ASCC is a relatively rare malignancy. Several studies reported favourable prognosis in Female to Male patients (pts).Our work aims to identify and quantify sex-based differences in cancer-associated genomic alterations to better inform future precision medicine initiatives and provide insights on potential different survival based on sex. A cohort of 1,380 ASCC pts (952 F,428 M) underwent genomic profiling on tissue biopsies using FoundationOne®/FoundationOne®CDx assays, to examine key differences in mutational patterns based on sex and HPV status. HPV-16 was prevalent in F while HPV-6 in M. PD-L1 expression: over 70% positive (1%), ∼20% high (50%) with similar rates in HPV+ vs HPV- (74.5% vs 63.9%; p=0.16) and sex (F:74% vs M:70.4%; p=0.80). TMB-High (10+mutations/Mb) was found in ∼18% without significant differences by sex (p=0.80); a slightly elevated rate was seen in HPV+ vs HPV- (18.4% vs 14.0%; p=0.16); 34% had PIK3CA alterations (37.1% in HPV+ vs.16.8% in HPV- ; p<.01 with similar rates by sex F:37.1% vs 20.8%; M:37.1% vs 13.3%); in contrast higher prevalence in HPV- vs HPV+ resulted to TP53 (44.9% vs 5.6% p<.01), TERT(31.3% vs 2.7% p<.01), CDNK2A (29% vs 2.9%p<.01), CDNK2B (11.7% vs 1.6% p<.01) and NOTCH1 (14.5% vs 5.1% p<.01); F had higher rates of alterations in PTEN (15.3% vs 8.4%p<.01) ,KMT2D (21% vs 13.1%, p<.01), CBFB (3.3% vs 0.2%; p<.01) and CREBBP (5.4 vs 2.6%; p=0.06),whereas M showed higher rates of alterations in TERT(15.2 vs 3.5% p<.01), TP53 (20.3% vs 7.8% p<.01),CDKN2A (14% vs 3.8%p<.01),CDKN2B (5.4% vs 2.2% p=.02), MYC (4.2% vs 1.6% p=.03) as well as amplifications on 11q13 such as CCND1(7%vs3.2%p=0.02), FGF19 (7%vs3.3%p=0.02), FGF3(7.2%vs3.6%,p=0.02), FGF4 (7% vs 3.5% p=0.02). BRCA1 and BRCA2 mutations were in 5% pts with mild M predominance (7% vs 4%) regardless HPV expression. The higher incidence of HPV positivity in F compared to M remains the main hypothesis to justify the better prognosis of ASCC in women. A large proportion of PD-L1+ and TMB-High (∼70%), PIK3CA alterations (∼30%) and BRCA1/2 gene alteration (5%) may predict response to possible new therapeutic approaches for pts with ASCC like immunotherapy, targeted tyrosine kinase inhibitors, platinum chemotherapy and PARP inhibitors.

Background: Most of iCCA patients die because of hepatic progression, even in metastatic stage. Chemotherapy leads to modest increase in life expectancy; arterial-directed therapies (ADT), such as chemoembolization (TACE) or radioembolization (TARE), have been proposed to obtain local disease control, eventually leading to a survival benefit. Methods: We conducted a multicenter retrospective study involving 8 Italian Cancer Centers to evaluate efficacy outcomes and safety of ADT in advanced iCCA. Primary endpoint was overall survival (OS) from the first ADT. Results: 99 patients received at least one ADT from 2007 to 2017. TACE was performed in 74 patients, TARE in 25 patients. Median time from diagnosis of advanced disease to first ADT was 7.0 months. Median OS from first ADT was 11.9 months (95% CI 9.9-16.1); progression-free survival was 3.4 months (95% CI 3.2-4.0) with a disease control rate of 64% and an objective response rate of 20%. Adverse events (AE) after procedure were reported in 37 patients, more commonly low grade (G1-G2) abdominal pain (19%) and fever (18%); G3-G4 AE were reported in 11% of patients, while one fatal (G5) AE occurred due to brain hemorrhage one week after the procedure. No survival differences were observed in patients receiving more than one ADT (n.47) compared to those receiving only one procedure (n.52). OS according to procedure (TARE or TACE) was 19.1 and 10.5 months respectively (HR 0.53; 95% CI 0.32-0.88; p.031). Extrahepatic disease and Ca19.9 levels >100 kU/L were significantly associated with worse OS at univariate analysis (HR 1.77 and 2.73, respectively). Conclusions: Patients receiving ADT had good survival outcomes when compared with historical data of systemic chemotherapy, although authors acknowledge these data could also be driven by a selection bias. Procedures were feasible and tolerable, with limited serious AEs. Notably, patients receiving more than one procedure did not gain an OS benefit compared to those receiving only one ADT. According to these retrospective data, performing ADT in presence of extrahepatic disease may be questionable. Specific prospective studies should be designed in order to confirm ADT role in iCCA. Legal entity responsible for the study: Istituto Oncologico Veneto IRCCS. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.

•Natural history of biliary cancers metastatic to bone•The role of skeletal events in patients with biliary cancer•Biliary cancer and bone metastases: role of bisphosphonates.

