Transarterial Chemoembolization (TACE) for Inoperable Intrahepatic Cholangiocarcinoma

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1 Cardiovasc Intervent Radiol (2007) 30: DOI /s Transarterial Chemoembolization (TACE) for Inoperable Intrahepatic Cholangiocarcinoma S. Herber Æ G. Otto Æ J. Schneider Æ N. Manzl Æ I. Kummer Æ S. Kanzler Æ A. Schuchmann Æ J. Thies Æ C. Düber Æ M. Pitton Received: 27 March 2007 / Revised: 27 March 2007 / Accepted: 28 March 2007 / Published online: 17 May 2007 Ó Springer Science+Business Media, LLC 2007 Abstract The aim of this retrospective study was to determine the safety and efficacy of chemoembolization (TACE) as palliative treatment for patients with unresectable intrahepatic cholangiocarcinoma (CCA) and to compare the results with those in the literature. Fifteen patients with histology-proven CCA (5 men, 10 women) had received palliative treatment with TACE over a 6- year period. The treatment protocol comprised repeated TACE at a minimum of 8-week intervals. TACE was performed with a mixture of 10 ml Lipiodol and 10 mg mitomycin C injected into the tumor-supplying vessels. Follow-up investigations after 8 10 weeks comprised contrast-enhanced multislice spiral CT and laboratory control. Statistical evaluation included survival analysis using the Kaplan-Meier method. During the investigation period 58 TACEs (3.9 ± 3.8; 1 15) were performed in 15 patients. Mean tumor size was 10.8 ± 4.6 cm (range, cm). Unifocal tumor disease was diagnosed in eight patients, and multifocal disease in seven. Mean survival was 21.1 months (95% CI, months). At the end of the investigation period 3 patients are still alive, and 12 patients have died. The 1-, 2-, and 3-year survival rate was 51.3%, 27.5%, and 27.5% respectively. S. Herber (&) J. Schneider N. Manzl I. Kummer C. Düber M. Pitton Department of Diagnostic and Interventional Radiology, University of Mainz, Langenbeckstr. 1, Mainz, Germany herber@radiologie.klinik.uni-mainz.de G. Otto J. Thies Department of Hepatobiliary Surgery, University of Mainz, Mainz, Germany S. Kanzler A. Schuchmann I. Medical Clinic, University of Mainz, Mainz, Germany According to RECIST criteria interim best response to therapy was stable disease in 9 of 15 patients, a partial response in 1 of 15 patients, and tumor progression in 4 of 15 patients. No deaths and no acute liver failure occurred under TACE therapy. Major complications were observed in two patients, comprising anaphylactic shock owing to contrast medium administration in one and gastric ulceration due to lipiodol displacement in the second patient. These results demonstrate that TACE is a safe procedure with a moderate number of complications for patients suffering from inoperable CCA. According to recently published data on i.v. chemotherapy we suggest that TACE might be able to prolong survival in selected patients who would succumb under other palliative treatment modalities. Keywords TACE Chemoembolization Cholangiocarcinoma Survival Kaplan-Meier Mitomycin C Lipiodol Introduction Cholangiocarcinoma (CCA) is an uncommon neoplasm with a poor prognosis. The 5-year survival rate, including resected patients, is actually between 5% and 18% [1 3]. The tumor, first described by Durand-Fardel in 1840, arises from biliary epithelial cells, and more than 90% of CCAs are adenocarcinomas. Almost 60% 70% of CCAs occur at the hepatic duct bifurcation, and the remainder occur either in the distal part of the common bile duct (20%30%) or, very rarely, within the liver (5% 15%) [1 3]. Whereas the incidence of extrahepatic tumors is declining, several studies have shown an increasing incidence and mortality for intrahepatic CCA. Its incidence is estimated to be 1 2

2 S. Herber et al.: TACE for Inoperable Intrahepatic Cholangiocarcinoma 1157 cases per 100,000, with a peak age over 65 years and a slight male preponderance [2]. Owing to the usually late diagnosis, untreated CCA represents a rapidly fatal process. Even if surgical resection is the only potentially curative treatment, disease is already unresectable at presentation in the majority of patients [2, 4]. Only a minority of patients with extrahepatic proximal or distal CCA may be candidates for liver transplantation, whereas patients with intrahepatic CCAs are commonly not eligible [5]. Those patients frequently show multifocal tumor growth or bilobar tumor or lymphatic tumor spread so that alternative therapeutic modalities are required. Systemic chemotherapy has provided