Advanced Biliary Tract Adenocarcinoma Research Articles

Bevacizumab Erlotinib Switch Maintenance in Chemo-Responsive Advanced Gallbladder and Cholangiocarcinoma (BEER BTC): A Multicenter, Open-Label, Randomized, Phase II Trial.

Patients with chemotherapy-responsive advanced biliary tract cancers (BTCs) are usually observed after 6 months of gemcitabine-based therapy. There is limited prospective evidence for maintenance strategies after chemotherapy. This investigator-initiated, open-label, randomized, integrated phase II-III study enrolled adult patients with advanced BTC from two cancer centers in India. Patients with histologically confirmed advanced biliary tract adenocarcinoma who had at least disease stabilization after 6 months of gemcitabine-based chemotherapy were randomly assigned (1:1) to either active surveillance or switch maintenance, which was a combination of bevacizumab 5 mg/kg intravenous once every 21 days plus erlotinib 100 mg once daily. Both arms were continued until disease progression, unacceptable toxicity, or patient decision to withdraw. The primary end point of the phase II component of the trial was investigator-evaluated progression-free survival. This trial is registered with Clinical Trials Registry of India (CTRI/2019/05/019323I). From May 2021 to November 2022, 98 patients were randomly assigned to active surveillance (n = 49) or bevacizumab-erlotinib (n = 49). A majority of patients had gallbladder cancer (80%). The median follow-up was 13.4 months. The median progression-free survival was 3.1 months (95% CI, 2.47 to 3.64) in the active surveillance group versus 5.3 months (95% CI, 3.53 to 7.04) in the bevacizumab-erlotinib group (hazard ratio, 0.51 [95% CI, 0.33 to 0·74]; P = .0013). The most common grade 3 class-specific adverse events associated with bevacizumab-erlotinib were acneiform rash 1 (2%) and oral stomatitis 1 (2%) with erlotinib and bleeding 1 (2%) with bevacizumab. The combination of bevacizumab and erlotinib as switch maintenance improves progression-free survival with an acceptable safety profile compared with active surveillance in patients with advanced BTCs in this phase II study. The trial moves on to the phase III component to evaluate improvement in overall survival.

312P Trastuzumab plus lapatinib for second-line treatment of human epidermal growth factor receptor 2-positive advanced biliary tract adenocarcinoma: A retrospective single-centre study

312P Trastuzumab plus lapatinib for second-line treatment of human epidermal growth factor receptor 2-positive advanced biliary tract adenocarcinoma: A retrospective single-centre study

Trastuzumab (T) plus gemcitabine-cisplatin (GC) for treatment naïve HER2 positive biliary tract adenocarcinomas (BTC): A multicentre open-label, phase II study (TAB).

4089 Background: HER2 over-expression or amplification is seen in 4%-16% of BTCs and is a therapeutic target of interest. Gemcitabine-cisplatin (GC) is one of the standard regimens of choice in advanced BTCs. We aimed to evaluate the clinical activity of GC plus anti-HER2 antibody trastuzumab as initial treatment in HER2-positive BTC. Methods: This study was an investigator-initiated, open-label, single-arm, multi institutional, phase II trial in patients (pts) aged 18 years or older with HER2-positive (defined as IHC 3+ or IHC 2+ and FISH positive), treatment naïve BTCs. Patients received GC (Gem 1000 mg/m2 IV and Cisplatin 25mg/m2 IV on day 1 and 8, q 3 weeks) combined with Trastuzumab at 8mg/kg as initial dose followed by 6mg/kg q 3 -weekly till disease progression (PD) or unacceptable toxicities. The primary end-point of the study was an improvement in 6-month progression free survival (PFS) from 40% (historical cohort) to 60% in the study arm. Next generation sequencing to evaluate HER2 and other mutations was conducted on the tissue samples of the patients screened for this study. Results: From March 2020 to August 2022, of the 876 patients were screened for HER2 status, 118 (13.4%) were found to have HER2 positive status and 90 of them were enrolled into the study. A majority of patients had GBC (95.6%) and at-least 2 sites of metastatic disease beyond primary (77.8%). With a median follow up of 8.5 months, 72 patients had PD and the median PFS was 7.95 months (95% CI: 6.84 -9.06; median overall survival (OS) was 9.95 months (95% CI: 9.25 – 10.66). Partial responses (PR) were seen in 8 patients (8.9%) and 61 had stable disease (67.7%) for a disease control rate of 76.6%. Common chemotherapy-related grade 3 or 4 adverse events were anemia [26 (28.9%)], neutropenia [18(20%)] and thrombocytopenia [8(8.9%)] while one patient has Trastuzumab related asymptomatic fall in cardiac ejection fraction (>=10%). The presence of isolated TP53 mutations predicted for inferior PFS compared to patients with other mutations (TERT promoter, HER2, PIK3CA etc) or no detected mutations (6.51 months vs. 12.02 months vs. 10.58 months; p<0.001). Conclusions: The combination of GC and trastuzumab shows near doubling of survival in treatment naive HER2 positive BTC in a prospective manner for the first time and sets the stage for a larger phase III trial with the combination. Evaluating mutations like TP53, HER2, TERT promoter and PIK3CA along with HER2 testing could be considered as a preferred modality to select these patients for anti HER2 therapy. Clinical trial information: CTRI/2019/11/021955 . [Table: see text]