The combination of gemcitabine-oxaliplatin (GEMOX) and Panitumumab compared to GEMOX alone was evaluated in this phase II randomized trial as first-line treatment in advanced biliary tract cancer (BTC). Despite the molecular selection for KRAS-wild-type status, progression-free-survival (PFS) and overall survival (OS) were not improved. Abstract Background : Biliary tract cancer (BTC) is a rare and lethal disease with few therapeutic options. Preclinical data suggest that the EGFR pathway could be involved in its progression. Methods : In this open-label, randomized Phase II trial we recruited chemotherapy-naïve patients with advanced BTC displaying a wild-type KRAS status. Patients were randomized to gemcitabine (1000 mg/m 2 ) and oxaliplatin (100 mg/m 2 ) with (Arm A) or without (Arm B) panitumumab (6mg/kg), for up to 12 cycles. The primary endpoint was progression free survival (PFS) analyzed by intention-to-treat. This study is registered with ClinicalTrials.gov (NCT01389414). Results : We enrolled 89 patients (45 in Arm A and 44 in Arm B) between 06/2010 and 09/2013. After a median follow-up of 10.1 months, median PFS was 5.3 months in Arm A (95%CI 3.3–7.2) and 4.4 months (95%CI 2.6–6.2) in Arm B (p=0.27). No survival differences were observed, being median OS 9.9 months in Arm A and 10.2 months in Arm B (p=0.42). In subgroup analysis, no differences in PFS according to

Introduction: The combination of a platinum derivative and gemcitabine has been recently set as the standard CT1 in aBTC. After progression, no established CT2 is available, and results from limited phase II trials and retrospective series suggest poor efficacy for different cytotoxic agents. We assessed the value of CT2 after a platinum-gemcitabine CT1 in aBTC by performing a systematic review of the literature. Methods: We identified eligible studies using the Medline database and the on-line abstract datasets of the Annual Meeting of the American Society of Clinical Oncology (ASCO), the biannual European Society of Medical Oncology Congress since 2002 (ESMO) and the annual World Gastrointestinal Congress since 2006. Progression-free survival (PFS) was the primary end-point of the analysis, while overall survival (OS) and response-rate (RR) were secondary objectives. Results: A total of 486 patients treated with platinum-gemcitabine CT1 from 5 different studies were included in the pooled analysis. All trials reported PFS data, while OS and RR data were available for only 4 trials (441 patients) and 3 trials (390 patients), respectively. Details about the CT2 regimens used were available for 312 patients: fluoropyrimidine (5-fluorouracil or capecitabine) plus platinum (oxaliplatin or cisplatin) (n = 128), 5-fluorouracil plus irinotecan (n = 62), single-agent fluoropyrimidine (n = 39), gemcitabine plus cisplatin (n = 17), other regimens (n = 66). Median PFS with CT2 obtained by a weighted pooled analysis of the available series was 3.11 months (95% CI: 2.82-3.40). Median OS was 6.29 months (95% CI 5.59-7.00) and overall RR was 9.2%. Conclusion: The current analysis confirmed the limited efficacy of CT2 after platinum-gemcitabine CT1 in unselected populations of aBTC patients. While waiting for effective biologic agents in aBTC, ongoing randomized trials should identify the optimal CT2 regimen and validate prognostic factors for individual patient management.

Background: Biliary tract cancer (BTC) is a rare and lethal disease with very few therapeutic options. Preclinical data suggest that Epithelial growth factor receptor (EGFR) pathway activation could be involved in BTC pathogenesis, envisaging a potential role of anti-EGFR monoclonal antibodies. Methods: Eighty-nine patients (pts) with advanced BTC harboring wild-type KRAS status, ECOG PS 0-2, without prior systemic therapy, were randomized to receive gemcitabine and oxaliplatin (GEMOX) with (arm A, 45 pts) or without (arm B, 44 pts) panitumumab (6 mg/kg), every 2 weeks for up to 12 cycles. In arm A maintenance therapy with panitumumab was allowed in case of clinical benefit after 12 cycles. Randomization was stratified for ECOG status (0-1 vs 2) and histology (intrahepatic-IHC vs extrahepatic-EHC) cholangiocarcinoma and gallbladder carcinoma-GB). Primary endpoint was progression free survival (PFS); secondary ones were response rate (RR) (RECIST v1.1), overall survival (OS) and safety. Results: After a median follow-up of 10.1 months (mo) and 86 PFS events (radiological progression or death), median PFS was 5.3 mo in Arm A (95% CI 3.3–7.2) and 4.4 mo (95% CI 2.6–6.2) in Arm B (p = 0.27). No survival differences were observed, being median OS 9.9 mo (95% CI 5.4-14.3) in Arm A and 10.2 mo in Arm B (95% CI 6.4-13.9, p = 0.42). Median PFS for IHC patients was 5.7 mo in Arm A (95% CI 2.7–8.7) and 6.2 mo in Arm B (95% CI 3.1–9.2). Median PFS for EHC and GB was 4.9 mo in Arm A (95% CI 2.4–7.4) and 3.8 mo in Arm B (95% CI 2.3–5.3). However, pts with IHC treated with panitumumab had an improvement in OS of 3.3 mo compared to control group (15.1 vs 11.8 mo; p = 0.13). Among patients evaluable for response (84/89) RR was 26.6% in Arm A and 18.1% in Arm B, with DCR favoring the experimental arm (75.5% vs 68.1%, p = 0.99). As for safety, skin toxicity was the main adverse event in arm A, affecting up to 80% of pts. Neurotoxicity, constitutional and gastrointestinal symptoms were equally common in both arms, but a higher incidence of diarrhea (55.5 vs 31.8%), mucositis (22.2 vs 13.7%) and constipation (24.4 vs 15.9%) was seen in patients treated with panitumumab. Conclusions: The study did not meet its primary endpoint. A trend toward better RR was observed in pts treated with panitumumab. Pts with wild-type KRAS IHC may receive greater benefit from P-GEMOX treatment. Further analyses on potential markers of response/resistance are currently ongoing.