disappointing results in the past and photodynamic therapy is not feasible in larger tumors [1 5]. However, recently published reports have focused on the value of TACE and chemoperfusion in the treatment of unresectable CCA. Even if TACE is well established in the palliative treatment of hepatocellular carcinoma (HCC), its effectiveness for CCA is not yet known [6 8]. To address this issue, we retrospectively analyzed patients with intrahepatic CCA who had been treated by means of TACE over the past 6 years. The aim of the work is to demonstrate our results with respect to the literature and to evaluate the safety and efficacy of this treatment concept in intrahepatic CCA. Patients and Methods During a 6-year period between October 2000 and June 2006 we treated 15 patients with histologically confirmed CCA by TACE. In each case, diagnosis was confirmed by either needle biopsy, laparoscopy, or open laparotomy. The decision for TACE was made by an interdisciplinary tumor board in each individual case. Approval for TACE as palliative treatment for inoperable liver cancer was granted by the institutional investigation and ethics committee. The treatment protocol called for repeated TACE treatment with a minimum interval of 8 weeks between procedures using a mixture of mitomycin C and Lipiodol (Lipiodol ultra fluid; Andre Guerbet, Aulnaysous-Bois, France). Patients were excluded from TACE treatment if one of the following was found: decompensated liver disease (Child- Pugh class C, Okuda stage III, massive ascitis, serum bilirubin >3 mg/dl), bacterial infection, extrahepatic tumor spread, or any contraindication for an arterial procedure (impaired clotting test, platelet count <50,000/mm 3, or prothrombin activity <50%). A partial thrombosis of the portal vein did not represent a contraindication to TACE treatment; as a result of our own experience in patients with HCC, TACE was even performed in patients with a thrombosis of the right or left main branch of the portal vein. TACE was stopped if one of the following conditions was established: progressive disease, occlusion of the hepatic artery, extrahepatic tumor spread, or progressive liver decompensation (Child-Pugh stage C, Okuda stage III, massive ascitis). Imaging Modalities Before TACE, contrast-enhanced helical computed tomography (CT) was performed. Dynamic CT images were obtained using a multislice CT scanner (Siemens Volume Zoom; Erlangen, Germany). A native CT scan was obligatory, including arterial and portal venous phase acquisitions. Investigation parameters were as follows: slice thickness, 3 mm; increment, 2.5 mm; collimation, 2 mm; 150 ml km i.v. (Imeron 300; Bracco Altana Pharma GmbH, Konstanz, Switzerland); 50 ml 0.9% NaCl bolus; flow, 5 ml/s; 150 mas; and 120 kv. After TACE a native CT scan was carried out on the same or the following day to document the Lipiodol distribution and to exclude displacement of the embolizing agent. Technical Procedure Under local anesthesia (20 ml mepivacaine-1% HCl) transfemoral access using a 5-Fr catheter sheath was selected for all patients and a 4- to 5-Fr standard catheter was used for angiography (Sidewinder- or Cobra-shaped; Terumo, Tokyo). First, the arterial liver supply was documented. The mesenteric artery was examined to visualize any atypical liver blood supply. Then, the common hepatic artery was cannulated, and according to the individual anatomical disposition, the catheter was placed distal to the origin of the gastroduodenal artery and/or in the right or left lobar artery. If a stable catheter position could not be achieved, a 2.2-Fr microcatheter (Boston Scientific, Natick, MA, USA) was used for superselective intubation of the segment vessels. TACE was performed with a suspension consisting of 10 ml Lipiodol (Lipiodol ultrafluid; Andre Guerbet, Aulnay-sous-Bois, France) and 10 mg mitomycin C mixed directly before administration. According to the tumor growth the complete dose of the chemotherapeutic suspension was administered at the level of the lobar or segmental artery in one single lobe unless bilobar tumor had been diagnosed. In those cases the total dose was distributed to the two liver lobes (right vs. left liver lobe, two-thirds vs. one-third of the total quantity) under fluoroscopic control over a period of min. The treatment was deemed technically successful after delivery of the total amount of the chemotherapeutic suspension and/or stasis or reflux in the appropriate section. If hypervascularized parts of the tumor remained after infusing 10 ml Lipiodol or an inappropriate deceleration of the arterial

