall survival was 13.4 months 6.7 (Fig 3) (7 13,15,16,18 20). The overall weighted average for Kaplan Meier-calculated 1-year survival was 58.0% 14.5 (Fig 4). There was not a substantial difference in survival between studies reporting these data. The single exception to this was the study by Poggi et al(15), in which the median overall survival from the time of the first procedure was 30 months (Fig 3). Although this median far exceeds the remainder of the reported survival times from the other studies used in this analysis, the small number of subjects in this report (N ¼ 9) had little influence on the overall average weighted survival rate; the adjusted weighted median after excluding this report only decreased from 13.4 months to 12.2 months. The reported length of time between transarterial chemoembolization treatment and the postprocedure imaging evaluation was relatively consistent. Of the 10 studies that reported such data, nine described initial imaging 1 3 months following therapy (four studies reporting imaging at 3 mo, three studies reporting imaging at 1 2 months, and two studies providing a range of 1 3 months) (7,9,10,13,15,16, 18,19,21). The single remaining study(14) described initial imaging performed 2 4 months after transarterial chemoembolization. The vast majority of studies reported patients being evaluated with computed tomography (CT) (9,10,15,18 20) or with CT or magnetic resonance imaging (7,13,14,16). Only one study (22) mentioned the use of ultrasound (in addition to CT) to evaluate response. Nearly one fourth of the reported subjects (22.8%) had a complete or partial response on imaging based on RECIST, whereas more than half (53.9%) had stable disease based on the same criteria (Fig 5). The cumulative responses on imaging follow-up per RECIST were complete response in 1.6%, partial response in 21.2%, stable disease in 53.9%, and progressive disease in 23.2% (Fig 5). It is important to note that the imaging response criteria used was largely RECIST, not modified RECIST. The former criteria, which were used in 10 of the 12 studies that reported imaging response (modified RECIST was used in one (12), and a nonvalidated scoring system was used in one [22]), reports response as a change in diameter of the lesion, not the degree of residual contrast enhancement. However, of the eight total patients who exhibited a complete response, five were patients from the one study that used modified RECIST (12). Extracting these patients from the data set, and using only studies in which RECIST were used, would provide a complete response rate of only 0.8% (three of 399 patients). In determining complication rates, 84 severe toxicities (National Cancer Institute/World Health Organization grade Z 3) were reported (18.9% of all subjects in those studies that reported complications; Table 2). There appeared to be a relatively even distribution of complication types, including hematologic and nonhematologic complications. Interestingly, there were higher reported serious complication rates in the more recent reports (published in 2010 or later) compared with the earlier reports (2009 or earlier; 17.1% vs 12.3%; P ¼.16, w 2 analysis). One observation that bears evaluation was the relatively high severe complication rate when irinotecan was used as the chemotherapy agent during transarterial chemoembolization; two of the three studies in which irinotecan was used (7,14) showed higher severe complication rates (30.8% and 30.6%) than the 18.8% average. However, when all three studies in which irinotecan was used (7,10,14) were pooled, there was no significant increase in overall severe complication rate compared with studies in which irinotecan was not used (20.9% vs 18.2%, respectively; P =.673, w 2 analysis). There were four deaths within 30 days of transarterial chemoembolization, corresponding to a reported mortality rate of 0.7%. Many subjects experienced postembolization syndrome; however, because of diverse reporting practices by the various authors, a specific rate could not be calculated. When reported, the incidences of postembolization syndrome ranged from 16% to 100%, but the majority of studies subjectively described postembolization syndrome occurring in most of their subjects. For the studies that presented such data, there were a total of 1,453 procedures performed cumulatively, averaging 4.1 treatments per subject. However, this mean is skewed by the presence of one very large study (N = 115) (8) in which the average number of procedures performed

