Intrahepatic CCC Research Articles

Therapeutic effect of regional chemotherapy in diffuse metastatic cholangiocarcinoma

Background: Current therapeutic options in diffuse metastatic cholangiocarcinoma (CCC) are limited with unsatisfactory results. We evaluated the efficacy of regional chemotherapy (RegCTx) using arterial infusion (AI), hypoxic stop-flow abdominal perfusion (HAP), upper abdominal perfusion (UAP) and isolated-thoracic perfusion (ITP) in 36 patients with metastatic perihilar and intrahepatic CCC.

Therapeutic Effect of Regional Chemotherapy in Diffuse Metastatic Cholangiocarcinoma.

Simple SummaryCholangiocarcinoma are mostly diagnosed at a late stage and early recurrence is also very common with 5-year survival rates of <5% in unresectable, and 33% in resectable disease. Systemic therapy options are limited with unsatisfactory outcome. The aim of our study was to assess the efficacy of regional chemotherapy in diffuse metastatic cholangiocarcinoma. In 36 diffuse metastatic cholangiocarcinoma patients 189 cycles of regional chemotherapy using arterial infusion and perfusion techniques have been applied. Regional chemotherapy provided an excellent outcome with a median therapy specific survival of 12 months. Regional chemotherapy is effective and superior to current available and proposed therapy options in diffuse metastatic cholangiocarcinoma.Background: Current therapeutic options in diffuse metastatic cholangiocarcinoma (CCC) are limited with unsatisfactory results. We evaluated the efficacy of regional chemotherapy (RegCTx) using arterial infusion (AI), hypoxic stop-flow abdominal perfusion (HAP), upper abdominal perfusion (UAP) and isolated-thoracic perfusion (ITP) in 36 patients with metastatic perihilar and intrahepatic CCC. Methods: Ten patients had previously undergone a liver resection and in 14 patients the previous systemic chemotherapy (sCTx) approach had failed. A total of 189 RegCTx cycles (90 AI, 74 UAP, 13 HAP and 12 ITP) were applied using cisplatin alone or with Adriamycin and Mitomycin C. A minimum of three cycles were applied in 75% of the study population. The response was evaluated using RECIST criteria with MediasStat 28.5.14. Mortality, morbidity and survival analysis were performed using a prospective follow-up database and SPSS–28.0. Results: No procedure related mortality occurred. The overall morbidity was 56% and dominated by lymph fistulas at the inguinal access site. No grade III or IV haematological complication occurred. The overall response rate was 38% partial response, 41% stable and 21% progressive disease. Median overall survival was 23 months (95%CI 16.3–29.7). The RegCTx specific survival was 12 months (95%CI 6.5–17.5) in completely therapy naive patients but also in patients who had failed a sCTx attempt previously. Conclusion: RegCTx is feasible, safe and superior to the current proposed therapeutic options in metastatic CCC. The role of RegCTx should be determined in a larger cohort of diffuse metastatic CCC patients but also at early stages especially in initially not resectable but potentially resectable patients.

Liver transplantation for intrahepatic and hilar cholangiocellular carcinoma: Most recent updates in the literature.

Liver transplantation (LT) for non‐hepatocellular carcinoma is still a debatable indication. Recently, hilar cholangiocellular carcinoma (hCCC) has attracted interest as a new indication for LT, but LT in this case should be carefully considered. Based on the recent meta‐analysis for intrahepatic CCC (IHCCC) and our results from incidental IHCCC transplanted for other diseases such as primary sclerosing cholangitis, the indication for LT for IHCCC should be limited to a single tumor less than 2 cm. For hCCC, with pre‐transplant chemoradiotherapy and careful selection criteria, long‐term survival after LT could be attained. In order to improve the results of LT for intrahepatic and hCCC, further studies are required on the ingenuity of immunosuppressive therapy combined with chemotherapy, and optimal treatment methods to prevent recurrence, as well as initial case selection.

Efficacy and safety of nab-paclitaxel plus gemcitabine-cisplatin (GemCis/nab-P) in Korean patients with advanced biliary tract cancers (aBTC): Multicenter retrospective analysis.