3 1158 S. Herber et al.: TACE for Inoperable Intrahepatic Cholangiocarcinoma blood flow was found in the control angiography, a maximum of 10 ml additional pure Lipiodol was administered, not to exceed a total quantity of 20 ml Lipiodol. After administration of the chemotherapeutic drug, the arterial liver supply was documented again by selective angiography and the technical success was confirmed by a native CT scan carried out immediately after the TACE procedure. The patients were usually hospitalized for one night and were discharged the next day if no complications developed. Nausea, pain, or fever that occurred in association with the TACE treatment was treated symptomatically with antiemetics (e.g., 5 15 mg ondansetrone i.v.), analgesics (e.g., mg metamizole i.v.), or antipyretics (e.g., mg paracetamol tbs/supp). No antibiotic prophylaxis was given routinely. Laboratory Studies, Clinical Findings Biochemistry and tumor markers were checked every 6 weeks. In all patients the CA 19-9 levels, transaminases (AST, ALT), serum cholinesterase, blood count, and coagulation parameters (PTT, thrombin time, prothrombin activity) were assessed. The degree of cirrhosis was classified according to the Child-Pugh (Child stages A C) and the Okuda classifications (stages I III). CT Evaluation CT scans were analyzed to determine the number of tumor lesions, the maximal diameter of the marker lesion in the disease process, occurrence, and/or absence of pathological lymph nodes, and extrahepatic tumor spread. The correct distribution of the embolizing agent was confirmed on the postinterventional native CT scan. The patency of the portal vein and of the hepatic arteries and liver veins was determined in the venous phase in the preinterventional CT scan and during catheter angiography. An infiltration of the liver capsule was suggested if the tumor had contact to the liver capsule over a longer distance [9]. In patients who received TACE more than six times an interim analysis was performed after three procedures. Tumor response was assessed on the basis of the crosssectional CT images in the arterial and portal venous phase, comparing the first and the last available CT scans. Tumor response was evaluated using the RECIST classification (Response Evaluation Criteria in Solid Tumors) [10]. Up to five marker lesions were analyzed and the sum of the nonmeasurable lesions, <1-cm diameter in cross-sectional spiral CT, was registered. According to RECIST, unidimensional measurements of the sum of the longest diameters of the marker lesions were carried out. Response was defined as follows: complete response, disappearance of all target lesions; partial response, >30% decrease from baseline; progressive disease, >20% increase from baseline or any new tumor lesion; and stable disease, all other cases. In cases of repetitive treatment the best interim result (best response) was rated. Statistics The primary study end point was the mean survival of the patients treated with TACE. Secondary end points were the complications and negative side effects. The retrospective database was analyzed using the statistical program SPSS (version 12.0 for Windows). Continuous ordinal data are expressed as means ± SDs and as qualitative data with frequency and rate. Survival was calculated using the Kaplan- Meier method from the first TACE treatment to death. The statistical significance of laboratory values was determined by means of the Wilcoxon test. A two-tailed p-value of <0.05 was considered to be statistically significant. Clinical Course/Complications and Side Effects The clinical course of disease, independently of the CT findings, was defined in three categories as follows: favorable, survival for >18 months; intermediate, survival for between 6 and 18 months; and fatal, survival for <6 months. Complications were classified according to the practical guidelines of the Society of Interventional Radiologists into minor and major complications [11]. Results Demographics During the investigation period 15 patients (5 men, 10 women) with inoperable CCA had been treated with TACE. The mean age of the patients was 63.6 ± 11.7 years. A total of 58 TACE procedures (mean, 3.9 ± 3.8; range, 1 15) were accomplished. Liver cirrhosis was present in only one case (patient 3), whereas liver histology revealed no evidence of cirrhosis in the other patients. The functional liver status was rated according to the Child-Pugh classification. Child-Pugh class A was present in 14 patients and Child-Pugh class B in 1. Mild to moderate ascitis was found in 11 patients. Due to the extensive tumor spread, segmental cholestasis was observed in six patients, requiring percutaneous drainage in three subsequent patients. In 4 patients, tumor thrombosis of the intrahepatic portal branches was present, whereas the main trunk of the portal vein and its segmental branches were patent in 11. In one patient a radiofrequency ablation was