5 1222 Metaanalysis: Transarterial Therapy for Cholangiocarcinoma Ray et al JVIR Figure 2. Forest plot of overall survival from the time of diagnosis. **Published only in abstract form. Figure 3. Forest plot of overall survival from the time of first treatment. was more than seven per subject. If this single study is excluded, the mean number of procedures decreases to 2.7 per subject. Only two studies did not use an embolization agent but rather performed transarterial chemotherapeutic infusion therapy (11,20). Indwelling port systems and intermittent arterial access were used in these studies. In all 16 studies, chemotherapy agents varied widely, and included irinotecan, mitomycin C, gemcitabine, cisplatin, doxorubicin, 5-fluorouracil, and oxaliplatin. Embolic agents

6 Volume 24 Number 8 August Figure 4. Forest plot of 1-year overall survival by Kaplan Meier method. **Published only in abstract form. Figure 5. Cumulative weighted response per RECIST. RECIST = Response Evaluation Criteria In Solid Tumors. were also diverse, and included Gelfoam (Upjohn, Kalamazoo, Michigan), polyvinyl alcohol particles, Embosphere particles (Biosphere, Rockland, Massachusetts), drug-eluting beads, degradable starch microspheres, and Lipiodol (Guerbet, Roissy, France; Table 1). In a separate analysis, overall survival rates from the time of first treatment with drug-eluting beads (with irinotecan and/or doxorubicin) (7,10,14,16) was compared versus those in studies in which drug-eluting beads were not used. There was no significant difference in overall survival between those subjects treated with drug-eluting beads (16.5 mo) and those not treated with this technique (12.0 mo; P ¼.41, Student t test). Reported overall 1-year survival for the patients treated with drug-eluting beads was also not significantly different

7 Table 2. Toxicities following Intraarterial Therapies in Published Reports (7 22) Toxicities* Study, Year Chemotherapeutic Agents PES Complications Severe Minor Kuhlmann et al (7), 2012 Irinotecan, mitomycin Almost all PES; 2 deaths from biliary sepsis Vogl et al (8), 2012 Multiple groups (mitomycin C, gemcitabine, 0 NA NA and both, with/without cisplatin) Park et al (9), 2011 Cisplatin 34 NA NA All severe: anemia (n ¼ 3), thrombocytopenia (n ¼ 6), neutropenia (n ¼ 1), increased INR (n ¼ 1); nonhematologic: increased AST (n ¼ 2, increased ALT (n ¼ 1), increased ALP (n ¼ 1), increased bilirubin (n ¼ 1), decreased albumin (n ¼ 1), pain (n ¼ 3), nausea (n ¼ 1) Schiffman et al (10), 2011 DEBIRI (n ¼ 35), DEBDOX (n ¼ 7) 4 7/42 4 (16.7) Atrial fibrillation (grade 2; n ¼ 2), hepatic insufficiency (grade 3; n ¼ 2), and sepsis (grade 4; n ¼ 1), fatal HRS (n ¼ 1), pneumonia (grade 2; n ¼ 1) Andrasina et al (11), 2010 Cisplatin and 5-FU NA NA 13 (80) NA Chaiteerakij et al (12), 2010 NA NA NA NA NA Kiefer et al (13), 2010 Mitomycin C, doxorubicin, cisplatin 5 NA 107 (65) Pulmonary infarct (grade 2; n ¼ 1), pulmonary edema (grade 4; n ¼ 1), elevated cardiac enzymes (n ¼ 1), ARF (n ¼ 1), severe PES (n ¼ 1), hyperglycemia (n ¼ 1) Harder et al (14), 2010 Irinotecan 4 NA 4 (31) RUQ pain (grade 3; n ¼ 4), RUQ pain (grade 1/2; n ¼ 6) Poggi et al (15), 2009 Oxaliplatin 11 NA NA Abdominal pain (grade 3; n ¼ 9), hypertensive crisis (grade 3; n ¼ 1), cholangitis (grade 3; n ¼ 1) Aliberti et al (16), 2008 Doxorubicin (100) Hepatic abscess (n ¼ 1), 95% grade 2 nausea/vomiting (n ¼ 27), 100% neoplastic fever Gusani et al (17), 2008 Gemcitabine (100%), cisplatin, oxaliplatin 7 NA Most MI (grade 4; n ¼ 1), hepatic abscess (grade 4; n ¼ 1), thrombocytopenia (n ¼ 1), sepsis (n ¼ 1) Kim et al (18), 2008 Cisplatin NA NA Most Hepatic abscess (n ¼ 1), most patients with fever, nausea, or vomiting (low grade) Shitara et al (19), 2008 Mitomycin C 5 62/20 NA Duodenal ulcer (grade 3; n ¼ 3), RUQ pain (grade 3; n ¼ 2), nausea (grade 3; n ¼ 1), anorexia (grade 3; n ¼ 1) Herber et al (20), 2007 Mitomycin C 2 12/58 6 (40) Anaphylactic shock (grade 4; n ¼ 1), gastric ulceration (grade 4; n ¼ 1), grade 1/2 nausea/vomiting (n ¼ 4), RUQ pain (n ¼ 6), hepatic artery spasm (n ¼ 2) Burger et al (21), 2005 Cisplatin, doxorubicin, mitomycin C 1 2/17 NA Fatal massive UGI bleeding (n ¼ 1) Kirchhoff et al (22), 2005 Cisplatin, doxorubicin 0 NA NA Common nausea and fever Values in parentheses are percentages where appropriate. ALP ¼ alkaline phosphatase, ALT ¼ alanine transaminase, ARF ¼ acute renal failure, AST ¼ aspartate