Nab-paclitaxel plus tegafur gimeracil oteracil potassium capsule (S-1) as first-line treatment for advanced biliary tract adenocarcinoma: a phase 2 clinical trial.

This study aimed to evaluate the efficacy and safety of a new combination of nab-paclitaxel plus tegafur gimeracil oteracil potassium capsule (S-1) for patients with advanced biliary tract carcinoma (BTC). Patients were treated with nab-paclitaxel at a dose of 125 mg/m2 on day 1 and 8, and S-1, 80 to 120 mg/day on days 1-14 of a 21-day cycle. Treatments were repeated until disease progression or unacceptable toxicity occurred. The primary endpoint was objective response rate (ORR). The secondary endpoints were median progression-free survival (PFS), overall survival (OS), and adverse events (AEs). The number of patients enrolled were 54, and 51 patients were evaluated for efficacy. A total of 14 patients achieved partial response (PR) with an ORR of 27.5%. The ORR varied by sites, with 53.8% (7/13) for gallbladder carcinoma, 18.4% (7/38) for cholangiocarcinoma. The most common grade 3 or 4 toxicities were neutropenia and stomatitis. The median PFS and OS were 6.0 and 13.2 months, respectively. The combination of nab-paclitaxel with S-1 showed explicit antitumor activities and favorable safety profile in advanced BTC and could serve as a potential non-platinum and -gemcitabine-based regimen.

A phase Ib study of anlotinib plus TQB2450 as second-line therapy for advanced biliary tract adenocarcinoma.