4 S. Herber et al.: TACE for Inoperable Intrahepatic Cholangiocarcinoma 1159 Table 1 Summary of the demographic data for 15 patients treated with TACE for cholangiocarcinoma Gender Men 5 Women 10 Mean age, yr (range) 63.6 ± 11.7 ( ) Functional liver status Cirrhosis, yes/no 1/14 Child-Pugh Class A 14 Child-Pugh Class B 1 Ascitis 11 No ascitis 4 Cholestasis Absent 9 Present 6 Portal vein thrombosis Absent 11 Present 4 TACE Total number (mean ± SD; range) 58 (3.9 ± 3.8; 1 15) Additional therapy Liver resection 1/15 Radiofrequency ablation 2/15 Systemic chemotherapy prior to TACE 4/15 Table 2 Overall tumor characteristics Tumor characteristic Tumor size: max. diameter, cm (range) 10.8 ± 4.6 ( ) Unifocal lesion 8 Multifocal lesions 2 5 lesions lesions 1 >10 lesions 3 Tumor spread Unilobar tumor 6 Bilobar tumor 9 Tumor mass <50% 11 >50% 4 Capsule infiltration Absent 12 Present 3 Central necrosis Present 11 Absent 4 Vascularity Hyperdense tumor periphery 13 performed after TACE. One patient received a hemihepatectomy after a single-shot TACE. A summary of the demographic data is given in Table 1. In 8 of 15 patients a unifocal tumor was found; 7 patients had multifocal tumor lesions. In three patients a miliary type of CCA was diagnosed, with a diffuse tumor spread over both liver lobes. A unilobar tumor was diagnosed in 6 of 15 patients, whereas bilobar tumor spread was found in 9 patients. By cross-sectional CT imaging the tumor mass was calculated to be more than 50% of the liver mass in 4 of 15 patients. In three patients the tumor infiltrated the liver capsule. The mean diameter of the largest tumor lesion was 10.8 ± 4.6 cm (range, cm). Large tumors presented distinct tumor necrosis in the central parts in 11 of 15 patients, with a lack of contrast enhancement in those areas. A peripheral, hypervascularized zone was present in 13 of 15 patients, whereas in 2 patients the tumor periphery was hypovascularized (Table 2). The laboratory panel demonstrated stable results with regard to the parameters of liver synthesis (i.e., prothrombin activity and serum protein) and a slight increase in the serum bilirubin concentration. Tumor markers (i.e., CA 19-9) decreased slightly in the course of disease without reaching statistical significance (Table 3). Table 3 Laboratory parameters pre- and post-tace treatment (±SD) Pre-TACE Post-TACE p-value a Quick (%) 95.5 ± ± Serum protein (g/l) 70.9 ± ± Bilirubin (mg/dl) 1.6 ± ± c-gt (U/L) 329 ± ± AP (IU/L) 346 ± ± ALT (IU/L) 53.8 ± ± CA 19-9 (IU/ml) 45.4 ± ± a Calculated by Wilcoxon test Tumor Characteristics Course of Disease At the end of the investigation period, 3 of 15 patients were still alive, whereas 12 patients had died. The mean survival was 21.1 months (95% CI, ). One-, 2-, and 3-year survival rates were 54.5%, 27.5%, and 27.5%, respectively (Fig. 1). Local tumor response was rated according to the RECIST criteria. Stable disease was observed in 9 of 15, a partial response in 1, and tumor progression in 4 of 15 patients. Despite the imaging findings, the clinical course was, depending on survival, divided into the categories favorable course, intermediate, and fatal course. Among four patients of whom three have already died and one is still alive a favorable course with more than 18 months

5 1160 S. Herber et al.: TACE for Inoperable Intrahepatic Cholangiocarcinoma cum. survival 1,0 0,8 0,6 0,4 0,2 0,0 Survival function survival curve censored patients inidicate survivors 0,00 10,00 20,00 30,00 40,00 50,00 60,00 70,00 survival months Fig. 1 Kaplan-Meier survival curve of 15 patients who underwent TACE for intrahepatic cholangiocarcinoma (CCA). Mean survival was 21.1 months (median, 16.3 months; 95% CI, months) survival was found. Among another seven patients of whom five have already died and two are still alive an intermediate course was found with a survival between 6 and 18 months. Finally, four patients demonstrated a fatal course with a poor survival, ranging