Introduction: In literature few data on the natural history of bone disease in Biliary Cancers are available. We conducted a national multicenter retrospective survey to explore the impact of bone metastases in this setting of tumors. Patients and methods: Data on clinical-pathology, skeletal outcomes, skeletal-related events (SREs), and bone-directed therapies were collected from 110 patients affected by biliary cancer with bone metastasis. Results: Intrahepatic Cholangiocarcinoma was the most common primary tumor (75 patients, 68%), followed by Gallbladder carcinoma (14%), Extrahepatic Cholangiocarcinoma (9%) and Klatskin's tumors (8%). 58% of patients developed bone metastases during the course of the disease, in the remaining cases skeletal disease was just evident at the time of biliary cancer diagnosis. The axial skeleton was the most common involved site (76%). SREs were experienced by 47 patients (42%), 32 of them experienced one SRE, 13 two SREs, only 2 at least 3 SREs. The necessity for radiotherapy was the most common first SRE (62,5% of patients). Bisphosphonates were administered in 47% of patients; zoledronic acid was the most used (98%). 18 patients experienced at least one SRE during treatment with biphosphonates (36%). Median time to first SRE from bone metastases diagnosis was 1,2 months (Cl 95% 0,5–1.8 months) and median survival was 6,5 months (Cl 95% 4-9 months). Survival analysis showed that, among the clinical and tumoral features considered, only ECOG PS correlates with survival after bone metastases diagnosis. The use of zoledronic acid seems to correlate with longer survival (p 0,007, Cl 95%): the median survival in patients treated with bisphosphonates was 9 months (Cl 95% 7,2-11,3 months) versus 5 months of untreated patients (Cl 95% 3,4–6,4). Among patients who received zoledronic acid before the first SRE, the median time to appearance of first SRE was significantly prolonged compared to control (6 months vs 1 month for control; p: 0.05). Conclusions: This study demonstrates that bone metastatic biliary cancer patients are a heterogeneous population in term of skeletal events and of survival. Moreover for the first time in literature it documents the role of bifosphonates in delaying time to the first SRE and increasing the median survival. These data may support the beneficial effects of ZOL in patients affected by biliary cancer metastatic to bone.

Advanced biliary tract adenocarcinoma (BTA) is a rare tumor with a poor prognosis. Since no standard salvage chemotherapy regimen exists, we explored the activity of capecitabine alone or combined with mitomycin C.

Introduction: The Vecti-BIL study is a randomized phase II study of gemcitabine and oxaliplatin (GEMOX) with or without panitumumab as first-line treatment for KRAS wild-type biliary tract cancer (BTC). Preliminary results have shown a trend towards better progression-free survival (PFS) and objective response rate (RR) for the combination with panitumumab, although it was not statistically significant.Methods: Eighty-nine patients (pts) were randomized to GEMOX (gemcitabine, 1000 mg/m2 and oxaliplatin, 100 mg/m2) chemotherapy with (arm A, 45 pts) or without (arm B, 44 pts) panitumumab (6 mg/kg), every 2 weeks for up to 12 cycles. Maintenance therapy with panitumumab alone was allowed in arm A in case of clinical benefit after 12 cycles. Stratification factors were ECOG status (0-1 vs. 2) and histology (intrahepatic-IHC vs. extrahepatic-EHC and gallbladder carcinoma-GB). The primary endpoint was PFS. Secondary endpoints were RR (RECIST version 1.1), overall survival (OS), and safety.Results: After a median follow-up of 10.1 months (mo), median PFS was 5.3 mo in arm A (95% CI 3.3–7.2) and 4.4 mo (95% CI 2.6–6.2) in arm B (p = 0.27). Among the 84 evaluable pts, RR was 26.6% in arm A and 18.1% in arm B, with disease control rate favoring the experimental arm (75.5% and 68.1% respectively). No survival differences were observed, being median OS 9.9 mo (95% CI 5.4–14.3) in arm A and 10.2 mo in arm B (95% CI 6.4–13.9, p= 0.42). Subgroup analysis showed that median PFS for the 42 IHC pts was 5.7 in Arm A (95% CI 2.7–8.7) and 6.2 mo in Arm B (95% CI 3.1–9.2). Median PFS for EHC (19 pts) and GB (28 pts) was 4.9 mo in arm A (95% CI 2.4–7.4) and 3.8 mo in arm B (95% CI 2.3–5.3). However, pts with IHC exposed to panitumumab had an improvement in OS of 3.3 mo compared to control group (15.1 mo vs. 11.8 mo; p = 0.13). The safety profile was similar to that observed in other panitumumab-based combinations, being skin toxicity (80%), asthenia (64.4%) and diarrhea (55.5%) the most common toxicities in arm A, and neurotoxicity (56.8%), nausea (54.5%) and asthenia (52.2%) in arm B.Conclusion: Although the study did not meet its primary endpoint, a trend toward better RR was observed in pts treated with panitumumab. Pts with IHC may particularly benefit from P-GEMOX treatment. Further analyses on potential markers of response/resistance are currently ongoing. Introduction: The Vecti-BIL study is a randomized phase II study of gemcitabine and oxaliplatin (GEMOX) with or without panitumumab as first-line treatment for KRAS wild-type biliary tract cancer (BTC). Preliminary results have shown a trend towards better progression-free survival (PFS) and objective response rate (RR) for the combination with panitumumab, although it was not statistically significant. Methods: Eighty-nine patients (pts) were randomized to GEMOX (gemcitabine, 1000 mg/m2 and oxaliplatin, 100 mg/m2) chemotherapy with (arm A, 45 pts) or without (arm B, 44 pts) panitumumab (6 mg/kg), every 2 weeks for up to 12 cycles. Maintenance therapy with panitumumab alone was allowed in arm A in case of clinical benefit after 12 cycles. Stratification factors were ECOG status (0-1 vs. 2) and histology (intrahepatic-IHC vs. extrahepatic-EHC and gallbladder carcinoma-GB). The primary endpoint was PFS. Secondary endpoints were RR (RECIST version 1.1), overall survival (OS), and safety. Results: After a median follow-up of 10.1 months (mo), median PFS was 5.3 mo in arm A (95% CI 3.3–7.2) and 4.4 mo (95% CI 2.6–6.2) in arm B (p = 0.27). Among the 84 evaluable pts, RR was 26.6% in arm A and 18.1% in arm B, with disease control rate favoring the experimental arm (75.5% and 68.1% respectively). No survival differences were observed, being median OS 9.9 mo (95% CI 5.4–14.3) in arm A and 10.2 mo in arm B (95% CI 6.4–13.9, p= 0.42). Subgroup analysis showed that median PFS for the 42 IHC pts was 5.7 in Arm A (95% CI 2.7–8.7) and 6.2 mo in Arm B (95% CI 3.1–9.2). Median PFS for EHC (19 pts) and GB (28 pts) was 4.9 mo in arm A (95% CI 2.4–7.4) and 3.8 mo in arm B (95% CI 2.3–5.3). However, pts with IHC exposed to panitumumab had an improvement in OS of 3.3 mo compared to control group (15.1 mo vs. 11.8 mo; p = 0.13). The safety profile was similar to that observed in other panitumumab-based combinations, being skin toxicity (80%), asthenia (64.4%) and diarrhea (55.5%) the most common toxicities in arm A, and neurotoxicity (56.8%), nausea (54.5%) and asthenia (52.2%) in arm B. Conclusion: Although the study did not meet its primary endpoint, a trend toward better RR was observed in pts treated with panitumumab. Pts with IHC may particularly benefit from P-GEMOX treatment. Further analyses on potential markers of response/resistance are currently ongoing.

Introduction: Advanced biliary tract cancer (aBTC) is a disease that scarcely benefits of systemic therapies but it often remains limited to liver, suggesting that locoregional strategies might be applied to increase treatment options and improve outcome. Transarterial chemo-embolization (TACE) and radio-embolization (TARE) are thus sometimes offered to pts, despite the lack of experimental evidences on their efficacy. The aim of this retrospective analysis is to evaluate the safety and efficacy of TACE/TARE in aBTC. Methods: We retrospectively collected data on patients with histologically-proven unresectable aBTC treated with TACE/TARE at our Institutions. TACE was performed with infusion of 2mL of microspheres loaded with chemotherapy drugs into the tumor-supplying vessel. TARE is an innovative locoregional treatment which involves the delivery of SIR-Spheres® (SIRT) that contain the β-emitter yttrium-90 into the arterial supply of the liver. Data on pts, treatments and tumor characteristics were collected and analyzed to investigate feasibility and activity on these locoregional therapies. Results: From August 2011 to December 2014 82 TACE (median 2, range 1-7) and 13 TARE (median1, range 1-2) were performed in 49 pts with the following characteristics: M/F: 25/24, median age: 64 years (range 32-78), PS (ECOG) 0/1/2: 28/20/1, intrahepatic cholangiocarcinoma 42 (86%), extrahepatic cholangiocarcinoma 5 (10%) and gallbladder cancer 2 (4%), unilobar/bilobar: 19/20. Twenty-one out of 49 pts (43%) presented liver-predominantly disease with extrahepatic localizations: 12 confined to lymph nodes, 6 pts lung metastases, 2 lung + lymph nodes and 1 bone metastases. TACE used doxorubin (n = 31), oxaliplatin (n = 5), and irinotecan (n = 1) as active drugs while TARE employed SIRT technology (n = 12). Twelve pts received TACE pts before starting any chemotherapy, 2 of them as neoadjuvant treatment to improve resectability and 8 as first line treatment; additional 17 pts received TACE/TARE as first line for the relapse after adjuvant gemcitabine-based chemotherapy (8 pts) or as consolidation strategy after a partial response or a stabilization to systemic chemotherapy for their aBTC (9 pts). Twenty-two pts received TARE/TACE in second or later lines. According to RECIST criteria, the liver tumor response was complete in 3 pts, partial response in 11 pts, stable disease in 28 and progression in 7. Twenty-one out of 28 RECIST stabilization showed an increase in the central necrosis of the lesions configuring a morphological response. Two patients became resectable and underwent liver resection after locoregional treatment. No hepatic progression was observed within 4 weeks after procedures. Treatment was well tolerated with no deaths or acute liver failure within 30-days post infusion. Grade 1-2 toxic effects occurred in 18% of pts and included abdominal pain (n = 4), fever (n = 3), fatigue (n = 2); only two pts had a hepatic abscess as major complication. At a median follow-up from TACE/TARE of 10 months, 27 out of 49 pts are alive. Conclusion: TACE and TARE seem to be safe and well-tolerated therapies in aBTC, however their employment is widely inhomogeneous across treatment lines. These promising modality approaches and the better timing for their use need to be confirmed in larger and controlled studies.

Background: The role of CT2 after progression to CT1 with gemcitabine plus a platinum derivative in aBTC has not been established. We aimed to refine the role of CT2 after standard CT1 in a large retrospective pts cohort and by pooling our results with the available literature evidence.Patients and methods: We collected the clinical records of aBTC pts treated with CT2 after progression to a first-line gemcitabine plus cisplatin or oxaliplatin regimen. We then performed a pooled analysis of published data: eligible studies were identified by the Medline database and the on-line abstract datasets of the Annual Meeting of the American Society of Clinical Oncology, the biannual European Society of Medical Oncology Congress since 2002 and the annual World Gastrointestinal Congress since 2006.Results: A total of 174 pts were included in the survey: CT2 demonstrated low response rate (RR: 3.4%), with median progression-free (mPFS) and overall survival (mOS) of 3.0 and 6.6 months, respectively. Comparing different CT2 regimens, combination chemotherapy demonstrated a slight increase in disease control rate compared to monotherapy (32% vs. 21%, p = 0.140), as well as modestly improved mPFS (3.1 vs. 2.9 months; p = 0.072) and mOS (7.1 vs. 5.0 months; p = 0.006). An Eastern Cooperative Oncology Group (ECOG) performance status of 0 and low pre-treatment CA19.9 levels were associated with better prognosis at univariate analysis (p < 0.0001). Data from other five series were identified by literature search, for a total of 499 pts analyzed. Types of CT2 used were the following: fluoropyrimidine plus platinum (FOLFOX, XELOX, 5-fluorouracil plus cisplatin) in 138 pts, FOLFIRI in 92 pts (in 13 of whom in combination with bevacizumab), 5-fluorouracil or capecitabine monotherapy in 88 pts, gemcitabine plus cisplatin or oxaliplatin in 30 pts, and other regimens in 151 pts. The results of the pooled analysis confirmed low RR (10.2%; 95%CI 7.3%-13.1%) and limited efficacy of CT2 in unselected pts populations (mPFS: 3.1 months, 95%CI 2.9-3.4; mOS: 6.3 months, 95%CI 5.6-7.0).Conclusions: Our analysis confirms the limited value of CT2 after a standard CT1 in aBTC pts. Randomized trials are needed to definitively assess the benefit of CT2 over best supportive care in this setting. In the meanwhile, CT2 may be offered to aBTC pts selected on the basis of several clinical prognostic parameters. Background: The role of CT2 after progression to CT1 with gemcitabine plus a platinum derivative in aBTC has not been established. We aimed to refine the role of CT2 after standard CT1 in a large retrospective pts cohort and by pooling our results with the available literature evidence. Patients and methods: We collected the clinical records of aBTC pts treated with CT2 after progression to a first-line gemcitabine plus cisplatin or oxaliplatin regimen. We then performed a pooled analysis of published data: eligible studies were identified by the Medline database and the on-line abstract datasets of the Annual Meeting of the American Society of Clinical Oncology, the biannual European Society of Medical Oncology Congress since 2002 and the annual World Gastrointestinal Congress since 2006. Results: A total of 174 pts were included in the survey: CT2 demonstrated low response rate (RR: 3.4%), with median progression-free (mPFS) and overall survival (mOS) of 3.0 and 6.6 months, respectively. Comparing different CT2 regimens, combination chemotherapy demonstrated a slight increase in disease control rate compared to monotherapy (32% vs. 21%, p = 0.140), as well as modestly improved mPFS (3.1 vs. 2.9 months; p = 0.072) and mOS (7.1 vs. 5.0 months; p = 0.006). An Eastern Cooperative Oncology Group (ECOG) performance status of 0 and low pre-treatment CA19.9 levels were associated with better prognosis at univariate analysis (p < 0.0001). Data from other five series were identified by literature search, for a total of 499 pts analyzed. Types of CT2 used were the following: fluoropyrimidine plus platinum (FOLFOX, XELOX, 5-fluorouracil plus cisplatin) in 138 pts, FOLFIRI in 92 pts (in 13 of whom in combination with bevacizumab), 5-fluorouracil or capecitabine monotherapy in 88 pts, gemcitabine plus cisplatin or oxaliplatin in 30 pts, and other regimens in 151 pts. The results of the pooled analysis confirmed low RR (10.2%; 95%CI 7.3%-13.1%) and limited efficacy of CT2 in unselected pts populations (mPFS: 3.1 months, 95%CI 2.9-3.4; mOS: 6.3 months, 95%CI 5.6-7.0). Conclusions: Our analysis confirms the limited value of CT2 after a standard CT1 in aBTC pts. Randomized trials are needed to definitively assess the benefit of CT2 over best supportive care in this setting. In the meanwhile, CT2 may be offered to aBTC pts selected on the basis of several clinical prognostic parameters.

The role of second-line chemotherapy (CT) is not established in advanced biliary tract cancer (aBTC). We investigated the outcome of aBTC patients treated with second-line CT and devised a prognostic model. Baseline clinical and laboratory data of 300 consecutive aBTC patients were collected and association with overall survival (OS) was investigated by multivariable Cox models. The following parameters resulted independently associated with longer OS: Eastern Cooperative Oncology Group performance status of 0 (P<0.001; hazard ratio (HR), 0.348; 95% confidence interval (CI) 0.215–0.562), CA19.9 lower than median (P=0.013; HR, 0.574; 95% CI 0.370–0.891), progression-free survival after first-line CT ⩾6 months (P=0.027; HR, 0.633; 95% CI 0.422–0.949) and previous surgery on primary tumour (P=0.027; HR, 0.609; 95% CI 0.392–0.945). We grouped the 249 patients with complete data available into three categories according to the number of fulfilled risk factors: median OS times for good-risk (zero to one factors), intermediate-risk (two factors) and poor-risk (three to four factors) groups were 13.1, 6.6 and 3.7 months, respectively (P<0.001). Easily available clinical and laboratory factors predict prognosis of aBTC patients undergoing second-line CT. This model allows individual patient-risk stratification and may help in treatment decision and trial design.

ABSTRACT Aim: Gemcitabine (GEM) and nab-paclitaxel (nab-P) significantly improved overall survival over GEM in metastatic pancreatic adenocarcinoma (PA). Given the synergism of taxanes with platinum compounds and fluoropyrimidines, we determined the recommended phase 2 dose (RP2D) of nab-P in combination with cisplatin, capecitabine, and GEM (PAXG regimen) in a phase Ib trial in patients (pts) with stage III PA (NCT01730222). Methods: GEM, cisplatin and capecitabine were given at fixed dose (800, 30, and 1250 mg/m2, respectively) q 2 weeks. Doses of nab-P were escalated in cohorts of 3 to 6 pts from 100 (level 1), to 125 (level 2) and 150 mg/m2 (level 3) q 2 weeks. The maximum tolerated dose (MTD) was defined as the dose at which > 2 out of 3-6 pts developed dose-limiting toxicity (DLT) during the first month of therapy. DLT was defined as G ≥ 4 neutropenia lasting ≥ 7 days; G ≥ 3 febrile neutropenia, fever ≥38.5°C, thrombocytopenia, diarrhea, nausea or vomiting; G ≥ 2 neurological toxicity or failure to recover to grade ≤ 1 toxicity (except alopecia) or to baseline values after delaying the initiation of next cycle by > 2 weeks. Results: Between Dec 2012 and Mar 2014, 23 pts (16 males; median age 63 years) with unresectable (according to a surgical team performing >100 duodenocephalopancreasectomy/year) stage III PA, were enrolled at a single institution (3 at level 1, 5 at level 2, 15 at level 3). To date, 197 cycles of PAXG were administered. Therapy is ongoing in 5 pts at level 3. No DLT has occurred. Worse per patient toxicity was G3/4 neutropenia 29/29%; G3 fatigue 14%; G3 neuropathy, anemia, nausea, diarrhea 7%. After 123 cycles at 150 mg/m2 the nab-P dose-intensity was 90%. To date, a partial response (PR) was observed in 15 pts (65%) and stable disease (SD) in 8 pts; among 20 pts with positive PET scan a complete response was observed in 8 (40%), PR in 10 (50%), SD in 2; 19 pts had elevated basal CA19-9 which was reduced by >50% in 18 (95%); 15/16 (94%) pts with mature follow-up were progression-free at 6 months from therapy start. Conclusions: The RP2D of nab-P in the PAXG regimen was 150 mg/m2 every 2 weeks. Preliminary results are promising and a phase II randomized trial with this regimen is ongoing. Disclosure: M. Reni: Participation in an Advisory Board : Merck; Celgene; CLOVIS; Genentech; Boehringer L. Gianni: advisory board Celgene. All other authors have declared no conflicts of interest.