transaminase, DEBDOX ¼ drug-eluting beads with doxorubicin, DEBIRI ¼ drug-eluting beads with irinotecan, 5-FU ¼ 5-fluorouracil, HRS ¼ hepatorenal syndrome, INR ¼ International Normalized Ratio, MI ¼ myocardial infarction, NA ¼ not reported, NCI ¼ National Cancer Institute, PES ¼ postembolization syndrome, RUQ ¼ right upper quadrant, UGI ¼ upper gastrointestinal, WHO ¼ World Health Organization. n Toxicities from any cause, events/subjects or procedure. Severe toxicities are NCI/WHO grade 4 3; minor are NCI/WHO grade o 3. Study published only in abstract form. Gemcitabine was administered in all patients: with/without cisplatin (n ¼ 2) or with/without oxaliplatin (n ¼ 4), or gemcitabine with/without cisplatin in combination (n ¼ 14) or gemcitabine and cisplatin followed by oxaliplatin (n ¼ 4) Metaanalysis: Transarterial Therapy for Cholangiocarcinoma Ray et al JVIR

8 Volume 24 Number 8 August than in those patients treated with standard transarterial chemoembolization therapy (61.8% vs 59.7%, respectively; P ¼.339, Student t test). DISCUSSION In the present metaanalysis of 16 studies examining outcomes following transarterial therapies in unresectable cholangiocarcinoma, heterogeneity and small sample sizes across studies made some comparisons difficult. However, some important conclusions may be drawn. The median survival from the time of diagnosis of 15.7 months (13.4 mo from time of treatment) following transarterial therapies is generally higher than rates reported with the use of only systemic treatments. Historically, most studies of single-agent chemotherapy regimens report overall survival rates ranging from 5 to 8 months (1,23 26). As always, however, one must be mindful of selection bias when comparing specific disease interventions with historical controls, as many of the subjects represented in the historical studies may have been excluded from transarterial therapies for various reasons. Two recent studies (27,28) have reported improved survival rates for subjects undergoing combination systemic chemotherapy (gemcitabine and cisplatin) in this population. Although somewhat confusing because of how the data were reported, by combining the results following treatment of various forms of cholangiocarcinoma (eg, intrahepatic, extrahepatic, and gallbladder carcinoma), both these studies (27,28) demonstrated mean survival times (11.7 mo and 13.0 mo) for intrahepatic and/or nongallbladder cholangiocarcinoma that are more favorable than historical survival rates for the same disease processes. Regarding tumor response per RECIST, more than three fourths of all subjects showed a response or stable disease; however, the majority of these subjects (53.9% of all patients) exhibited stable disease by imaging criteria. It is important to note that, with one exception (N ¼ 32), all the studies included in this analysis used RECIST to evaluate response (12). With the increasing use of newer imaging response criteria (eg, modified RECIST, European Organization for Research and Treatment of Cancer), in which enhancement patterns rather than overall size of the lesion are measured, it is expected that imaging responses will increase as a result of the use of these less stringent criteria. Therefore, care should be taken when comparing studies that use different imaging response criteria. Complication rates were relatively high, with severe complications (ie, National Cancer Institute/World Health Organization grade 4 3) seen in a total of 18.9% of patients. In addition, most studies reported minor toxicities in the majority of subjects. These minor toxicities were largely those associated with postembolization syndrome (minor pain, fever, nausea/vomiting, fatigue), whereas the major toxicities were highly variable but tended to be nonhematologic. Finally, there was a very low overall 30- day mortality rate (0.7%). The limitations of the present study include insufficient data to allow comparative conclusions to be drawn in terms of efficacy based on type of chemotherapeutic agent(s) used for transarterial therapies. In addition, many other technical factors such as the type of embolic agent used and how selective the embolization procedures were potentially confound the results of this analysis as a result of the substantial heterogeneity and lack of power in the reported cases. Many of the studies did not report whether their patients were treatment-naive or had received chemotherapy previously. Of those studies that did report on