between 2.5 and 4.5 months. In those four patients either a military-type tumor was present or a giant tumor (maximum diameter, 16.0 cm) with extensive involvement of the corresponding liver lobe was found. Liver failure owing to the TACE procedure was not considered to be responsible for death in any of the patients. However, in one patient (patient 6), who is still alive at the end of the investigation period, liver function worsened substantially. The initial spiral CT demonstrated a large unifocal CCA complicated by a partial thrombosis of the portal vein and a severe segmental cholestasis. The cholestasis was treated by percutaneous drainage using a 10-Fr Yamakawa-type prosthesis. After the cholestasis parameters (i.e., AP and c-gt) and the bilirubin level had normalized, TACE therapy was started. A total of five TACE procedures was performed. However, the activated prothrombin ratio decreased in this patient from 115% to 66% and the serum bilirubin increased from 0.7 to 2.0 mg/dl. Additionally, moderate ascitis developed that had not been present in the initial CT scan. For these reasons and because of stable tumor disease, the repeated TACE therapy was interrupted and the disease is still under control in this patient. PTCD was carried out in two further patients who developed severe jaundice before the TACE treatment. In patient 8 the serum bilirubin level was 11.3 mg/dl before biliary drainage. After successful drainage the bilirubin level normalized and TACE therapy could be started. The drainage was routinely performed at 8-week intervals. A total of seven TACE procedures was performed and the overall survival was 38.7 months. Whereas the intrahepatic tumor was stable, this patient finally died as a result of extrahepatic tumor spread with peritoneal carcinosis. In patient 3 radiofrequency thermoablation (RFTA) was performed prior to TACE. This patient suffered from two isolated liver tumors with a maximum diameter of 5 cm. The RFTA, carried out under general anesthesia, was technically successful. There was no evidence of a residual, viable tumor at postinterventional CT and MRI examinations. However, at the 3-month follow-up, CT and MRI demonstrated new, hypervascularized tumor lesions. Because of the close proximity to the gallbladder and the potential danger of a heat-induced perforation of the gallbladder wall, we decided against repeated RFTA and the TACE procedure was started. The overall survival of this patient was 9.0 months (Table 4). Complications and Side Effects TACE therapy was tolerated well by most patients; however, in 6 of 15 patients mild to moderate problems in terms of postembolization syndrome occurred during the repeated procedures. Most frequently (six of six) patients reported a dull pain in the right upper quadrant that started during the TACE procedure and that usually resolved after symptomatic treatment with analgesics ( mg metamizole i.v.; mg paracetamol tbs/supp) on the same or the next day. Accompanying nausea and vomiting developed in four subsequent patients; vomiting was treated with metoclopramide (10 20 mg i.v.) or ondansetrone/tropisetrone infusion (2 5 mg i.v.). In one patient a gastroscopy was performed the next day, showing hypertensive gastropathy and esophageal varices grade III that required endoscopic ligature. Severe spasms of the appropriate hepatic artery developed in two patients, which had been treated five and six times before, respectively. In those cases the catheter was removed from the spastic vessel segment and nitroglycerin was given sublingually. Finally, the spasm was resolved and the chemotherapeutic agent could be discharged. In one patient (no. 4) Lipiodol displacement during the sixth TACE was visualized in the postinterventional CT scan. A pathologic enhancement of the gastric tissue was seen owing to Lipiodol displacement presumably through the gastroduodenal artery resp. gastric branches. Subsequently the patient developed gastric ulceration, which was confirmed by endoscopy the next day. The ulceration was treated by proton pump inhibition over 7 days (20 mg i.v. omeprazole daily). The situation improved so that TACE could be continued. The same patient developed anaphylactic shock after the 12th TACE from the contrast medium injection (Fig. 2 A C). After hemodynamic stabilization the patient had to be admitted to the intensive care unit. Again, after improvement, TACE was continued using gadolinium as contrast medium for the intervention (Table 5).