4075 Background: Although with modest efficacy, mFOLFOX is recommended as standard second-line chemotherapy for advanced biliary tract adenocarcinoma. Several clinical trials are exploring the combination treatment of anti-angiogenic drugs and immune checkpoint inhibitors. Anlotinib is an oral small molecule inhibitor of receptor tyrosine kinases, with inhibitory effects on tumor angiogenesis and growth. Anlotinib plus TQB2450,an anti-PD-L1 mAb, have shown anti-tumor activity in preclinical study and here we investigate the efficacy and safety of different dosage of this regimen as second-line treatment for advanced biliary tract adenocarcinoma. Methods: Patients with advanced biliary tract adenocarcinoma who had progressed after first-line treatment received anlotinib (once daily for 2 weeks on/1 week off) plus TQB2450 (1200mg once) every three weeks. The planned anlotinib dose levels to be explored were 10mg (starting) and 12mg daily. Dose expansion was performed after the determination of the maximum tolerable dose. Response to treatment was evaluated using the RECIST 1.1 criteria, supplemented by iRECIST. The primary endpoints were MTD, ORR, and the secondary endpoints were PFS, OS and safety. Results: Both 10mg and 12mg of anlotinib were tolerable after the initial safety observation of different doses from May 2019 to April 2020. 34 patients (8 cases of gallbladder cancer [GBC], 22 of intrahepatic cholangiocarcinoma [ICC] and 4 of extrahepatic cholangiocarcinoma [ECC]) were enrolled, 22 patients in the 10mg dose group and 12 in the 12mg dose group. The median age was 57 (37-72) years and 55.9% (19) of the patients were female. At the analysis cut-off date of 31 December 2020, the median follow-up duration was 14.9 months. Of the 34 patients, 4 patients had partial response (PR, 2 cases in the 10mg group and 2 in the 12mg group), including 2 cases with GBC and 2 with ICC, 17 had stable disease (SD, shrinkage, 12 in the 10mg group and 5 in the 12mg group) and 5 SD (enlargement, 4 in the 10mg group and 1 in the 12mg group), 7 had progression disease (PD, 5 in the 10mg group and 2 in the 12mg group) and 1 patient of ECC could not be evaluated. In the overall population, the median PFS (mPFS) was 5.95 (95%CI: 3.78-11.50) months. The mPFS was 5.29 (95%CI: 3.45-10.32) months in 10mg group and 12.98 (95%CI: 1.38-NR) in 12mg group. The median OS was not reached and the 12-month OS rate was 64.71% (60.87% in the 10mg group and 72.73% in the 12mg group). Grade 3 or higher toxicities were observed in 8 patients, with elevated transaminase (n = 4, 11.8%), elevated bilirubin (n = 3, 8.8%), fatigue (n = 1, 2.9%), hypertension (n = 1, 2.9%) and prolonged QTc (n = 1, 2.9%). Conclusions: Anlotinib plus TQB2450 as second-line therapy for advanced biliary tract adenocarcinoma was well tolerated and showed promising efficacy. No unexpected adverse events were observed in both drugs. This regimen is worthy of further exploration. Clinical trial information: NCT03825705.

An exploratory study of fruquintinib as second-line treatment for patients with advanced or metastatic biliary tract cancer.

TPS4657 Background: Biliary tract cancer (BTC) is a relatively uncommon but highly fatal malignancy and most patients with BTC are diagnosed at advanced stages. Currently, no standard second-line treatment has been established following recurrence from the first-line treatment. VEGF is highly expressed in more than 50% of BTC, which indicates anti-angiogenesis might be a potentially effective method to improve the outcome in BTC. Fruquintinib is a novel small molecule tyrosine kinase inhibitor targeting VEGFR1, VEGFR2, and VEGFR3 and is currently being evaluated in clinical trials for multiple cancers including lung cancer, gastric cancer and colorectal cancer, and showed strong anti-tumor activity. However, the effect and safety of fruquintinib has not been investigated in the setting of second-line treatment for BTC. Methods: The study is a multicenter, single-arm, phase 2 trial of fruquintinib (5 mg, po, for 3 weeks, followed by 1 week off, 4 weeks for a cycle) for patients with advanced or metastatic BTC who have failed to first-line chemotherapy. The primary endpoint is progression-free survival (PFS) with the null hypotheses of 8 weeks, and the median PFS≥15 weeks as evidence of the study drug activity (α=0.05, 80% power, one-sided). The number of patients required to complete the study is 27. Allowing for 20% expulsion rate, the study needs 33 patients. The secondary endpoints include objective response rate (ORR), disease control rate (DCR), overall survival (OS), safety and quality of life (QoL). Meanwhile, the study also set an exploratory objective to evaluate the mutation status of related genes in plasma (cfDNA) and tumor tissue and explore the interplay between mutation patterns with efficacy. Major eligibility requirements: Age ≥18 years; Histologically or cytologically confirmed diagnosis of advanced or metastatic biliary tract adenocarcinoma; First-line chemotherapy failed (tumor progression or intolerable adverse events); No less than 3 months of expected survival; ECOG PS≤1; At least one measurable lesion according to RECIST 1.1 criteria; Adequate organ function. Eligible patients with advanced or metastatic BTC refractory to first-line chemotherapy will be enrolled at 7 medical centers in China. The study is open and actively enrolling at time of submission. Clinical trial information: NCT04156958 .

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.

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.

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).

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.

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

4029 Background: Gemcitabine plus a platinum has been reported to be the most effective treatment against advanced biliary tract adenocarcinoma (ABTA). S-1 has also shown potent antitumor activity as monotherapy or in combination with platinum. The aim of this study was to evaluate the efficacy and safety of combination chemotherapy with S-1 and cisplatin (SP) versus gemcitabine and cisplatin (GP) as first-line therapy in ABTA. Methods: Patients with ABTA including gallbladder cancer, intrahepatic cholangiocarcinoma (IHCCC), extrahepatic bile duct carcinoma, and ampulla of Vater cancer were randomized to receive either S-1 (40 mg/m2 bid orally D1-14) and cisplatin (60 mg/m2 IV D1) or gemcitabine (1,000 mg/m2 IV fixed dose rate of 10 mg/m2/min on D1,8) and cisplatin (60 mg/m2 IV on D1). Cycles were repeated every 3 weeks. The primary end point was 6-month progression-free survival (PFS) and randomized phase II trial design was used to select the better regimen for further investigation. Secondary endpoints was the response rate (RR) and overall survival (OS). Results: Between March 2008 and March 2009, a total of 96 eligible patients (SP = 47, GP = 49) were enrolled. Overall response rates for patients assigned to GP and SP were 18.4% (95% CI 7.5-29.2%) and 21.3% (95% CI, 9.6-33%, p = 0.721), respectively. With a median follow-up duration of 14.1 months for all patients (95% CI, 12.7-15.5 months), 6-months PFS was 44.0% in GP and 35.3% in SP [unadjusted HR (GP/SP) = 0.85, 95% CI, 0.52-1.36, p = 0.488]. The median OS and estimated 1-year survival rate were 10.1 months and 42.2% in GP and 9.9 months and 21.9% in SP (unadjusted HR [GP/SP] = 0.72, 95% CI = 0.45-1.17, p = 0.187). Grade 3 to 4 toxicities for SP vs. GP were: neutropenia (31.8% vs. 49%), anemia (2.3% vs. 22.4%), thrombocytopenia (4.5% vs. 22.4%), asthenia (2.1% vs. 4.1%), and diarrhea (4.3% vs. 0%). Febrile neutropenia developed only in GP arm (4.1%). Conclusions: Despite of more frequent hematologic toxicities and inconvenience associated weekly visit, GP showed better 6-months PFS and OS based on statistical design, gemcitabine in combination with cisplatin was selected over SP for further investigation in ABTA. No significant financial relationships to disclose.

The cisplatin, epirubicin, 5‐fluorouracil, gemcitabine (PEFG) regimen in advanced biliary tract adenocarcinoma

Biliary tract adenocarcinoma (BTA) is an uncommon tumor with a poor prognosis and no standard, systemic chemotherapy. The combined cisplatin, epirubicin, 5-fluorouracil, and gemcitabine (PEFG) regimen is an effective, upfront treatment for advanced pancreatic cancer. In this study, the authors assessed the activity and safety of this combination regimen in patients with advanced BTA. PEFG (cisplatin 40 mg/m(2) and epirubicin 40 mg/m(2) on Day 1; gemcitabine 600 mg/m(2) on Days 1 and 8; and 5-fluorouracil [FU] 200 mg/m(2) daily as a continuous infusion) was administered to chemotherapy-naive patients who had a cytologic or histologic diagnosis of locally advanced or metastatic BTA, aged <or=75 years, and a performance status (PS) >60 either until they had evidence progressive disease or for a maximum of 6 months. Tumor size was assessed every 2 months during treatment. Between May 1999 and December 2005, 37 patients (62% metastatic) who had a median age of 62 years and a median PS of 90 received the PEFG regimen at the authors' institution. Primary tumor sites were the intrahepatic bile duct in 10 patients (27%), the extrahepatic bile duct in 8 patients (22%), the gallbladder in 12 patients (32%), and the ampulla of Vater in 7 patients (19%). A partial response was observed in 16 patients (43%), and stable disease was observed in 12 patients (32%). The median overall survival (OS) was 12.1 months, and the 1-year OS rate was 52%. The median progression-free survival (PFS) was 7.9 months, and the 6-month PFS rate was 67%. The main grade 3/4 toxicity was neutropenia in 18% of cycles followed by thrombocytopenia in 9% of cycles, nausea/vomiting in 5% of cycles, and febrile neutropenia, fatigue, anemia, and stomatitis in 2% of cycles. The current results demonstrated that PEFG was an active regimen with a manageable toxicity profile for patients with advanced BTA.

Abstract C122: Clinical implication of ERCC1 overexpression in advanced biliary tract adenocarcinoma patients treated with cisplatin-based palliative chemotherapy

Abstract Several clinical studies have shown that excision repair cross-complementation group1 (ERCC1) overexpression is associated with resistance to platinum-based chemotherapy and poor prognoses in several tumors. However these studies have never been tried for biliary tract cancer.The aim of this study was to evaluate the significance of ERCC1 expression as a predictive marker, we analyzed the association between ERCC1 expression and treatment outcomes in advanced biliary adenocarcinoma patients treated with cisplatin-based palliative chemotherapy. 74 patients with histologically confirmed adenocarcinoma of biliary tract were enrolled at 5 institutions between January 2002 and August 2008. Of 74 patients, 65 was assessed by immunohistochemistry from biopsy specimens. ERCC1 expression was positive in 33 out of 65 specimens (51%). 30 (46.2%) of 65 patients showed clinical benefits(including complete response, partial response and stable disease). Among 30 patients who obtained clinical benefits, eleven (37%) were positive for ERCC1 expression and nineteen (63%) were negative (p=0.048). With a median follow-up of 7.3 months (range, 0.8–47.5 months), median progression free survival (PFS) and overall survival (OS) were 3.0 months (95% CI, 1.3–4.7 months) and 7.8 months (95% CI, 5.9–9.7 months), for the total study population. Among patients treated with cisplatin, those who had ERCC1-negative tumors showed longer survival. On univariate analysis, PFS was 1.9 months for patients with ERCC1 positive tumor and 4.6 months for those with ERCC1 negative tumor (P = 0.014). OS was significantly longer in the ERCC1-negative group than in the ERCC1-positive group (9.1 vs 7.3 months, respectively; P = 0.017). A Cox proportional hazard model showed that negative ERCC1 expression (hazard ratio 0.401, 95% CI, 0.176–0.912; P = 0.029), clinical response (hazard ratio 0.290, 95% CI 0.120–0.705; P = 0.006), peritoneal metastasis (hazard ratio 0.260, 95% CI 0.082–0.828; P = 0.023) and primary cancer site (hazard ratio 0.228, 95% CI 0.064–0.814; P = 0.023) were significant independent prognostic factors for the prolongation of OS. These results suggest that advanced biliary tract adenocarcinoma patients with ERCC1-negative tumors show both clinical benefit and survial benefit from palliative chemotherapy with a cisplatin-containing regimen. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C122.

Prognostic factors and predictive model in patients with advanced biliary tract adenocarcinoma receiving first‐line palliative chemotherapy

Advanced biliary tract adenocarcinoma (BTA) has been a rare but fatal cancer. If unresectable, palliative chemotherapy improved the quality and length of life, but to the authors' knowledge, prognostic factors in such patients have not been well established to date. In the current study, prognostic factors were investigated in patients with advanced BTA receiving first-line palliative chemotherapy. Data from 213 patients with advanced BTA who were in prospective phase 2 or retrospective studies from September 2000 through October 2007 were used. With a median follow-up duration of 29.7 months, the median overall survival (OS) was 7.3 months (95% confidence interval [95% CI], 6.3 months-8.3 months). A Cox proportional hazards model indicated that metastatic disease (hazards ratio [HR], 1.521; P=.011), intrahepatic cholangiocellular carcinoma (HR, 1.368; P=.045), liver metastasis (HR, 1.845; P<.001), Eastern Cooperative Oncology Group performance status (HR, 1.707; P<.001), and alkaline phosphatase level (IU/L) (HR, 1.001; P<.001) were statistically significant independent predictors of poor prognosis. Patients were classified into 3 risk groups based on the prognostic index (PI), which was constructed using the regression coefficients of each variable. The median OS was 11.5 months (95% CI, 9.6 months-13.5 months) for the low-risk group (PI<or=1.5; n=67), 7.3 months (95% CI, 5.7 months-8.9 months) for the intermediate-risk group (PI>1.5 but <or=2.2; n=75), and 3.6 months (95% CI, 2.9 months-4.1 months) for the high-risk group (PI>2.2; n=70 [P<.001]). Five prognostic factors in patients with advanced BTA were identified. The predictive model based on PI appears to be promising and may be used for the management of individual patients and to guide the design of future clinical trials, although external validation is needed.

Clinical implication of ERCC1 overexpression in advanced biliary tract adenocarcinoma patients treated with platinum-based palliative chemotherapy

e22018 Background: Several clinical studies have shown that Excision repair cross-complementation group1 (ERCC1) overexpression is associated with resistance to platinum-based chemotherapy and poor prognoses in several tumors. However these studies have never been tried for biliary tract cancer. The aim of this study was to evaluate the association between ERCC1 expression and treatment outcomes in advanced biliary tract adenocarcinoma patients treated with platinum-based palliative chemotherapy. Methods: We analyzed 45 patients with histologically confirmed adenocarcinoma of biliary tract at 5 institutions between January 2002 and March 2008. ERCC1 expression was assessed by immunohistochemistry from biopsy specimens. Results: ERCC1 expression was positive in 17 of 45 specimens (37.8%). 26 (57.8%) of 45 patients showed clinical benefits(including complete response, partial response and stable disease). Among 26 patients who obtained clinical benefits, seven (27%) were positive for ERCC1 expression and ninety (73%) were negative (p=0.079). With a median follow-up of 6.6 months (range, 0.9–39.4 months), median Progression free survival (PFS) and Overall survival (OS) were 4.4 months (95% CI, 3.2–5.6 months) and 8.5 months (95% CI, 6.1–10.9 months), respectively, for the total study population. On univariate analysis, PFS was 2.3 months for patients with ERCC1 positive tumor and 5.3 months for those with ERCC1 negative tumor (P = 0.053). However OS was significantly longer in the ERCC1-negative group than in the ERCC1-positive group (10.0 vs 4.4 months, respectively; P = 0.001). Other factors affecting the prolongation of OS were objective response rate (P = 0.016) and clinical benefits (P = 0.001). A Cox proportional hazard model showed that negative ERCC1 expression (hazard ratio 0.405, 95% CI, 0.200–0.820; P = 0.012) and clinical benefit (hazard ratio 0.183, 95% CI 0.080–0.420; P = 0.001) were significant independent prognostic factors for the prolongation of survival. Conclusions: These results suggest that advanced biliary tract adenocarcinoma patients with ERCC1-negative tumors show a survival benefit from palliative chemotherapy with a platinum- containing regimen. No significant financial relationships to disclose.

Efficacy and Safety of S-1 Monotherapy in Patients with Advanced Biliary Tract Adenocarcinoma

Aim: We investigated the efficacy and safety of S-1 monotherapy for the treatment of advanced biliary tract adenocarcinoma (BTA) in a clinical practice setting. Methods: We reviewed clinical data from 217 patients with advanced BTA who were treated with S-1 monotherapy between August 2004 and September 2007. Results: 162 eligible patients were identified. The primary tumors were intrahepatic (n = 57), in the gall bladder (n = 50), in extrahepatic bile ducts (n = 41) and in the ampulla of Vater (n = 14). Sixteen of 120 assessable patients achieved partial responses, with a response rate of 13.3% (95% CI 7.2–19.4%). Another 51 patients had stable disease, with an overall tumor control rate of 55.8% (95% CI 46.9–64.7%). The median time to progression was 2.7 months and the median overall survival time was 6.9 months. Response rates and survival differed significantly according to the primary site of the tumor (p = 0.002 and p < 0.001, respectively), with extrahepatic bile duct adenocarcinoma having the best prognosis. The treatment regimen produced only mild toxicity in most cases (grade 1 or 2), even for patients with hyperbilirubinemia. Conclusion: S-1 has a favorable toxicity profile and can be safely administered to BTA patients with hyperbilirubinemia. The efficacy of S-1 against advanced BTA depends on the tumor site and is most effective in patients with extrahepatic BTA.

Irinotecan With 5-FU/FA in Advanced Biliary Tract Adenocarcinomas

Biliary cancer has a poor prognosis and lacks a standard palliative chemotherapy. The purpose of this prospective single-arm phase II study was to determine the activity and tolerability of irinotecan, 5-fluorouracil, and folinic acid in advanced biliary cancer. Patients with inoperable intrahepatic cholangiocarcinoma (ICC) or gallbladder cancer (GBC) and no prior chemotherapy were eligible. Irinotecan 80 mg/m2, followed by folinic acid 500 mg/m2 and 5-FU 2000 mg/m2 infused over 24 hours (Fufiri) were administered weekly 6 times, every 8 weeks. The primary endpoint was response rate, and secondary endpoints were overall survival (OS), progression-free survival (PFS), and toxicity. Seventeen patients with ICC and 13 patients with GBC were enrolled. All patients were evaluable for safety. WHO grade 3/4 drug-related adverse events occurred in 8 patients (27%), consisting of diarrhea and leukopenia in 5 and 3 patients, respectively. One patient with diarrhea grade 4 finally succumbed to sepsis. Objective response rate was 10% (95% confidence interval, 2.1%-26.5%), with an additional 10% of patients showing stable disease. Median overall survival was 166 days and 273 days, and median progression-free survival was 84 days and 159 days for ICC and GBC, respectively. Fufiri is a well-tolerated regimen in patients with ICC and GBC but has only modest activity in advanced biliary tract cancer.

Irinotecan with 5-FU/FA in advanced biliary tract adenocarcinomas—A two-center phase II trial (GBFiri)

14088 Background: The majority of patients with biliary tract cancer present with advanced, unresectable tumors. Irinotecan and 5-Fluorouracil/folinic acid (FOLFIRI) have synergistic activity in gastrointestinal cancers. The aim of this study was to determine the tolerability and activity of systemic chemotherapy with FOLFIRI in patients with intrahepatic cholangiocarcinoma (CCC) or gallbladder cancer (GBC). Methods: This was a prospective, multicenter, non-randomised, open-label, phase II trial. Eligibility criteria: Inoperable adenocarcinoma of the biliary tract, measurable disease, age 18–80 years, ECOG PS 0–2. Patients received irinotecan 80 mg/m2 as a 30 min infusion, followed by folinic acid 500 mg/m2 over 2 h and 5-FU 2000 mg/m2 over 24h weekly × 6 followed by a 2 week rest. Treatment was continued until progression or limiting toxicity. Response to therapy was assessed after every other cycle according to RECIST criteria. Primary end point was response rate, secondary end points were overall survival, progression free survival and toxicity. Results: 30 pts (CCC 17, GBC 13) were enrolled. A total of 387 doses (Median 12.9; 1 to 36) were administered with an overall relative dose intensity of 98%. 30 patients are evaluable for safety. WHO grade 3/4 drug related adverse events occured in 7 patients (23%): Leukopenias in 2, anemia in 1, and diarrhea in 4 patients. 14 patients completed 2 cycles and were evaluable for response. Response rates: CR 0/30, PR 3/30 (10%) and SD 3/30 (10%). 8 patients presented with disease progression at restaging. Median overall survival: CCC 166 days, GBC 327 days. Progression-free-survival: CCC 84 days, GBC 159 days. Conclusions: FOLFIRI is a well tolerated regimen in patients with biliary cancer that can be safely administered on an outpatient basis. FOLFIRI has no substantial activity in CCC and moderate activity in GBC. Further studies are required to define a standard palliative chemotherapy for treatment of biliary cancer. No significant financial relationships to disclose.