274 Background: A recent phase II trial (NCT02392637) demonstrated prolonged survival by treatment with GemCis/nab-P in patients (pts) with aBTC. Further evaluation in real-world setting is necessary to measure the clinical outcomes of GemCis/nab-P in daily practice in Asian pts. Methods: This is a multicenter retrospective analysis of data from 3 institutes in Korea. Between September 2019 and August 2020, a total of 104 pts who received GemCis/nab-P for the management of aBTC were included in this analysis. Results: Median age was 64 years (range, 34-84), and 60 pts (57.7%) were male. GemCis/nab-P was used as the starting regimen in 60 pts (57.7%), 16 pts (15.4%) received GemCis/nab-P after failure of GemCis ± investigational drug (mainly immune checkpoint inhibitors), and 28 pts (26.9%) added nab-P to initial Gem/Cis without progressive disease. Baseline characteristics were as follows: Intrahepatic cholangiocarcinoma (CCC)/extrahepatic CCC/gallbladder cancer in 42 (40.4%)/33 (31.7%)/29 (27.9%); metastatic or recurred/locally advanced in 82 (78.8%)/22 (21.2%) pts. According to RECIST v 1.1, objective response rates (ORR) and disease control rate (DCR) were 30.8% and 81.8% of all pts, 33.4% and 88.4% in initial GemCis/nab-P, 28.6% and 73.8% in intrahepatic CCC, 36.3% and 96.9% in extrahepatic CCC, and 27.6% and 75.9% in gallbladder cancer groups, respectively. In nab-P addition group, while the ORR and DCR of pts without GemCis failure were 39.3% and 85.7%, those with GemCis failure were 6.3%, 50.0%, respectively. Median overall survival and progression-free survival were not reached, with a median follow-up duration of 3.3 months (95% confidence interval [CI], 2.9-6.7). The most common grade 3-4 toxicities were neutropenia (n=36, 34.6%), anemia (n=17, 16.4%), thrombocytopenia (n=10, 9.6%), and febrile neutropenia (n=9, 8.1%). In patients with locally advanced BTC (n=22), 5 patients (22.7%) were converted to resectable disease and underwent surgery. Conclusions: GemCis/nab-P showed consistent real-life efficacy and safety outcomes for Korean aBTC pts compared with those from the phase 2 trial. [Table: see text]

Liver Transplantation in Mixed Hepatocellular Carcinoma and Cholangiocarcinoma

Mixed hepatocellular carcinoma and cholangiocarcinoma (HCC-CC) are rare tumors, and the risk factors associated with them are not well understood yet. Moreover, the diagnosis of mixed HCC-CC can be complicated due to the difficulty in distinguishing mixed HCC-CC from HCC and intrahepatic CCC on radiological images. Serum tumor markers are useful when the radiological images are inconclusive. It remains unclear whether the prognosis of mixed HCC-CC differs from that of HCC. However, several studies have reported that the tumor recurrence and patient survival rates of mixed HCC-CC were similar to those of HCC after liver transplantation (LT) and liver resection. In this paper, we report that LT in patients with mixed HCC-CC achieves outcomes which are similar to those seen in LT for HCC. Therefore, the diagnosis of mixed HCC-CC should not be considered as a contraindication for LT. (J Liver Cancer 2019;19:85-90)

Aspirin use is associated with a reduced risk of cholangiocarcinoma: a systematic review and meta-analysis.

BackgroundAspirin has been revealed to probably decrease the risk of cholangiocarcinoma (CCC), which, nevertheless, is of controversy. To this end, a systematic review and meta-analysis was performed to investigate the above-described association.MethodsWe thoroughly searched PubMed, EMBASE, and ISI Web of Science for relevant studies published prior to October 2017, followed by random-effects model for calculation of pooled ORs and corresponding 95% CIs. Additionally, subgroup and sensitivity analyses were carried out to confirm whether the outcomes were stable.ResultsNine articles, consisting of 12,535 CCC patients and 92,97,450 healthy controls, were enrolled in this study. We demonstrated a significantly decreased risk of CCC in those using aspirin, with studies being heterogeneous (OR=0.69; CI=0.43–0.94; I2=97.4%). Moreover, this relationship was detected only in case-control studies (OR=0.65; 95% CI=0.38–0.93), rather than cohort studies (OR=0.94; 95% CI=0.70–1.27). Besides, in separated analysis of intrahepatic CCC and extrahepatic CCC, aspirin was more strongly correlated with a declined risk of intrahepatic CCC (OR=0.33, 95% CI=0.26–0.39; I2=93.6%) than the risk of extrahepatic CCC (OR=0.56, 95% CI=0.41–0.73; I2=0%).ConclusionCollectively, the aspirin administration was correlated with a significant 31% decreased risk of CCC, particularly in the intrahepatic CCC.