6 S. Herber et al.: TACE for Inoperable Intrahepatic Cholangiocarcinoma 1161 Table 4 Patients tumor characteristics including course of disease, CT findings, and additional therapy Patient No. Gender; age (yr) No. TACEs. Course/status Tumor size (cm)/location Tumor lesions (no.) CT findings/complications Additional therapy Survival (mo) 1 M; Stable/dead 6 3/right lobe 1 Nausea, vomiting, fever M; Progression/ 7 5/right lobe 1 Mild segmental cholestasis 8.8 dead 3 M; Progression/ dead 4 F; Stable/Alive 13 9/right lobe 5 F; Stable/dead 16 9/both lobes 6 F; Partial response/ Alive 7 F; Progression/ dead 8 F; 46.4y 7 Stable/dead 8 7.5/left lobe 9 F; Progression/ dead 5 4/right lobe 2 Chemotherapy; RFTA pre-tace 1 Gastric ulcer due to Lipiodol displacement /left lobe 1 Portal vein thrombosis, functional decompensation PTCD /left lobe 6 Periportal adenopathy /both lobes 10 F; Stable/dead 12 9/both lobes 11 M; Stable/dead 2 2/both lobes 12 F; Progression/ dead 14 7/right lobe 13 F; Stable/dead 13 7/both lobes 14 M; Stable/dead 18x16/right lobe 1 Peritoneal carcinomatosis, cholestasis >10 (miliary tumor) Chemotherapy; PTCD pre-tace 38.7 Periportal adenopathy Chemotherapy Hilar infiltration, cholestasis PTCD pre-tace 9.2 >10 Miliary tumor 15 F; Stable/alive 12x9/both lobes >10 Miliary tumor Note. Chemotherapy was carried out with gemcitabine prior to TACE in each case Nausea, vomiting, fever Chemotherapy Periportal adenopathy Portal vein thrombosis Resection post- TACE Portal vein thrombosis 3.5 Portal vein thrombosis 7.0 Discussion We present the results for patients treated at a single center with TACE for intrahepatic CCA. The tumors in all patients were rated as unresectable by an interdisciplinary tumor board due to the extensive tumor spread and the infiltration or encasement of intrahepatic vessels or due to severe limiting comorbidity. Four of 15 patients were admitted to TACE because of substantial tumor progression under gemcitabine chemotherapy. TACE was offered to those patients as perhaps the last alternative treatment approach. In the remaining patients TACE was given as first-line therapy. This proceeding was based, on one hand, on the disappointing results that systemic chemotherapy has shown in the past. The median survival for patients treated with systemic chemotherapy ranges even in modern phase II trials only between 6.5 and 11.5 months [13 16]. On the other hand, the decision for TACE was influenced by the positive experiences that we have collected in the past decade in treating patients with HCC [17, 21, 22]. However, whereas the value of palliative TACE in patients with HCC has been confirmed by recent randomized trials [6, 7], to our knowledge only a few rare case series have dealt with the effect of chemoembolization or chemoperfusion in patients with CCA [8, 23 24]. Although the majority of CCAs are hypovascular and therefore they might appear not to be suitable for an arterial embolization, the arterial supply of the biliary tree arises from branches of the hepatic artery. Accordingly it should be possible to target intrahepatic CCAs much more selectively by chemoembolization than by systemic chemotherapy [8]. But there is no consensus about the ideal i.v. chemotherapy in CCA; however, there is even less agreement about the chemotherapeutics for locoregional treatment. In addition to mitomycin C, which has been used for several years in the treatment of HCC and CCA,

7 1162 S. Herber et al.: TACE for Inoperable Intrahepatic Cholangiocarcinoma Fig. 2 (A C) Patient 4, a 57-year-old woman. Histologically confirmed CCA, tumor grade G3, with large infiltration of the right and left (segment 4) liver lobe. Contrast-enhanced helical spiral CT (A) shows a cm, centrally hypodense tumor with a hypervascularized peripheral rim (arrows). After chemoembolization (B) postinterventional CT demonstrates peripheral Lipiodol accumulation (arrows), with only a slight enhancement in the central parts (star). After the 12th TACE (C) and a 2.5-year course, the arterial phase reveals complete peripheral devascularization and a moderate decrease in tumor size gemcitabine, cisplatin, and doxorubicin are used for chemoembolization either as monotherapy or in combination with other chemotherapeutics [8, 18 20, 23 25, 28 31]. At our institution TACE was performed with a mixture consisting of a fixed dose of mitomycin C as a single chemotherapeutic drug and ml of Lipiodol at 8- week intervals. Instead of this, Burger et al. used a combination therapy of doxorubicin, cisplatin, and mitomycin C, with subsequent particulate embolization [8]. In contrast to Burger and to other authors, we did not administer permanently or even temporarily occluding agents due to the potential danger of irreversible vessel occlusion that might prevent further TACE treatments [8, 23, 24]. According to this Kirchhoff et al. reported an unintentional vessel occlusion in four of eight patients following particulate embolization [23]. Therefore, only a median of 2.0 TACE could be performed in each patient. Kirchhoff et al. reported that follow-up angiography revealed progressive rarefication of the intrahepatic arteries. They suggested that this finding might be related either to the toxicity of the chemotherapeutic agent and subsequent arteritis or, and this appears more appropriate, to ischemic reactions that could have been aggravated by the use of particulate embolization [23]. If we consider that 75% tumor necrosis is the best one can achieve in half of the treated patients, even with the use of an aggressive regimen as presented by Burger et al., the role of occluding agents in CCA should be discussed critically [8]. When further treatment sessions are required the approach to the segmental, tumor-supplying vessels should not be aggravated by particulate embolization. In our cohort treatment did not have to terminated in any patient because of premature vessel occlusion, which may be related to the fact that we refrained from using particles. So far we have performed a mean of 3.9 TACEs in each patient. Vogl et al. presented a dose-increase study in 2006 dealing with chemoembolization in patients with hepatic malignancies [24]. They administered gemcitabine as intraarterial monotherapy or in combination with starch microspheres. Although only 12 patients were included in each group, they found some benefit for patients treated with chemoembolization compared to the study group, which received only chemoperfusion. For assessment of therapeutic success they used contrast-enhanced helical spiral CT in follow-up investigations, as we did. Actually multislice detector CT revealed a peripheral hypervascularized

8 S. Herber et al.: TACE for Inoperable Intrahepatic Cholangiocarcinoma 1163 Table 5 Side effects and complications No complications 9 of 15 pts Complications 6 of 15 pts Number Classification Complications (total no.) minor/2 major Nausea/vomiting 4 Minor B Abdominal pain 6 Minor B Spasm of hepatic arteries 2 Minor B Lipiodol displacement 1 Major D Anaphylactic shock 1 Major D Death (30 ± 3 days) 0 Note. A total of 12 minor and 2 major complications were registered in six patients owing to simultaneous occurrence of vomiting and abdominal pain in four patients zone in most cases, and accordingly, the majority of tumors presented a ring-like pattern of Lipiodol accumulation in the tumor periphery in postinterventional CT controls. [8, 26, 27]. But even though the local Lipiodol enhancement facilitated the depiction of the tumor and its borders, one should be aware that owing to the use of Lipiodol, the portion of viable tumor and the degree of necrosis could not be assessed reliably. Therefore, treatment success or failure was not proved by the assessment of tumor necrosis but by evaluation of the tumor size that was determined according to the RECIST criteria [10]. The objective response rate, i.e., partial or complete response, was strictly disappointing [8]. In only one single patient did analysis of our CT data indicate a significant decrease in tumor size rated as a partial response. In this patient the maximum tumor size decreased by almost 40% after five TACE procedures. The patient is still alive 13.5 months after diagnosis of a large CCA with a maximum diameter of 12 cm in the cross-sectional image. Due to progressive deterioration of liver function, TACE was suspended after the partial response since the time of writing. Meanwhile liver function has stabilized and the patient is still in fair condition. The mean overall survival in our cohort was 21.1 months, with a median survival of 16.3 months. The 95% confidence interval was 