previous treatment (7,9 11,13,15,16,18 22), previous exposure to therapy was highly variable (0% 100%), and the data were typically not presented in such a way to allow stratification of the groups. The fact that the included studies were published over a relatively long period of time (8 y) also adds to the potential for selection bias and technical heterogeneity. Two of the studies (N ¼ 32 and N ¼ 13) included in the final analysis (12,14) were published in abstract form only, raising concerns that these publications did not undergo a robust peer-review process. The subjects included in the final analysis were from manuscripts published around the world, including Asia, Europe, and North America; this raises the concern that the underlying disease process, techniques used in treatment, indication for repeat treatment, and selection bias for patients undergoing transarterial therapy may skew the results, or perhaps make the overall results less generalizable to any specific patient population. The lack of standardization of reporting findings poses notable limitations when evaluating the entire dataset. Finally, although care was taken to identify all pertinent published articles, it is possible that some published data were missed in the initial and follow-up searches. Although not included in the present metaanalysis, there have been several recent studies evaluating selective internal radiation therapy with yttrium-90 ( 90 Y) in the treatment of cholangiocarcinoma (29 31). These early data are promising, and demonstrate median survival rates from the time of first 90 Y treatment ranging from 9.3 to 22.0 months. As is common with early studies, 90 Y therapy was often used as salvage therapy in these publications, with many subjects (as many as 79%) having received previous systemic chemotherapy or presenting with extrahepatic disease (as many as 48%) (29,30). Further studies are needed to more fully elucidate the role of selective internal radiation therapy in the treatment of cholangiocarcinoma. As demonstrated by the present metaanalysis, transarterial chemotherapy based treatments for cholangiocarcinoma appears to confer a survival benefit compared with systemic therapies. This survival benefit appears to be most substantial when compared versus single-agent systemic chemotherapy, although the data are less compelling for combination chemotherapy for intrahepatic cholangiocarcinoma and nongallbladder cholangiocarcinoma. As

9 1226 Metaanalysis: Transarterial Therapy for Cholangiocarcinoma Ray et al JVIR demonstrated by this metaanalysis, transarterial chemotherapy based treatments for cholangiocarcinoma demonstrated a favorable response by imaging criteria, and has an acceptable postprocedural complication profile. Such therapies should be strongly considered in the treatment of patients with this devastating illness. REFERENCES 1. Khan SA, Thomas HC, Davidson BR, Taylor-Robinson SD Cholangiocarcinoma. Lancet 2005; 366: Erratum in: Lancet 2006; 367: Zechlinski JJ, Rilling WS. Transarterial therapies for the treatment of intrahepatic cholangiocarcinoma. Semin Intervent Radiol 2013; 30: Lo CM, Ngan H, Tso WK, et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology 2002; 35: Llovet JM, Real MI, Montaña X, et al. Arterial embolization or chemoembolization versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomized controlled trial. Lancet 2002; 359: Marelli L, Stigliano R, Triantos C, et al. Transarterial therapy for hepatocellular carcinoma: which technique is more effective? A systematic review of cohort and randomized studies. Cardiovasc Intervent Radiol 2007; 30: Patt YZ, Hassan MM, Aguayo A, et al. Oral capecitabine for the treatment of hepatocellular carcinoma, cholangiocarcinoma, and gallbladder carcinoma. Cancer 2004; 101: Kuhlmann JB, Euringer W, Spangenberg HC, et al. Treatment of unresectable cholangiocarcinoma: conventional transarterial chemoembolization compared with drug eluting bead-transarterial chemoembolization and systemic chemotherapy. Eur J Gastroenterol Hepatol 2012; 24: Vogl TJ, Naguid NNN, Nour-Eldin NEA, et al. Transarterial chemoembolization in the treatment of patients with unresectable cholangiocarcinoma: results and prognostic factors governing treatment success. Int J Cancer 2011; 131: Park SY, Kim JH, Yoon HJ, Lee IS, Yoon HK, Kim KP. Transarterial chemoembolization versus supportive therapy in the palliative treatment of unresectable intrahepatic cholangiocarcinoma. Clin Radiol 2011; 66: Schiffman SC, Metzger T, Dubel G, et al. Precision hepatic arterial irinotecan therapy in the treatment of unresectable intrahepatic cholangiocellular carcinoma: optimal tolerance and prolonged overall survival. Ann Surg Oncol 2011; 18: Andrasina T, Valek V, Panek J, et al. Multimodal oncological therapy comprising stents, brachytherapy, and regional chemotherapy for cholangiocarcinoma. Gut Liver 2012; 4(suppl):S82 S Chaiteerakij R, Schmit G, Mettler TA, Andrews J, Roberts LR. Transarterial chemoembolization (TACE) improved survival in unresectable intrahepatic cholangiocarcinoma. 