We have read with great interest the recent paper by Lamarca et al. [1.Lamarca A. Hubner R.A. Ryder W.D. Valle J.W. Second-line chemotherapy in advanced biliary cancer: a systematic review.Ann Oncol. 2014; 25: 2328-2338Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar], in which the authors conducted a systematic review of the literature to evaluate the level of evidence behind the use of second-line chemotherapy for patients with advanced biliary tract cancer (aBTC). The authors collected data of 761 patients from 14 phase II trials and 9 retrospective analyses, reporting a mean overall survival (OS) of 7.2 months and a mean progression-free survival (PFS) of 3.2 months. Response rate and disease control rate (DCR) were 7.7% and 49.5%, respectively, suggesting that a cohort of aBTC patients may benefit from second-line chemotherapy. We really thank the authors for their efforts: due to the paucity of reliable data in this setting, the topic is of great interest. In order to further reduce the impact of study heterogeneity on the results, we suggest to the authors to exclude the reports of targeted agents and limit the analyses to chemotherapy only: this could be particularly important when alternative end points (such as PFS) are being investigated as surrogate for OS in pooled series.Our group has recently conducted a retrospective evaluation of 300 patients with aBTC who underwent second-line chemotherapy [2.Fornaro L. Cereda S. Aprile G. et al.Multivariate prognostic factors analysis for second-line chemotherapy in advanced biliary tract cancer.Br J Cancer. 2014; 110: 2165-2169Crossref PubMed Scopus (63) Google Scholar]. Our results are consistent with those of Lamarca, with a median PFS of 3.2 months and a 34% DCR. Second-line chemotherapy in aBTC therefore represents an unresolved issue and prospective randomized trials are needed. Ongoing ABC-06 trial (NCT 01926236) is the first randomized phase III trial comparing mFOLFOX chemotherapy with active symptom control (ASC) alone. If we completely agree with the ABC-06 investigators that ASC is correct as control arm from a strict scientific perspective, we could speculate if it is still acceptable in the light of the abovementioned results [1.Lamarca A. Hubner R.A. Ryder W.D. Valle J.W. Second-line chemotherapy in advanced biliary cancer: a systematic review.Ann Oncol. 2014; 25: 2328-2338Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar, 2.Fornaro L. Cereda S. Aprile G. et al.Multivariate prognostic factors analysis for second-line chemotherapy in advanced biliary tract cancer.Br J Cancer. 2014; 110: 2165-2169Crossref PubMed Scopus (63) Google Scholar]: are we taking the chance not to achieve the answers we really need? Lessons learned from pancreatic cancer tell us that the original design of the CONKO group phase III study in second-line setting (with a similar design to the ABC-06 trial) was prematurely closed because ASC was not accepted by participating centres and a new trial was performed with 5-fluorouracil as control arm, even though a formal demonstration of the value of second-line chemotherapy was lacking at the time [3.Pelzer U. Schwaner I. Stieler J. et al.Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group.Eur J Cancer. 2011; 47: 1676-1681Abstract Full Text Full Text PDF PubMed Scopus (282) Google Scholar, 4.Oettle H. Riess H. Stieler J.M. et al.Second-line oxaliplatin, folinic acid, and fluorouracil versus folinic acid and fluorouracil alone for gemcitabine-refractory pancreatic cancer: outcomes from the CONKO-003 Trial.J Clin Oncol. 2014; 32: 2423-2429Crossref PubMed Scopus (320) Google Scholar]. Since both the report from Lamarca et al. and our paper do not allow to identify a preferable second-line regimen, would a single-agent chemotherapy arm (e.g. fluoropyrimidine) be a more suitable comparator for mFOLFOX? Our group has recently completed a randomized phase II study to assessing the therapeutic activity of capecitabine alone or in combination with mitomycin C as second-line therapy (NCT01530503). In order to strength the value of fluoropyrimidines in this setting, we sought for OS differences between patients receiving gemcitabine-based first-line chemotherapy and fluoropyrimidine-based second-line chemotherapy and patients receiving the reverse sequence: in our series, neither second-line OS [6.0 versus 7.8 months, hazard ratio (HR) 0.769; 95% confidence interval (CI) 0.165–1.373] nor OS calculated from the beginning of first-line (15.7 versus 14.9 months, HR 1.054; 95% CI 0.450–1.658) differ between these two groups.In their review, the authors underline the need for prognostic factors to better select aBTC patients with higher chances of benefit from rescue chemotherapy [1.Lamarca A. Hubner R.A. Ryder W.D. Valle J.W. Second-line chemotherapy in advanced biliary cancer: a systematic review.Ann Oncol. 2014; 25: 2328-2338Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar]. Different retrospective series tried to identify prognostic factors in patients with aBTC in first line [5.Park I. Lee J.L. Ryu M.H. et al.Prognostic factors and predictive model in patients with advanced biliary tract adenocarcinoma receiving first-line palliative chemotherapy.Cancer. 2009; 115: 4148-4155Crossref PubMed Scopus (53) Google Scholar]. In our retrospective series, performance status, CA19.9 level, surgery on primary tumour and first-line PFS were identified as independent prognostic parameters at multivariate analysis for second-line chemotherapy: such factors can be combined and different patient subgroups can be thus identified by means of these easily available variables [2.Fornaro L. Cereda S. Aprile G. et al.Multivariate prognostic factors analysis for second-line chemotherapy in advanced biliary tract cancer.Br J Cancer. 2014; 110: 2165-2169Crossref PubMed Scopus (63) Google Scholar]. We claim that prospective trials such as the ABC-06 could be intriguing opportunities in order to validate our prognostic score: we should not miss the opportunity to make the times really change in aBTC management.disclosureThe authors have declared no conflicts of interest. We have read with great interest the recent paper by Lamarca et al. [1.Lamarca A. Hubner R.A. Ryder W.D. Valle J.W. Second-line chemotherapy in advanced biliary cancer: a systematic review.Ann Oncol. 2014; 25: 2328-2338Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar], in which the authors conducted a systematic review of the literature to evaluate the level of evidence behind the use of second-line chemotherapy for patients with advanced biliary tract cancer (aBTC). The authors collected data of 761 patients from 14 phase II trials and 9 retrospective analyses, reporting a mean overall survival (OS) of 7.2 months and a mean progression-free survival (PFS) of 3.2 months. Response rate and disease control rate (DCR) were 7.7% and 49.5%, respectively, suggesting that a cohort of aBTC patients may benefit from second-line chemotherapy. We really thank the authors for their efforts: due to the paucity of reliable data in this setting, the topic is of great interest. In order to further reduce the impact of study heterogeneity on the results, we suggest to the authors to exclude the reports of targeted agents and limit the analyses to chemotherapy only: this could be particularly important when alternative end points (such as PFS) are being investigated as surrogate for OS in pooled series. Our group has recently conducted a retrospective evaluation of 300 patients with aBTC who underwent second-line chemotherapy [2.Fornaro L. Cereda S. Aprile G. et al.Multivariate prognostic factors analysis for second-line chemotherapy in advanced biliary tract cancer.Br J Cancer. 2014; 110: 2165-2169Crossref PubMed Scopus (63) Google Scholar]. Our results are consistent with those of Lamarca, with a median PFS of 3.2 months and a 34% DCR. Second-line chemotherapy in aBTC therefore represents an unresolved issue and prospective randomized trials are needed. Ongoing ABC-06 trial (NCT 01926236) is the first randomized phase III trial comparing mFOLFOX chemotherapy with active symptom control (ASC) alone. If we completely agree with the ABC-06 investigators that ASC is correct as control arm from a strict scientific perspective, we could speculate if it is still acceptable in the light of the abovementioned results [1.Lamarca A. Hubner R.A. Ryder W.D. Valle J.W. Second-line chemotherapy in advanced biliary cancer: a systematic review.Ann Oncol. 2014; 25: 2328-2338Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar, 2.Fornaro L. Cereda S. Aprile G. et al.Multivariate prognostic factors analysis for second-line chemotherapy in advanced biliary tract cancer.Br J Cancer. 2014; 110: 2165-2169Crossref PubMed Scopus (63) Google Scholar]: are we taking the chance not to achieve the answers we really need? Lessons learned from pancreatic cancer tell us that the original design of the CONKO group phase III study in second-line setting (with a similar design to the ABC-06 trial) was prematurely closed because ASC was not accepted by participating centres and a new trial was performed with 5-fluorouracil as control arm, even though a formal demonstration of the value of second-line chemotherapy was lacking at the time [3.Pelzer U. Schwaner I. Stieler J. et al.Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group.Eur J Cancer. 2011; 47: 1676-1681Abstract Full Text Full Text PDF PubMed Scopus (282) Google Scholar, 4.Oettle H. Riess H. Stieler J.M. et al.Second-line oxaliplatin, folinic acid, and fluorouracil versus folinic acid and fluorouracil alone for gemcitabine-refractory pancreatic cancer: outcomes from the CONKO-003 Trial.J Clin Oncol. 2014; 32: 2423-2429Crossref PubMed Scopus (320) Google Scholar]. Since both the report from Lamarca et al. and our paper do not allow to identify a preferable second-line regimen, would a single-agent chemotherapy arm (e.g. fluoropyrimidine) be a more suitable comparator for mFOLFOX? Our group has recently completed a randomized phase II study to assessing the therapeutic activity of capecitabine alone or in combination with mitomycin C as second-line therapy (NCT01530503). In order to strength the value of fluoropyrimidines in this setting, we sought for OS differences between patients receiving gemcitabine-based first-line chemotherapy and fluoropyrimidine-based second-line chemotherapy and patients receiving the reverse sequence: in our series, neither second-line OS [6.0 versus 7.8 months, hazard ratio (HR) 0.769; 95% confidence interval (CI) 0.165–1.373] nor OS calculated from the beginning of first-line (15.7 versus 14.9 months, HR 1.054; 95% CI 0.450–1.658) differ between these two groups. In their review, the authors underline the need for prognostic factors to better select aBTC patients with higher chances of benefit from rescue chemotherapy [1.Lamarca A. Hubner R.A. Ryder W.D. Valle J.W. Second-line chemotherapy in advanced biliary cancer: a systematic review.Ann Oncol. 2014; 25: 2328-2338Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar]. Different retrospective series tried to identify prognostic factors in patients with aBTC in first line [5.Park I. Lee J.L. Ryu M.H. et al.Prognostic factors and predictive model in patients with advanced biliary tract adenocarcinoma receiving first-line palliative chemotherapy.Cancer. 2009; 115: 4148-4155Crossref PubMed Scopus (53) Google Scholar]. In our retrospective series, performance status, CA19.9 level, surgery on primary tumour and first-line PFS were identified as independent prognostic parameters at multivariate analysis for second-line chemotherapy: such factors can be combined and different patient subgroups can be thus identified by means of these easily available variables [2.Fornaro L. Cereda S. Aprile G. et al.Multivariate prognostic factors analysis for second-line chemotherapy in advanced biliary tract cancer.Br J Cancer. 2014; 110: 2165-2169Crossref PubMed Scopus (63) Google Scholar]. We claim that prospective trials such as the ABC-06 could be intriguing opportunities in order to validate our prognostic score: we should not miss the opportunity to make the times really change in aBTC management. disclosureThe authors have declared no conflicts of interest. The authors have declared no conflicts of interest.