9.4 to 32.5 months. This result is comparable to those reported by Burger et al. and Vogl et al. [8, 24]. In their recently published studies, they reported a survival of 23.0 and 20.2 months, respectively. The 1- and 3-year survival in our cohort calculated by the Kaplan-Meier method was 54.5% and 27.3%, respectively. According to this Tanaka et al. reported quite similar results for a chemoperfusion study in 2002 [25]. They implanted arterial ports with access to the hepatic artery and performed chemoperfusion of the intrahepatic CCA. Their mean number of treatment cycles was an astonishing 51. Thereby they reached a mean survival of 26 months with a >50% response rate [25]. Whereas our regimen was similar to those of Burger et al. and Vogl et al., the study by Kirchhoff and colleagues included, besides TACE, systemic chemotherapy with intravenous application of gemcitabine. They reported a median survival of only 12 months and, as mentioned above, attributed this fair result to the high rate of premature vessel occlusions [23]. Which patients profit from this treatment? TACE failed to improve survival in patients suffering from a military-type tumor with disseminated nodules and giant tumors with multiple satellites. In those patients the mean survival was disappointing, at 3.4 months. TACE did not prolong survival or improve the quality of life, and in retrospect, the indication has to be questioned very critically. Death in those patients was attributed to rapid tumor progression combined with tumor cachexia. In contrast, patients with a more focal tumor disease that was ideally limited to a single liver lobe showed the best outcome. The mean survival in these cases was 27.5 months, which is superior to most of the historical data for i.v. chemotherapy [29, 32 34]. In particular, four patients showed a favorable course of disease with a long-term survival of >18 months. In seven others we achieved some improvement, with survival of between 9.0 and 17.3 months. As mentioned at the beginning, systemic chemotherapy with gemcitabine was carried out in four patients prior to TACE. Comparable to Burger et al., who reported a benefit of TACE in three patients in whom systemic chemotherapy had failed, two patients in our cohort potentially benefited from the TACE treatment and one showed a 9.0-month survival after the last TACE, although the intrahepatic tumor growth could not be stopped. The other patient was a woman who showed tumor progression under systemic chemotherapy and was therefore referred for TACE as the last therapeutic option. She showed a very favorable course of disease, with survival of >3 years, but finally died as a result of extrahepatic tumor spread with peritoneal carcinomatosis and tumor consumption. In patients suffering from HCC, TACE has been shown its ability to substantially shrink carcinomas and to enable either operation or locoregional thermoablation therapy [15, 16]. So far in the cohort of Burger et al., operation was enabled due to TACE treatment in two patients who converted from inoperable to operable status [8]. In our small cohort TACE therapy was performed in one patient prior to extended right hemihepatectomy. The follow-up CT 3 months after TACE revealed a stable tumor size but there was no evidence of tumor shrinkage. So far we cannot claim that our treatment regimen is of value in terms of downsizing the tumor or giving a curative therapy option such as surgery.

9 1164 S. Herber et al.: TACE for Inoperable Intrahepatic Cholangiocarcinoma The limitations of the present study are obvious. First, this evaluation was carried out retrospectively, which implicates all the disadvantages associated with retrospective work. Second, this study had to contend with the same problems shared by most recently published studies: a small cohort of patients owing to the uncommon disease being studied. Therefore, the results have to be interpreted with caution, and a bias due to a natural positive course that might be present in an individual patient has to be taken into consideration. Conclusion In patients with intrahepatic CCA, TACE has been suggested to be a safe method with a moderate and tolerable frequency of complications, considering the dismal prognosis for these patients. 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