Downstaging of unresectable intrahepatic or hilar cholangiocellular carcinoma by selective intra-arterial floxuridine and systemic cisplatin and gemcitabine. A dose finding single center phase IIa study.

478 Background: Patients with unresectable cholangiocarcinomas (CCC) have a poor prognosis even if palliative systemic chemotherapy is offered. A combined approach of systemic and intrahepatic chemotherapy may improve local control rates and allow downstaging. The aim of the study was to determine the maximum tolerated dose (MTD) of systemic intravenous gemcitabine in combination with intravenous cisplatin and hepatic arterial infusion with floxuridine in patients with unresectable intrahepatic or hilar CCC. Safety, toxicity, response rates and resectability rates after 3 months of combination treatment are reported. Methods: 12 patients were treated within a 3+3 dose escalation algorithm with 600, 800 or 1000 mg/m2 gemcitabine and a fixed dose of cisplatin 25 mg/m2 systemic chemotherapy on day 1, 8 every 3 weeks for 4 cycles and floxuridine 0,2 mg/kg on day 1-14 continous hepatic intra-arterial chemotherapy every 4 weeks for 3 cycles. PET/CT and/or CT scan was performed after 12 weeks. Results: The MTD of gemcitabine was 800 mg/m2 in this setting. Dose-limiting toxicities were recurrent biliary tract infections (n = 1) and neutropenic fever (n = 1). Response rates were: 27% partial remission and 73% stable disease. Although none of the patients achieved resectability after 3 months, 3-year-overall survival (OS) was 33%, median OS 21,9 months (1-49) and median progression-free survival 10,5 months (2-40). Conclusions: Combination of systemic gemcitabine and cisplatin plus intraarterial floxuridine is feasible and appears effective in disease control, but achievement of resectability seems challenging. Randomized trials comparing this combination to gemcitabine/cisplatin alone are warranted. Clinical trial information: NCT01692704.

Diagnostic and Prognostic Aspects of Hepatocellular Carcinoma – A Retrospective Analysis in 145 Patients

BACKGROUND: Prognosis of advanced hepatocellular carcinoma (HCC) is still poor. In this retrospective study prognostic factors for long-term survival and an immunohistochemical panel for discrimination of HCC from other liver malignancies were analyzed. MATERIALS AND METHODS: In 181 primary liver tumors clinical data, tumor characteristics and the primary mode of treatment were analyzed using univariate and multivariate statistics. In 156 cases (145 HCC, 36 intrahepatic CCC) the immunohistochemical profile of the tumor tissue using molecular markers as HepPar-1, AFP, CD34, CK7, CK20, CA19-9 and CDX2 was established routinely. Significance of marker expression, sensitivity, specify and positive predictive value of the analyzed markers in relation to histological subtype were estimated using SPSS 10.0 RESULTS: Median overall survival (OS) was 15 ± 19.2 months. Multivariate analysis identified tumour size (p = 0.001), grading (p = 0.002), proliferative activity (Ki67 level; p = 0.032), multifocal tumour (p = 0.045), liver function (Child-Pugh score, p = 0.045) and performed tumour resection (p < 0.0001) as independent prognostic factors for survival. HepPar-1 was the most frequently expressed marker in HCC (positive in 71.8%; p < 0.0001) whereas positive AFP staining was less common (positive in 48.7%; p < 0.0001). The CD34 protein as a marker for vascular-associated tissue showed a positive reaction in 54.1% of tissues from HCC patients in comparison to 2 patients (6%) with cholangiocarcinoma (p < 0.0001). CONCLUSIONS: Our data identified tumor stage, tumor biology and performed surgical therapy as independent prognostic factors for OS in HCC. Best predictive markers for differentiation between HCC and CCC were HepPar-1, CK7 and CA19-9. Using this panel fast and accurate differentiation by IHC was possible in more than 95% of the patients.

Hepatology highlights

Hepatology highlights

Developments of treatment of advanced intrahepatic cholangiocarcinoma: An analysis of systemic and local therapy modes in 57 patients.

346 Background: Treatment of advanced CCC remains difficult. Sophisticated therapy of individual locations is essential due to differing biological characteristics. Apart from recent systemic therapeutic approaches, combined treatments using, among others, locally ablative procedures offer chances of extended life expectancy. Methods: This analysis is based on a phase II study on treatment of advanced BTC (biliary tract cancer) with gemcitabine/docetaxel(G/D) in 79 patients (pts).Observing purely intrahepatic CCC, omitting Klatskin tumors, modes of therapy were advanced further. In addition to local ablation by TACE (TA) systemic therapy was modified using Gemcitabine/Oxaliplatin(G/O). TACE could only be employed initially in purely intrahepatic inoperable findings. Treatment was later adjusted using local brachytherapy followed by intraarterial chemotherapy with 5-FU (AL + i.a.). A retrospect data analysis of 57 pts diagnosed with advanced intrahepatic CCC was deployed after collecting cases prospectively. A matched pair analysis in relation to data from systemic treatment was performed. Ultimately, 5 groups were formed: 1- 12 pts being treated with TACE only (TA); 2- 15 pts receiving TACE initially followed by systemic therapy of progressive disease (TA+G/D); 3- 11 pts receiving G/D; 4- 14 pts receiving G/O; 5- 5 pts receiving AL+i.a. Treatment continued until either disease progressed or inacceptable side effects occurred. Results: Median time of survival in the TA group was 4.2 months, TA+G/D 20.1 months, G/D 8.5 months and G/O 15.0 months. Currently no conclusive data has been obtained in the AL+i.a. group, yet. Median time to tumour progress was 2.1 months in TA, 5.1 months in TA+G/D, 3.5 months in G/D and 7.7 months in G/O. In the G/O group a case of secondary respectability occurred. Results were achieved with an acceptable toxicity profile and satisfactory quality of life. Conclusions: When the advanced intrahepatic CCC, voiding Klatskin tumours, are limited to the liver and do not offer the possibility of surgical intervention, a combination of treatments should be commenced. Improved systemic protocols can additionally achieve extended time of survival.

Treatment of unresectable cholangiocarcinoma

Unresectable cholangiocarcinoma (CCC) has a poor prognosis. Patients with intrahepatic CCC have a very limited benefit from systemic chemotherapy (ChT). The aim of this prospective study was to evaluate the feasibility, safety, and efficacy of conventional transarterial chemoembolization (cTACE) with mitomycin-C and of irinotecan-eluting beads (iDEB-TACE), and to retrospectively compare them with ChT with oxaliplatin and gemcitabine. Between June 2002 and June 2010, three independent prospective trials were carried out and compared retrospectively. Following predefined study protocols, 26 patients with histologically proven intrahepatic CCC were treated with iDEB-TACE (200 mg irinotecan), 10 patients were treated with cTACE using 15 mg mitomycin-C mixed with 5-10 ml of ionized oil (lipiodol), followed by embolization with gelfoam, and 31 patients received systemic ChT with gemcitabine and oxaliplatin. Treatment response and progression-free survival (PFS) were assessed by computer tomography or MRI every 2 months according to Response Evaluation Criteria in Solid Tumors. Clinical and laboratory data were assessed for side-effects according to National Cancer Institute-Common Toxicity Criteria. iDEB-TACE resulted in PFS of 3.9 months and overall survival (OS) of 11.7 months, compared with a PFS of 1.8 months and OS of 5.7 months, respectively, in patients treated with cTACE, and a PFS of 6.2 months and OS of 11.0 months, respectively, in patients treated with oxaliplatin and gemcitabine. The medium follow-up of patients treated with iDEB-TACE was 12 months; 2 months after treatment, 13 patients (50%) had progressive disease, 11 patients (42%) had stable disease, and one patient had a partial response and became eligible for secondary liver resection. Local tumor control was achieved in 66% of patients; 4% had a partial response, 62% had stable disease, and 27% progressive disease. Common Toxicity Criteria grade III or IV toxicities for iDEB-TACE were abdominal pain (n=7), hepatic abscess (n=1), pleural empyema due to biliary leakage (n=1), and one death due to cholangitis with hepatic failure in a patient with liver cirrhosis. No hematological side-effects were observed. Almost every patient experienced a 'postembolization syndrome' with low-grade fever, nausea, and abdominal pain for up to 2 weeks. This is the first study demonstrating that treatment of patients suffering from intrahepatic CCC with iDEB-TACE is safe in patients with normal liver function, and results in a prolongation of PFS and OS. Local tumor control, PFS and OS seem similar to systemic ChT with oxaliplatin and gemcitabine, but superior to cTACE.

Transarterial chemoembolization of intrahepatic cholangiocarinoma with irinotecan-eluting beads: preliminary results

Purpose: Patients with unresectable cholangiocarcinoma have a poor prognosis with no standard systemic chemotherapy being established so far. According to recent publications patients with intrahepatic cholangiocarcinoma even respond to chemotherapy to a lesser extent than patients with extrahepatic choangiocarcinoma. Therefore, we performed a pilot study to evaluate the feasibility, safety, and efficacy of transarterial chemoembolization with drug-eluting beads (DEB-TACE) in patients with intrahepatic cholangiocarcinoma. Methods: Thirteen patients (7 female, 6 male) with unresectable intrahepatic cholangiocarcinoma and without evidence of extrahepatic tumor manifestation, aged 48 to 76 years (mean 66 years), underwent 21 sessions of DEB-TACE loaded with 200mg irinotecan between November 2007 and December 2008. Prior to DEB-TACE 7 patients (54%) had progressive disease and 2 (16%) had untolerable side effects under systemic chemotherapy, 3 patients (23%) had contraindications to and 1 (8%) patient refused systemic chemotherapy. Progression free survival was evaluated in 8 weeks intervals after therapy with computed tomography (CT) or magnetic resonance imaging (MRI) according to Response Evaluation Criteria in Solid Tumors (RECIST). Clinical and laboratory data were assessed for side effects according to NCI-CTC. Results: All 21 sessions of DEB-TACE were safely performed with no serious complications. 4 patients (31%) reported of heavy (grade 3) and 6 (46%) of moderate (grade 1 and 2) pain in the right upper abdomen up to two weeks after treatment. No haematological side effects or impairment of liver function tests (≥ grade 3) were observed. The median follow-up was 11 months (range, 4–16 months). Sixteen weeks after TACE, one patient (7%) had a partial response and was treated by liver resection, 8 of 13 patients (62%) had stable and 4 of 13 patients (31%) had progessive disease according to intention to treat analysis. Eight patients have no tumor progression so far with a mean progression free survival of 8.6 months. Conclusions: DEB-TACE with irinotecan is well tolerated and appears effective in patients with intrahepatic CCC. Even in patients pretreated with systemic chemotherapy DEB-TACE can lead to long lasting responses.

Identification of osteopontin as the most consistently over-expressed gene in intrahepatic cholangiocarcinoma: Detection by oligonucleotide microarray and real-time PCR analysis

To investigate the molecular pathways involved in human cholangiocarcinogenesis by gene expression profiling. Oligonucleotide arrays (Affymetrix U133A) were used to establish a specific gene expression profile of intrahepatic CCC in comparison to corresponding non-malignant liver tissue. To validate the expression values of the most overexpressed genes, RT-PCR experiments were performed. Five hundred and fifty-two statistically differentially expressed genes/ESTs (221 probes significantly up-regulated, 331 probes down-regulated; P < 0.05; fold change > 2; > or = 70%) were identified. Using these data and two-dimensional cluster analysis, a specific gene expression profile was obtained allowing fast and reproducible differentiation of CCC, which was confirmed by supervised neuronal network modelling. The most consistently overexpressed gene (median fold change 33.5, significantly overexpressed in 100%) encoded osteopontin. Furthermore, an association of various genes with the histopathological grading could be demonstrated. A highly specific gene expression profile for intrahepatic CCC was identified, allowing for its fast and reproducible discrimination against non-malignant liver tissue and other liver masses. The most overexpressed gene in intrahepatic CCC was the gene encoding osteopontin. These data may lead to a better understanding of human cholangiocarcinogenesis.

Effects of antiviral agents and HBV genotypes on intrahepatic covalently closed circular DNA in HBeAg-positive chronic hepatitis B patients

To evaluate the effects of antiviral agents and HBV genotypes on intrahepatic covalently closed circular DNA (ccc DNA) in HBeAg-positive chronic hepatitis B patients. Seventy-one patients received lamivudine (n = 35), or sequential therapy with lamivudine- interferon alpha 2b (IFN-alpha 2b, n = 24) for 48 wk, or IFN-alpha 2b (n = 12) for 24 wk. All subjects were followed up for 24 wk. Intrahepatic ccc DNA was measured quantitatively by PCR. HBV genotypes were analyzed by PCR-RFLP. Sequential lamivudine- INF-alpha therapy, lamivudine and INF-alpha monotherapy reduced ccc DNA of 1.7 log, 1.4 log and 0.8 log, respectively (P < 0.05). Seventeen out of the 71 patients developed HBeAg seroconversion, the reduction of ccc DNA in the HBeAg seroconversion patients was more significant than that in the HBeAg positive patients (3.0 log vs 1.6 log, P = 0.0407). Twenty-four weeks after antiviral therapy withdrawal, 16 patients had a sustained virological response, the baseline intrahepatic ccc DNA in the patients with a sustained virological response was significantly lower than that in the patients with virological rebound (4.6 log vs 5.4 log, P = 0.0472). HBV genotype C accounted for 85.9% (n = 61), and genotype B for 14.1% (n = 10), respectively, in the 71 patients. There was no significant difference in the change of ccc DNA level between HBV genotypes C and B (2.1 log vs 1.9 log). Forty-eight week sequential lamivudine-INF-alpha therapy and lamivudine monotherapy reduce ccc DNA more significantly than 24-wk INF-alpha monotherapy. Low baseline intrahepatic ccc DNA level may predict the long-term efficacy of antiviral treatment. HBV genotypes C and B have no obvious influence on ccc DNA load.

Presence of intrahepatic (total and ccc) HBV DNA is not predictive of HBV recurrence after liver transplantation

Previous studies reported that hepatitis B virus (HBV) deoxyribonucleic acid (DNA) can be detected in livers of patients who received transplants for hepatitis B despite the absence of serological markers of HBV recurrence. Quantification of HBV DNA was not performed and presence of covalently closed circular (ccc) DNA was not analyzed in most studies. We aimed to quantify total and ccc HBV DNA in explant liver and post-orthotopic liver transplantation (OLT) biopsies and to correlate the values with HBV recurrence post-OLT. Frozen liver tissue from 34 patients (9 with explant liver only, 9 with explant liver and post-OLT liver biopsies, and 16 with post-OLT biopsies only) in the National Institutes of Health HBV-OLT study was examined using real-time polymerase chain reaction (PCR). Among the 18 patients with explant liver, 7 were hepatitis B e antigen (HBeAg)-positive, 8 had detectable serum HBV DNA, and 10 received antiviral therapy prior to OLT. Total and ccc HBV DNA was detected in explant livers of 17 and 16 patients, respectively. Of the 10 patients who received antiviral therapy pre-OLT, serum HBV DNA was undetectable in 8 at transplantation but 7 had detectable total and ccc HBV DNA in their explant liver. Of the 25 patients with post-OLT biopsies, total HBV DNA was detected in 83% and ccc DNA in 17% of 47 biopsies, although only 2 patients had HBV recurrence. In conclusion, total and ccc HBV DNA could be detected in explant livers of most patients despite antiviral therapy pre-OLT. Total but not ccc HBV DNA could be detected in post-OLT liver biopsies of most patients despite undetectable serum HBV DNA and hepatitis B surface antigen (HBsAg). Our findings suggest that occult HBV reinfection occurs in most HBV patients after OLT and continued administration of appropriate prophylactic therapy is important in preventing overt HBV recurrence.

A prospective multicenter phase II trial of capecitabine plus oxaliplatin (CapOx) in advanced biliary system adenocarcinomas: The final results

4136 Background: To investigate the safety and efficacy of capecitabine and oxaliplatin combination therapy (CapOx) in unresectable or metastatic adenocarcinomas of the biliary system. Methods: 65 patients (pts) (27 male, and 38 female) were enrolled (median age, 61 yrs). Major eligibility criteria: histologically proven, measurable disease, age ≤ 75 yrs, ECOG PS 0–2. A total number of 364 cycles (median, 5; range, 1–16) of oxaliplatin (130 mg/m2, d1) plus capecitabine (2 g/m2, d 1–14) were administered 3 weekly for gallbladder carcinoma (GBC) (27 pts), extrahepatic (20 pts), and intrahepatic (18 pts) cholangiocarcinoma (CCC). Response rates were assessed according to WHO criteria. Clinical outcome was determined separately for pts with either GBC/extrahepatic CCC or intrahepatic CCC (mass-forming type). Results: Grade 4 toxicities (WHO): diarrhea in 1 pt (1% of cycles), thrombocytopenia in 1 pt (1%), leukocytopenia in 1 pt (1%), and fever in 2 pts (1%); grade 3 toxicities: nausea/vomiting in 1 pt (1%), diarrhea in 2 pts (1%), thrombocytopenia in 3 pts (2%), and fever in 1 pt (1%). Grade 3/4 peripheral sensory neuropathy (Lévis scale) was found in 13 pts (14% of cycles). Two pts were excluded from study because of oxaliplatin-related allergic reactions. One patient died due to sepsis and another due to cerebral insult during the first treatment cycle. The overall disease control rate in 47 pts with GBC or extrahepatic CCC was 72% (complete response (CR), n = 2 (4%); partial response (PR), n = 11 (23%); stable disease (NC), n = 21 (45%)), whereas progressive disease (PD) was found in 13 pts (28%). In 18 pts with intrahepatic mass-forming CCC, no CR or PR was observed, 5 pts (28%) had SD, and 13 pts (72%) experienced PD. Conclusions: The CapOx protocol is well tolerated and remarkably active for advanced GBC as well as extrahepatic CCC with a disease-control rate of 72%. However, activity appears to be limited in the subset of pts with intrahepatic mass-forming type tumors. Survival data will be presented at the meeting. No significant financial relationships to disclose.

Intrahepatic Hepatitis B Virus Covalently Closed Circular DNA Can Be a Predictor of Sustained Response to Therapy

This study aimed to determine whether intrahepatic hepatitis B virus (HBV) covalently closed circular (ccc) DNA and total HBV DNA levels at the end of therapy would predict sustained response to therapy. Hepatitis B e antigen (HBeAg)-positive chronic hepatitis B patients receiving either lamivudine monotherapy or combination of peginterferon and lamivudine had liver biopsy at the end of 1 year therapy and were followed for 52 more weeks after cessation of therapy. Serum HBV DNA, intrahepatic HBV ccc DNA, and total HBV DNA levels were determined. Forty-seven patients, including 34 males and 13 females, were studied. Twenty-seven patients received combination therapy, and 20 patients received lamivudine monotherapy. Twenty-nine patients had end-of-treatment virologic response, and 15 patients had sustained response 52 weeks after therapy. At the end of treatment, log serum HBV DNA levels correlated well with log intrahepatic HBV cccDNA and log intrahepatic total HBV DNA levels. Log intrahepatic cccDNA and log intrahepatic total DNA levels were significantly lower among patients with sustained virologic response. The adjusted odds ratio for log cccDNA was 5.3 (95% CI: 1.5-18.2, P = .009) and, for log intrahepatic HBV DNA, was 4.4 (95% CI: 1.3-14.7, P = .015) to predict sustained virologic response. Using log cccDNA at -0.80 copies/genome equivalent as cutoff, the sensitivity, specificity, and positive and negative predictive values and accuracy of predicting sustained virologic response were 73%, 78%, 56%, 86%, and 77% respectively. Intrahepatic HBV cccDNA and intrahepatic total HBV DNA levels at the end of therapy are superior to serum HBV DNA as surrogates of sustained virologic response.

Combination Therapy of Pegylated Interferon alpha 2b (PegIFN) and Adefovir Dipivoxil (ADV) in Chronic Hepatitis B (CH-B) Patients Reduces the Reservoir of Transcriptionally Active cccDNA and Hepatitis B Surface Antigen (HBsAg)

Introduction: We previously demonstrated that 48 weeks of ADV therapy resulted in a significant median 73% reduction of serum HBsAg (Werle, Gastroenterology 2004). Changes in HBsAg were significantly and positively correlated with changes in intrahepatic cccDNA, total intrahepatocellular HBV DNA and serum HBV DNA. The number of HBcAg positive hepatocytes remained stable. Aim: To determine the reduction of serum HBsAg titer from baseline to end-of- treatment in CH-B patients undergoing antiviral combination therapy. Methods: 21/26 patients with HBeAg positive and negative CH-B completed a 48-week course of treatment with ADV and PegIFN in a single center pilot study as of September 2004. HBsAg was quantified in patient sera by ELISA using the Monolisa® AgHBs Ultra Kit (Biorad, France) with purified HBsAg as the standard (Hytest, Finland). Intrahepatic ccc- and HBV DNA was quantified as described earlier. Results: At baseline, median serum HBsAg titer was 257µg/ml. After 48 weeks of combination therapy median serum HBsAg titer decreased to 136µg/ml, a 47% reduction. cccDNA decreased from median 6 copies/hepatocyte to 0.2 copies/hepatocyte (–1.46log). Total intrahepatocellular HBV DNA was reduced by –2.1log10, serum HBV DNA decreased by–4.7log10. Changes in HBsAg were positively correlated with changes in total intracellular HBV DNA and serum HBV DNA. Conclusions: 48 weeks of combination therapy with PegIFN and ADV results in an approx. 50% decrease in serum HBsAg in chronic hepatitis B patients. Earlier studies suggested the decline in HBsAg titer during antiviral therapy with a nucleotide analogue due to the reduced reservoir of transcriptionally active cccDNA rather than to the loss of infected hepatocytes. Further analysis of this non-cytolytical mechanism for the clearance of HBV-infection is currently under way.

A multicenter phase II study of capecitabine plus oxaliplatin (CapOx) in advanced biliary system adenocarcinomas

4091 Background: To evaluate the feasibility of capecitabine and oxaliplatin combination therapy (CapOx) in unresectable or metastatic adenocarcinomas of the biliary system. Patients and methods: 56 pts (25M, 31F) were included (median age, 63 yrs). Major eligibility: histologic proven, measurable disease, age 18–75 yrs, ECOG PS 0–2. A total number of 250 cycles (median: 5; range 1–16) of oxaliplatin (130 mg/m2, d1) plus capecitabine (2000 mg/m2, d 1–14) were administered 3 weekly for gallbladder carcinoma (GBC) (20 pts), extrahepatic (20 pts), and intrahepatic (16 pts) cholangiocarcinoma (CCC). Pts were assessed for response according to WHO standard criteria. Clinical outcome was determined separately for pts with either GBC/extrahepatic CCC or intrahepatic CCC (mass-forming type), because these two distinct presentations have been supposed to differ substantially from each other according to clinical behaviour. Results: Grade 4 toxicities (WHO) were diarrhea in 1 pt (1% of cycles), thrombocytopenia in 1 pt (1%), leukopenia in 1 pt (1%), and fever in 2 pts (1%); grade 3 toxicities were: diarrhea in 2 pts (1%), thrombocytopenia in 3 pts (2%), and fever in 1 pt (1%). Grade 3/4 peripheral sensory neuropathy (Lévis scale) was found in 10 pts (15%). Two pts were removed from study due to oxaliplatin-related allergic reactions. One patient harboring intrahepatic CCC died with septic shock after the first treatment cycle. On 31 evaluable pts with GBC or extrahepatic CCC the response-rate was as follows: complete response (CR), 2 pts (6% of the pts); partial response (PR), 7 pts (23%); stable disease (NC) 15 pts (48%). Thus, the overall disease control rate (CR + PR + NC) was 77%, whereas 7 pts (23%) had progressive disease (PD). In contrast, in 16 evaluable pts with intrahepatic mass-forming CCC no CR or PR was observed, but 4 pts (25%) were found to have NC, and in 12 pts (75%) PD was encountered. Conclusions: Our preliminary data suggest the CapOx regimen to be well tolerable and highly active for advanced GBC and extrahepatic CCC (disease-control rate: 77%), whereas outcome might be poorer in intrahepatic CCC. Survival data will be presented at the meeting. No significant financial relationships to disclose.

Cholangiocarcinoma

Cholangiocarcinomas (CCC) are rare tumors with an incidence of 2-4/100,000 per year. They are a heterogeneous group of neoplasias that include the most common perihilar or Klatskin tumor (60%), the intrahepatic (peripheral) CCC, the extrahepatic bile duct cancer, the gallbladder cancer and the cancer of the ampulla of Vater. At the time of diagnosis only 20% of patients can be treated by surgery, that offers the only chance for cure. Due to high recurrence rates liver transplantation is not indicated. Patients with advanced unresectable carcinoma have a dismal prognosis with an overall survival rate of only 6-8 months. Neither chemotherapy nor radiation therapy improves survival. In patients not eligible for curative surgery prevention or treatment of cholestatis is the main objective. This can be achieved endoscopically, percutaneously or by surgical biliodigestive anastomosis. Palliative chemotherapy results in response rates up to 20%. The most frequently used agents are 5-FU and Gemcitabine that can be combined with external or internal radiation. By combining different treatment modalities significant survival can be achieved in some patients. Evidence Based Medicine studies are needed before treatment strategies can be recommended for clinical practice.