61st Annual Meeting of the American Association for the Study of Liver Diseases (abstr.). Hepatology 2010; 52(suppl):1137A. 13. Kiefer MV, Albert M, McNally M, et al. Chemoembolization of intrahepatic cholangiocarcinoma with cisplatinum, doxorubicin, mitomycin C, Ethiodol, and polyvinyl alcohol: a 2-center study. Cancer 2011; 117: Harder J, Euringer W, Langer M, Thimme R, Blum HE, Spangenberg HC. Transarterial chemoembolization of intrahepatic cholangiocarcinomas with irinotecan-eluting beads: preliminary results. 60th Annual Meeting of the American Association for the Study of Liver Diseases (abstr.). Hepatology 2009; 50(suppl 4):1116A. 15. Poggi G, Amatu A, Montagna B, et al. OEM-TACE: a new therapeutic approach in unresectable intrahepatic cholangiocarcinoma. Cardiovasc Intervent Radiol 2009; 32: Aliberti C, Benea G, Massimo T, Giorentini G. Chemoembolization (TACE) of unresectable intrahepatic cholangiocarcinoma with slowrelease doxorubicin-eluting beads: preliminary results. Cardiovasc Intervent Radiol 2008; 31: Gusani NJ, Balaa FK, Steel AL, et al. Treatment of unresectable cholangiocarcinoma with gemcitabine-based transcatheter arterial chemoembolization (TACE): a single institution experience. J Gastrointest Surg 2008; 12: Kim JH, Yoon HK, Sung KB, et al. Transcatheter arterial chemoembolization or chemoinfusion for unresectable intrahepatic cholangiocarcinoma: clinical efficacy and factors influencing outcomes. Cancer 2008; 113: Shitara K, Ikami I, Munakata M, Muto O, Sakata Y. Hepatic arterial infusion of mitomycin C with degradable starch microspheres for unresectable intrahepatic cholangiocarcinoma. Clin Oncol 2008; 20: Herber S, Otto G, Schnieder J, et al. Transarterial chemoembolization (TACE) for inoperable intrahepatic cholangiocarcinoma. Cardiovasc Intervent Radiol 2007; 30: Burger I, Hong K, Schulick R, et al. Transcatheter arterial chemoembolization in unresectable cholangiocarcinoma: initial experience in a single institution. J Vasc Interv Radiol 2005; 16: Kirchhoff T, Zender L, Merkesdal S, et al. Initial experience from a combination of systemic and regional chemotherapy in the treatment of patients with nonresectable cholangiocellular carcinoma in the liver. World J Gastroenterol 2005; 11: Alberts SR, Gores GJ, Kim GP, et al. Treatment options for hepatobiliary and pancreatic cancer. Mayo Clin Proc 2007; 82: Mazhar D, Stebbing J, Bower M. Chemotherapy for advanced cholangiocarcinoma: what is standard treatment? Future Oncol 2006; 2: Okusaka T, Ishii H, Funakoshi A, et al. Phase II study of single-agent gemcitabine in patients with advanced biliary tract cancer. Cancer Chemother Pharmacol 2006; 57: Dingle BH, Rumble RB, Brouwers MC. The role of gemcitabine in the treatment of cholangiocarcinoma and gallbladder cancer: a systematic review. Can J Gastroenterol 2005; 19: Valle JW, Wasan H, Johnson P, et al. Gemcitabine alone or in combination with cisplatin in patients with advanced or metastatic cholangiocarcinomas or other biliary tract tumours: a multicentre randomised phase II study the UK ABC-01 Study. Br J Cancer 2009; 101: Okusaka T, Nakachi K, Fukutomi A, et al. Gemcitabine alone or in combination with cisplatin in patients with biliary tract cancer: a comparative multicentre study in Japan. Br J Cancer 2010; 103: Hoffmann RT, Paprottka PM, Schon A, et al. Transarterial hepatic yttrium-90 radioembolization in patients with unresectable intrahepatic cholangiocarcinoma: factors associated with prolonged survival. Cardiovasc Intervent Radiol 2012; 35: Saxena A, Bester L, Chua TC, Chu FC, Morris DL. Yttrium-90 radiotherapy for unresectable intrahepatic cholangiocarcinoma: a preliminary assessment of this novel treatment option. Ann Surg Oncol 2010; 17: Ibrahim SM, Mulcahy MF, Lewandowski RJ, et al. Treatment of unresectable cholangiocarcinoma using yttrium-90 microspheres: results from a pilot study. Cancer 2008; 113: