Biliary Tract Adenocarcinoma Research Articles

Nab-paclitaxel plus S-1 as first line treatment for advanced or metastatic biliary tract adenocarcinoma: A phase 2 study.

4089 Background: Gemcitabine plus cisplatin or S-1 can be used as first-line treatment for advanced or metastatic biliary tract adenocarcinoma. Multiple phase 2 studies found that gemcitabine, oxaliplatin, capecitabine, S-1 were not superior to gemcitabine plus cisplatin. Nab-paclitaxel plus S-1 was effective and well-tolerated in pancreatic cancer. Methods: Patients with pathological confirmed advanced or metastatic biliary tract adenocarcinoma (gallbladder carcinoma, intrahepatic cholangiocarcinoma ICC, extrahepatic cholangiocarcinoma ECC) were treated with Nab-paclitaxel plus S-1(Nab-paclitaxel 120mg/m2, d1 and d8; S-1 80-120mg/d, d1-14; q21d). Patients that received PR or SD (RECIST1.1)after 6 cycles were given S-1 maintenance treatment. The primary endpoint was ORR. The study used Simon’s Two Stage design. Results: From March 2016 to September 2018, we recruited 54 patients, with 27 males (50%). The median age was 58(34-73yrs). As of Dec 31 2018, the median treatment cycle was 4(1-6 cycles). 51 patients were evaluable for efficacy: PR 14(27.5%), SD 22 (DCR=PR+SD: 70.6%), PD 15 (29.4%). The median PFS was 6 months, and the median OS was 13.2 months. The response rate varied in different tumor location: gallbladder carcinoma 53.8% (7/13), ICC 18.2% (6/33), ECC 20% (1/5).Common grade 3/4 AEs were: leucopenia 17 (31.5%), hyperbilirubinemia 5(9.3%), Mucositis 4 (7.4%), neurotoxicity 2 (3.7%), diarrhea 2 (3.7%), omit 1(1.9%), fatigue 1 (1.9%), thrombocytopenia 1 (1.9%), ALT increase 1 (1.9%). Conclusions: Nab-paclitaxel plus S-1 as first line treatment for advanced or metastatic biliary tract adenocarcinoma was effective and well-tolerated, especially for gallbladder carcinoma (ORR 53.8%). This regimen need further exploration. Clinical trial information: NCT03830606.

Nivolumab alone or in combination with cisplatin plus gemcitabine in Japanese patients with unresectable or recurrent biliary tract cancer: a non-randomised, multicentre, open-label, phase 1 study

This study aimed to assess the safety and tolerability of the immune checkpoint inhibitor nivolumab, as monotherapy or combined with chemotherapy, in Japanese patients with biliary tract cancer. This multicentre, open-label, phase 1 trial was done at four cancer centres in Japan. Eligible patients were aged 20-79 years, had biliary tract adenocarcinoma (intrahepatic bile duct cancer, extrahepatic bile duct cancer, gallbladder cancer, or ampullary cancer), Eastern Cooperative Oncology Group performance status 0 or 1, adequate hepatic, renal, and haematological function, and tumour tissue samples for PD-L1 expression analysis. Patients with unresectable or recurrent biliary tract cancer that was refractory or intolerant to gemcitabine-based treatment regimens received nivolumab monotherapy (240 mg every 2 weeks [monotherapy cohort]). Chemotherapy-naive patients with unresectable or recurrent biliary tract cancer received nivolumab (240 mg every 2 weeks) and cisplatin (25 mg/m2) plus gemcitabine (1000 mg/m2) chemotherapy (combined therapy cohort). The primary objective was to assess tolerability and safety. The primary objective was assessed in the safety population of all patients who had received at least one dose of nivolumab. This study is registered with www.clinicaltrials.jp, number JapicCTI-153098, and follow-up is ongoing. 30 patients were enrolled into each cohort between Jan 13, 2016, and April 19, 2017. Data cutoff was Aug 31, 2017. In the monotherapy cohort, the most frequently reported treatment-related adverse events were decreased appetite (five [17%]), malaise (four [13%]), and pruritus (four [13%]). Grade 3-4 treatment-related adverse events were reported by three (10%) patients (rash, maculopapular rash, and amylase increase) and treatment-related serious adverse events were reported by one (3%) patient (pleurisy). In the combined therapy cohort, the most frequently reported treatment-related adverse events were neutrophil count decrease (any grade 25 [83%]; grade 3-4 in 23 [77%] patients) and platelet count decrease (any grade 25 [83%] of 30; grade 3-4 in 15 [50%] patients). Six (20%) patients reported 11 treatment-related serious adverse events (platelet count decrease [three patients], febrile neutropenia [two patients], neutrophil count decrease, anaemia, anaphylactic reaction, decreased appetite, pyrexia, and myocarditis [one patient each]). In the monotherapy cohort, median overall survival was 5·2 months (90% CI 4·5-8·7), median progression-free survival was 1·4 months (90% CI 1·4-1·4), and one of 30 patients had an objective response. In the combined therapy cohort, median overall survival was 15·4 months (90% CI 11·8-not estimable), median progression-free survival was 4·2 months (90% CI 2·8-5·6), and 11 of 30 patients had an objective response. Nivolumab had a manageable safety profile and signs of clinical activity in patients with unresectable or recurrent biliary tract cancer. This initial assessment of nivolumab for the treatment of advanced biliary tract cancer provides supportive evidence for future larger randomised studies of nivolumab in this difficult to treat cancer. Ono Pharmaceutical Co Ltd and Bristol-Myers Squibb Inc.

The influence of renal function on gemcitabine-based chemotherapy for advanced biliary tract cancer: An exploratory subgroup analysis of JCOG1113.

368 Background: JCOG1113 is a randomized phase III trial to evaluate gemcitabine (GEM) plus S-1 (GS) versus GEM plus cisplatin (GC) regarding overall survival (OS) for advanced biliary tract cancer (BTC) (UMIN000001685) and the non-inferiority of GS was demonstrated. It is necessary to consider renal function using cisplatin or S-1 because cisplatin has renal toxicity, and the toxicity of S-1 is affected by renal function. Therefore, we evaluated the influence of renal function on the efficacy and safety of GC and GS in JCOG1113. Methods: All enrolled patients (pts) in JCOG1113 (n = 354) were analyzed. Eligibility criteria included chemotherapy-naïve pts with recurrent or unresectable biliary tract adenocarcinoma, ECOG-PS of 0–1, CCr > 50 ml/min, and adequate organ function. Renal function was classified into two groups by creatinine clearance (CCr) as calculated by the Cockcroft-Gault formula; high CCr (CCr ≥ 80 ml/min) or low CCr (80 > CCr ≥ 50 ml/min). The impact of renal function on OS and progression-free survival (PFS) were compared using the Cox regression model. The adverse events (AEs) were compared using Fisher’s exact test. Results: Eighty-eight pts on GC and 88 pts on GS were included in the high CCr group, and 87 pts on GC and 91 pts on GS were included in the low CCr group. There were no differences between the groups regarding, sex, PS, primary site, biliary drainage, operation, or recurrence, except for age. The hazard ratio (HR) of GS to GC for OS was 1.12 (95% CI 0.81–1.56) in the high CCr group and 0.80 (95% CI 0.58–1.11) in the low CCr group. The HR of GS to GC for PFS was 1.06 (95% CI 0.78–1.44) in the high CCr group and 0.69 (95% CI 0.50–0.94) in the low CCr group. Grade 3-4 AEs of white blood cell count decreased (35.3%/23.6%), anemia (29.4%/7.9%) and platelet count decreased (18.8%/10.1%) were more common in GC than GS in the low CCr group. In contrast, the incidence of all grade 3-4 non-hematological AEs was higher (36.0%/11.8%) in GS than GC in the low CCr group ( p = 0.0002). Conclusions: GS was better in terms of OS, PFS, and hematological toxicities than GC in the low CCr group. GS might be recommended for the population with lower renal function in the treatment for advanced BTC.

Abstract 3431: Evaluation of genetic mutations and copy number alterations in biliary tract cancer using targeted exome sequencing

Abstract Background: Biliary tract cancer (BTC) is a heterogeneous group of cancers anatomically divided into the gallbladder cancer (GBC), intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC). None of molecular target agents has been proven to improve the prognosis of BTC yet. To gain a deeper understanding of BTC's pathophysiology and find its new potential therapeutic targets, this study is aimed to investigate genetic profiles of BTC and their clinical implications. Methods: A total of 69 patients who had been pathologically diagnosed as adenocarcinoma of biliary tract from January 2014 to November 2016 and had available surgical or biopsy specimen were enrolled for this study. With the DNA specimen extracted from previously-collected tumor tissue, somatic mutations and copy number variation (CNV) analyses were performed using targeted exome sequencing. Data regarding the baseline patient characteristics and treatment outcomes were retrospectively obtained by reviewing the patients' medical records. Results: Nineteen patients with GBC (28%), 24 patients with ICC (35%) and 26 patients with ECC (37%) were included in this analysis. Genetic mutation and copy number alteration (CAN) were observed in 59 (85%) and 35 (51%) patients, respectively while 5 patients (7%) did not have any genetic alterations. The most commonly mutated gene was TP53 (n=33, 47.8%), followed by KRAS (n=18, 26.1%), ARID1A (n=10, 14.5%) and IDH1 (n=9, 13.0%). IDH1 mutation appeared more frequently in patients with ICC (n=7, 29.2%, P=0.015) compared to those with GBC (n=1, 5.3%) or ECC (n=1, 3.8%) while ERBB2 and ERBB3 mutation were found only in GBC and ECC. HER2 amplification was observed in 7 patients (4 with GBC and 3 with ICC). Among those, one patient showed 3+ for HER2 test by immunohistochemistry (IHC) while four patients were 2+. All somatic mutations and CNVs documented in the present study were classified into five pathway modules which were identified by Nakamura et al. (Nature Genetics 2015). Majority of genetic alterations (n=45, 65.2%) belonged to Kinase-RAS module, followed by TP53 (n=41, 59.4%), TGF-β-SWI/SNF-MYC (n=22, 31.9%), Epigenetic (n=16, 23.2%) and RB-cell cycle (n=10, 14.5%) modules. Alterations in Epigenetic module were most common in ICC (vs. GB vs. ECC, 50.0% vs. 15.8% vs. 3.8%, P=0.002) while alterations in TGF-β-SWI/SNF-MYC module were most frequent in ECC (vs. GB vs. ICC, 46.2% vs. 3.6% vs. 31.6%, P=0.031). Conclusion: Genetic profile of BTC is heterogeneous according to its anatomic location. Our results indicate that subgroup of BTC patients may have benefit from targeted therapy such anti-IDH and anti-HER2 inhibitors. Citation Format: Heejung Chae, Changhoon Yoo, Deokhoon Kim, Seonmin Lee, Kim Dan Bi, Jae Ho Jeong, Heung-Moon Chang, Baek-Yeol Ryoo, Kyu-pyo Kim. Evaluation of genetic mutations and copy number alterations in biliary tract cancer using targeted exome sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3431.

Randomized phase III study of gemcitabine plus S-1 combination therapy versus gemcitabine plus cisplatin combination therapy in advanced biliary tract cancer: A Japan Clinical Oncology Group study (JCOG1113, FUGA-BT).

205 Background: Gemcitabine (GEM) plus cisplatin (GC) is the standard of care for advanced biliary tract cancer (BTC). However, GC is considered to be toxic because of nausea, vomiting, and appetite loss, and inconvenient due to requiring hydration before and after administration. GEM plus S-1 (GS) was reported to be promising with preferable efficacy and acceptable toxicity profile (UMIN000001685). This phase III study aimed to confirm the non-inferiority of GS to GC in terms of overall survival (OS). Methods: Eligibility criteria included chemotherapy-naïve patients with recurrent or unresectable biliary tract adenocarcinoma (gallbladder, intrahepatic biliary tract, extrahepatic biliary tract, or ampulla of Vater), an ECOG-PS of 0–1, and adequate organ function. In the GC arm, 1 g/m2 of GEM and 25 mg/m2 of cisplatin was infused on days 1 and 8 of a 21-day cycle. In the GS arm, 1 g/m2 of GEM was infused on days 1 and 8, and S-1 60, 80, or 100 mg/day according to body-surface area was administered from days 1 to 14 of a 21-day cycle. The primary endpoint was OS and the secondary endpoints included progression-free survival (PFS), response rate (RR), adverse events (AEs), clinically relevant AEs defined as any of grade 2 or more fatigue, appetite loss, nausea, vomiting, oral mucositis, and diarrhea. The sample size was calculated to be 350 with a one-sided alpha of 5%, a power of 80%, non-inferiority margin of 1.155 in terms of hazard ratio (HR). Results: From May 2013 to March 2016, 354 patients were enrolled. The non-inferiority of GS to GC was demonstrated (median OS: 13.4 months (m) in GC and 15.1 m in GS, HR 0.95; 90% confidence interval (CI), 0.78 to 1.15; P = 0.046 for non-inferiority). Median PFS was 5.8 m in GC and 6.8 m in GS (HR 0.86, 95% CI, 0.70-1.07). RR was 32.4% in GC and 29.8% in GS. Preliminary AEs data demonstrated that both treatments were generally well tolerated, although clinically relevant AEs were observed 34.7% in GC and 31.2 % in GS. Conclusions: GS demonstrated non-inferiority to GC in OS with good tolerability and was considered as new convenient option of standard of care without hydration for advanced BTC. Clinical trial information: UMIN000010667.

Pancreas-preserving resection of lower biliary tract adenocarcinoma: A coring-out technique.

Surgical resection for distal cholangiocarcinoma is usually carried out using pancreaticoduodenectomy (PD). However, because PD is a complex procedure with a high rate of postoperative complications, the surgical indications should be carefully considered, especially for patients with a decreased performance status, significant comorbidities, and/or anatomical anomalies. If curatively carried out, a less invasive, local resection may be an alternative procedure for such patients. In the current study, we present pancreas‐preserving resection of the lower biliary tract in a patient with early‐stage distal cholangiocarcinoma. This procedure was selected to avoid PD with arterial reconstruction because of arterial anomalies. After an abdominal exploration, a cholecystectomy was carried out and the common hepatic duct was transected. The bile duct was dissected from the pancreatic parenchyma without pancreatic resection, downward to the biliopancreatic ductal confluence. Next, a duodenotomy was done opposite Vater's ampulla. The duodenal mucosa around Vater's ampulla was incised and dissected, and the main pancreatic duct (MPD) was divided. The bile duct was completely separated from the pancreatic parenchyma, and the lower biliary tract was totally “cored‐out”. After resection, the MPD was re‐implanted into the duodenal wall, and the duodenotomy was closed. Finally, a Roux‐en‐Y hepaticojejunostomy was created. Postoperative course was uneventful. No tumor recurrence has been observed for 21 months after the operation. Thus, pancreas‐preserving resection of the lower biliary tract appeared to be appropriate for our patient. This organ‐preserving approach can be a useful, alternative procedure in selected patients.

Modified FOLFIRINOX regimen in advanced biliary tract adenocarcinoma.

484 Background: The treatment of advanced biliary tract adenocarcinoma is based on chemotherapy with Gemcitabine with Cisplatin or Oxaliplatin in various combinations. After seeing the high efficacy of FOLFIRINOX regimen in advanced pancreatic cancers, we studied the efficacy and safety of a modified FOLFIRINOX regimen in advanced biliary tract adenocarcinoma. Methods: We retrospectively reviewed patient with advanced biliary tract adenocarcinoma who were treated with modified FOLFIRINOX regimen from April 2013 to March 2016 in a tertiary hospital. The schedule of modified FOLFIRINOX was - Oxaliplatin 85 mg/m2, Irinotecan 150 mg/ m2, Leucovorin 400 mg/m2, and 5 fluorouracil 2400 mg/m2given as a 46-hour continuous infusion, every 2 weeks. All patients received primary prophylactic growth factors. The objective was to evaluate the efficacy and safety of FOLFIRINOX regimen. Results: 20 patients with untreated advanced biliary tract adenocarcinoma were enrolled. The median age was 55 (range 31 to 66 years). All patients had good performance status. 2 patients had a complete response (10%), 8 patients had a partial response (40%), 5 patients had stable disease (25%) and 5 patients had progression (25%). The median progression free survival was 6 months and the median overall survival was 10 months. The major toxicities were grade 3/4 neutropenia (30%), oral mucositis (20%), fatigue (20%) and neuropathy (10%). Dose reduction was required in 30% patients. Conclusions: A modified FOLFIRINOX regimen is an effective regimen in good performance status patients with advanced biliary tract adenocarcinoma. Dose modifications are required to reduce toxicity of the regimen. It needs to be further studied in a phase 3 study in comparison to Gemcitabine based regimens.

A phase II trial of regorafenib as a single agent in patients with advanced and metastatic biliary tract carcinoma and first-line chemotherapy failure.

TPS498 Background: Biliary tract cancers (including cholangiocarcinomas) are rare but aggressive malignancies with limited options for treatment. Currently, the combination of gemcitabine and cisplatin is considered the upfront systemic chemotherapy for patients with advanced and metastatic diseases. There is no ‘standard’ for second-line treatment. Several signaling pathways have been identified that might play a role in the development of biliary tract cancer and that may represent targets for directed therapies. Overexpression of VEGF and alterations of the Ras/Raf pathway have been identified in the majority of cholangiocarcinoma; some studies have shown these mutations to be associated with metastasis and poorer prognosis. Regorafenib is an oral multikinase inhibitor of multiple angiogenic and oncogenic kinases (VEGFR1-3, TIE2, PDGFR-β, FGFR1, KIT, RET, RAF) which has shown efficacy as a single agent in multiple solid tumors. This study evaluates the efficacy of regorafenib in patients with advanced/metastatic biliary tract cancer following the failure of first-line chemotherapy. Methods: Enrollment in this phase II, single-arm trial is ongoing. Eligible patients have unresectable advanced or metastatic biliary tract adenocarcinoma, and have failed first-line systemic chemotherapy. Patients receive regorafenib 120 mg orally daily in a 21 days on, 7 days off cycle. Tumor measurements take place every 3 cycles by CT or MRI imaging. Patients continue on therapy until disease progression or unacceptable toxicities. The primary end point of this study is median progression-free survival (PFS). To evaluate for evidence of activity, defined as a median PFS of 3.5 months or greater, with 83% power (one-sided test, α=0.10), target enrollment is 37 patients. Secondary endpoints include safety, overall response rate, disease control rate, median overall survival, and changes in biomarker levels. The correlation of these biomarkers and of tumor mutations with response to treatment is built into the study as well. As of September 2014, 9 patients had been enrolled. ClinicalTrials.gov Identifier: NCT02053376. Clinical trial information: NCT02053376.

Addressing unmet clinical needs: FISHing for bile duct cancer.

Addressing unmet clinical needs: FISHing for bile duct cancer.

Intraarterial 5-fluorouracil and interferon therapy is safe and effective for nonresectable biliary tract adenocarcinoma.

The prognosis in advanced biliary carcinoma has remained poor. The purpose of this study was to investigate the efficacy of intraarterial 5-fluorouracil and interferon therapy against unresectable biliary carcinoma. Patients with unresectable biliary carcinoma with performance status 0 or 1 were enrolled between January 2002 and September 2012. They received pegylated interferon-α 2a and intraarterial 5-FU every 4 weeks. The therapy was either terminated at the end of the first cycle for the patients with progressive disease or continued for at least three cycles. Patients' characteristics (physical, laboratory and radiographic) at the time of starting intraarterial 5-FU therapy were investigated. The relationship between the patients' characteristics and outcome, i.e., survival time and radiographic therapeutic evaluation of patients, was statistically analyzed. Tumor sites were the intrahepatic bile ducts in 23 patients and gallbladder in 2 patients. Previous treatment had been administered in ten patients. The overall response rate was 24% (6 partial responses in 25 patients). Stable disease was observed in 13 patients. The median overall survival was 358 days. Among the six partial responses, three patients received surgery, and one patient received radiofrequency ablation because clinical downstaging was obtained. The treatment was well tolerated. The survival analyses revealed that two factors (serum albumin ≥ 3.5 and hypovascular tumor) were significantly associated with overall survival. Combination therapy with 5-FU and interferon-α was safe and may improve the prognosis of advanced biliary carcinomas.

Imaging of malignancies of the biliary tract- an update.

Malignancies of the biliary tract include cholangiocarcinoma, gallbladder cancers and carcinoma of the ampulla of Vater. Biliary tract adenocarcinomas are the second most common primary hepatobiliary cancer. Due to their slow growing nature, non-specific and late symptomatology, these malignancies are often diagnosed in advanced stages with poor prognosis. Apart from incidental discovery of gall bladder carcinoma upon cholecystectomy, early stage biliary tract cancers are now detected with computed tomography (CT) and magnetic resonance imaging (MRI) with magnetic resonance cholangiopancreatography (MRCP). Accurate characterization and staging of these indolent cancers will determine outcome as majority of the patients’ are inoperable at the time of presentation. Ultrasound is useful for initial evaluation of the biliary tract and gallbladder masses and in determining the next suitable modality for further evaluation. Multimodality imaging plays an integral role in the management of the biliary tract malignancies. The imaging techniques most useful are MRI with MRCP, endoscopic retrograde cholangiopancreatography (ERCP), endoscopic ultrasound (EUS) and positron emission tomography (PET). In this review we will discuss epidemiology and the role of imaging in detection, characterization and management of the biliary tract malignancies under the three broad categories of cholangiocarcinomas (intra- and extrahepatic), gallbladder cancers and ampullary carcinomas.

A single-arm phase II trial of gemcitabine, oxaliplatin, and panitumumab in KRAS wild-type advanced biliary tract cancer.

255 Background: Biliary Tract Cancer (BTC) encompasses a group of aggressive, genetically heterogeneous tumors with limited systemic treatment options. Currently platinum and gemcitabine-based therapy is the standard first-line treatment. EGFR inhibition has proven beneficial across a number of gastrointestinal malignancies; and has shown specific advantages among KRASwild-type genetic subtypes of colon cancer. Methods: Patients with histologically confirmed, previously untreated unresectable or metastatic KRAS wild type biliary tract or gallbladder adenocarcinoma with ECOG performance status (PS) 0-2 were eligible. Patients were treated with Panitumumab 6mg/kg, Gemcitabine (GEM) 1000 mg/m2 (10 mg/m2/min), Oxaliplatin (OX) 85 mg/m2on days 1 and 15 of each 28 day cycle. The primary objective was to determine the objective response rate (ORR) by RECIST criteria v.1.1. Secondary objectives were to evaluate toxicity, progression free survival (PFS), and overall survival. Results: Of the 38 patients screened, 31 patients were found to have KRAS wild type genotype and enrolled. The median age was 61 years old, 55% males, 100% of patients had an ECOG PS of <1. Twenty-five patients had intrahepatic cholangiocarcinoma, and 3 each had extrahepatic and gall bladder carcinoma. Twenty-eight patients completed at least 2 cycles of therapy and were evaluable for response. The ORR was 50% (95% CI 23.8-76.2). With a median follow-up of 11 months, median PFS was 10.5 months (95% CI, 3.8 - 23.9 months) and median OS was 24.8 months (95% CI, 9.0 months-no upper bound). The most common grade 3 toxicities were fatigue 23%, anemia 23%, neuropathy 16%, elevated AST/ALT 16%, hyponatremia 13%, nausea 13%, rash 10%, neutropenia 7%, and hypomagnesemia 7%. Grade 4 toxicities included leukopenia 10%, and 1 case (3%) each of gallbladder perforation, hematoma, anemia, hyperkalemia, hyponatremia and hypokalemia. Conclusions: Completed analysis of this phase II study of GEMOX-panitumumab for KRAS wild type advanced BTC reveals encouraging results with promising response rates and PFS. The toxicity profiles were expected and manageable. Further investigation of this regimen and anti-EGFR therapy is warranted. Clinical trial information: NCT01308840.

Prognostic Significance of the Highest Peripancreatic Lymph Node in Biliary Tract Adenocarcinoma

Patients with biliary tract adenocarcinoma with nodal involvement have a poor prognosis. There is currently no standardized method for intraoperative lymph node assessment. The current study aimed to determine the prognostic significance of the highest peripancreatic lymph node (HPLN) in biliary tract malignancy. This was a retrospective study of patients undergoing potential curative resection of biliary tract adenocarcinoma from January 1995 through December 2010 who prospectively had intraoperative sampling of the HPLN. The median follow-up was 72.8 months. The primary end points were recurrence-free survival (RFS) and disease-specific survival (DSS). The rate of HPLN positivity in 110 patients undergoing exploration for potential curative resection was 30 % and did not vary with histologic subtype (gallbladder vs. cholangiocarcinoma). Eighty-five patients underwent complete gross resection. In this subset, median RFS and DSS were 34.3 months (95 % confidence interval [CI] 23.6-not reached [NR]) and 62.4 months (95 % CI 40.8-NR) for HPLN-negative patients, and 9.6 months (95 % CI 4.76-NR) and 20.5 months (95 % CI 7.4-NR) for HPLN-positive patients (p < 0.01), respectively. Median DSS was 14.6 months (95 % CI 9.6-25.4) for patients with unresectable disease. On multivariate analysis, HPLN status was an independent predictor of RFS (hazard ratio 3.73, 95 % CI 1.86-7.45; p < 0.01) and DSS (hazard ratio 3.98, 95 % CI 1.89-8.38; p < 0.01). HPLN status is prognostic of RFS and DSS in biliary tract adenocarcinoma. Intraoperative nodal staging by HPLN sampling warrants further investigation in a prospective trial.

Clinical significance of L-type amino acid transporter 1 expression as a prognostic marker and potential of new targeting therapy in biliary tract cancer

BackgroundThe expression of L-type amino acid transporter 1 (LAT1) has been described to play essential roles in tumor cell growth and survival. However, it remains unclear about the clinicopathological significance of LAT1 expression in biliary tract cancer. This study was conducted to determine biological significance of LAT1 expression and investigate whether LAT1 could be a prognostic biomarker for biliary tract cancer.MethodsA total of 139 consecutive patients with resected pathologic stage I-IV biliary tract adenocarcinoma were retrospectively reviewed. Tumor specimens were stained by immunohistochemistry for LAT1, Ki-67, microvessel density determined by CD34, and p53; and prognosis of patients was correlated. Biological significance of LAT1 expression was investigated by in vitro and in vivo experiments with LAT inhibitor, 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH) using cholangiocarcinoma cell line.ResultsIn total patients, high LAT1 expressions were recognized in 64.0%. The expression of LAT1 was closely correlated with lymphatic metastases, cell proliferation and angiogenesis, and was a significant indicator for predicting poor outcome after surgery. LAT1 expression was a significant independent predictor by multivariate analysis. Both in vitro and in vivo preliminary experiments indicated that BCH significantly suppressed growth of the tumor and yielded an additive therapeutic efficacy to gemcitabine and 5-FU.ConclusionsHigh expression of LAT1 is a promising pathological marker to predict the outcome in patients with biliary tract adenocarcinoma. Inhibition of LAT1 may be an effective targeted therapy for this distressing disease.

Is there a role for neoadjuvant and adjuvant therapy in biliary cancer?

A retrospective analysis of adjuvant and neoadjuvant therapy in patients with resectable biliary tract adenocarcinoma shows they confer no survival advantage in the treated groups, leading the authors to conclude they have no benefit. However, the study design does not allow definitive conclusions to be drawn about these treatments.

P-0158 Treatment Outcomes of Gemcitabine Versus Gemcitabine Plus Platinum for Biliary Tract Cancer: A Korean Cancer Study Group Retrospective Analysis

ABSTRACT Introduction A ABC-02 trial of gemcitabine plus cisplatin combination showed prolongation of overall survival in biliary tract cancer (BTC) patients. In this multicenter retrospective study, we evaluated the treatment outcomes of combination group compared with gemcitabine alone (G) in Korean BTC patients. Methods 151 patients with histologically confirmed adenocarcinoma of biliary tract were enrolled at 9 institutions between July 2000 and May 2011. 100 patients were treated with gemcitabine-platinum (GP) combination chemotherapy and the other 51 were treated with gemcitabine (G) monotherapy. Results With a median follow-up of 7.7 months (range, 0.4-38.3 months), the median overall survival was 9.2 months (95% Confidence Interval(CI) 7.5-10.9 months) among the 51 patients in the G group and 6.9 months (95% CI 5.9-7.9 months) among the 100 patients in the GP group (P Conclusion There is no difference in ORR, PFS and OS for patients treated with the G group or GP group. We showed the differences between this study and ABC-02 study. Gemcitabine monotherapy could also be effective in Korean BTC patients.

Randomized phase II trial of S-1 and cisplatin versus gemcitabine and cisplatin in patients with advanced biliary tract adenocarcinoma

Background. We evaluated the efficacy and safety of a combination of S-1 and cisplatin (SP) versus gemcitabine and cisplatin (GP) as first-line therapy for advanced biliary tract adenocarcinoma (ABTA). Material and methods. Patients were randomized to receive cisplatin (60 mg/m2 intravenously [IV] on Day 1) plus S-1 (40 mg/m2 bid orally on Days 1–14) or gemcitabine (1000 mg/m2 IV at 10 mg/m2/min on Days 1 and 8) every three weeks. The primary end point was six-month progression-free survival (PFS). Results. Of 96 eligible patients, 49 were randomized to GP and 47 to SP. At a median follow-up time of 14.2 months, the six-month PFS rates were 43.8% and 34.7%, respectively [unadjusted HR (GP/SP) =0.85, 95% CI 0.52–1.36]. The median OS values in the GP and SP groups were 10.1 months and 9.9 months, respectively [unadjusted HR (GP/SP) =0.72, 95% CI 0.45–1.17]. Grade 3-4 toxicities in the GP and SP groups included neutropenia (49.0% vs. 31.8%), anemia (22.4% vs. 2.3%), thrombocytopenia (22.4% vs. 4.5%), and asthenia (4.1% vs. 2.1%). Conclusion. Both GP and SP has comparable efficacy with favorable safety profile as first-line treatment for ABTA. (ClinicalTrials.gov number NCT 01375972).

Phase III study of gemcitabine/oxaliplatin (GEMOX) with or without erlotinib in unresectable, metastatic biliary tract carcinoma.

LBA4032 Background: Currently, there is no standard regimen for palliative chemotherapy in metastatic, unresectable biliary tract cancer (BTC). A phase II trial of erlotinib monotherapy showed a promising anti-tumor activity in BTC with tolerable toxicity. Additionally, gemcitabine + erlotinib demonstrated superior efficacy when compared to gemcitabine alone in pancreatic cancer. Hence, we conducted a phase III trial to compare between GEMOX vs GEMOX+erlotinib (Tarceva [T]) (GEMOX/T) as first-line chemotherapy in unresectable, metastatic BTC. Methods: Eligible patients were as follows: histologically confirmed adenocarcinoma of biliary tract (CCC), ampulla of vater (AOV) or gall bladder (GB); unresectable or metastatic; ECOG performance status of 0~2; adequate marrow, hepatic, renal and cardiac functions; no prior chemotherapy. The primary endpoint was progression free survival (PFS). The study regimen was gemcitabine 1,000mg/m2, oxaliplatin 100mg/m2, erlotinib 100mg qd daily q 2 weeks. Results: From February 2009 to August 2010, 268 pts were randomized, 133 patients to GEMOX arm and 135 patients to GEMOX/T arm. Patient characteristics: median age 61 yrs (range 30-82); male (63.4%); CCC (n=180, 67.2%), GB (n=82, 30.6%), and AOV (n=6, 2.2%). With a median follow-up of 13.9 months (range, 6.7 – 25.0), median PFS was 5.8 months (95% CI, 4.6 - 7.0) in GEMOX/T arm and 4.2 months (95% CI, 2.7 - 5.7) in GEMOX arm (P=0.080). In subgroup analysis (CCC, n=180), however, median PFS was significantly longer in GEMOX/T arm (5.9 months) when compared with GEMOX arm (3.0 months, P=0.049). The overall response rate was significantly higher in the GEMOX/T arm when compared with GEMOX arm. There was no significant difference in overall survival between the two arms (GEMOX/T: 9.5 months, 95% CI, 7.6 – 11.4; GEMOX: 9.5 months, 95% CI, 7.5 – 11.5; P=0.611). The EGFR mutation testing results in correlation to responsiveness to erlotinib will be presented at the meeting. Conclusions: This phase III represents the first multicenter, randomized trial to compare GEMOX vs GEMOX/T in unresectable, metastatic BTC. Although PFS was not prolonged in GEMOX/T, there was a significant benefit in terms of PFS in GEMOX/T arm for CCC patients.

A prospective study of capecitabine (cape), oxaliplatin (ox), bevacizumab (B), and radiation therapy (RT) (CAPOX-B RT) in patients with locally advanced or R1 biliary cancers: High risk of liver failure with extended hepatectomy.

e14593 Background: To evaluate the safety and efficacy of CAPOX-B RT for locally advanced or R1 biliary tract adenocarcinoma. Methods: Pts with locally advanced or R1 resected biliary cancers (incl...

Different relation between ERCC1 overexpression and treatment outcomes of two platinum agents in advanced biliary tract adenocarcinoma patients

The aim of this study is to evaluate the effect of excision repair cross-complementation group 1 (ERCC1) expression on treatment outcomes in advanced biliary tract adenocarcinoma (ABTA) patients treated with platinum-based chemotherapy. One hundred and six patients with histologically confirmed adenocarcinoma of biliary tract were enrolled at 5 institutions in South Korea between January 2002 and September 2008. Of 106 patients, 93 were assessed by immunohistochemistry from tissue specimens. Sixty-five patients were treated with cisplatin-based regimens and the other 28 treated with oxaliplatin-based ones. For total study population, no significant differences were noted in progression-free survival (PFS) and overall survival (OS) between ERCC1-negative and ERCC1-positive patients, respectively (4.2 vs. 2.9months, p=0.116; 7.0 vs. 7.8months, p=0.143). In patients treated with cisplatin-based regimens, median PFS and OS were significantly longer in ERCC1-negative group than in ERCC1-positive group, respectively (4.6 vs. 1.9months, p=0.014; 9.1 vs. 7.9months, p=0.017). Disease control rate (DCR) was better in patients with ERCC1 negative than in patients with ERCC1 positive (p=0.048). On the other hand, in patients treated with oxaliplatin-containing regimens, median PFS and OS tended to be longer in ERCC1-positive group, but these did not reach statistical significances. Response rate was better in patients with ERCC1 positive (p=0.005). ERCC1 shows a significant prognostic value in ABTA patients treated with cisplatin. A survival benefit was observed in ERCC1-negative patients from cisplatin-containing chemotherapy but not from oxaliplatin-containing ones. The action mechanism of ERCC1 on cisplatin may be different from that on oxaliplatin.