The photocatalytic activity of titanium dioxide is sometimes observed to increase upon addition of silica, but the origin of this enhancement is not clear. To shed light on this effect, we investigate the titania/silica system in case of perfect segregation using density functional theory. Two situations have been considered: a single silica monolayer covering a titania surface and a bulk titania/silica interface. In both cases, we find that the presence of silica strongly modifies the electronic structure of the catalyst. In the case of the bulk interface, the analysis of the projected density of states reveals that interface electronic states give a large contribution to the edges of valence and conduction bands. For a silica monolayer on a (101) surface of anatase, the spatial localization of the states near the edge of the valence band depends on the hydroxylation state of the monolayer. Similar to the bulk case, the hydrogen-free monolayer hosts interface states, whereas in the fully hydroxylated system, these disappear and all top valence band states are located inside the titania slab. These results can be rationalized in terms of the number of Ti atoms available for bonding with bridging oxygens at the interface, suggesting that the ratio of Ti-O-Si and 2Ti-O-Si linkages allowed by the interface bonding topology may v play an important role in photoabsorption processes.

Context Pancreatic adenocarcinoma (PA) is mostly metastatic at time of diagnosis with a poor survival. Objective We decided to explore whether metastatic site correlates with prognosis. Methods Patients with pathologic diagnosis of metastatic PA, treated at our Institution with upfront combination chemotherapy between April 1997 and August 2010 were eligible for this analysis. Baseline tumor assessment consisted of contrast enhanced computed tomography scan of the abdomen and the thorax. Results Two-hundreds and sixty-five patients with metastatic PA, median age 60 years; median PS 90; median CA 19-9 1,048 were eligible; 19 (7.2%) had prior pancreatic surgery. Metastases were located: in a single organ (n=150; 56.6%); liver (n=227; 85.3%); peritoneum (n=32; 12.1%); lung (n=53; 19.9%). Lung was the only metastatic site in 15 cases (5.6%). Median and 1-year overall survival (OS) was 9.0 months and 32.2%. Prior surgery correlated with better OS (11.7 and 51.0% versus 8.9 and 30.8%; P=0.006); liver metastases with worse OS (median and 1-year OS: 8.8 months and 29.7% versus 11.1 and 47.4%; P=0.005); while no difference in OS was observed based on number of metastatic sites (P=0.37); peritoneal (P=0.50) or lung metastases (P=0.10). Patients with lung as isolated metastatic site lived longer (17.3 months and 66.7%) with respect to the whole population (9.0 months and 30.1%; P=0.01) and to patients with lung metastases associated to other metastatic sites (8.8 months and 34.2%; P=0.07). Conclusions Prior surgery and metastatic site correlate with prognosis and should be used as a stratification criterion in prospective trials. Patients with lung as isolated metastatic site has a particularly good prognosis.

A randomised multi-centre phase II trial explored the role of MS in pts with MPA without progressive disease (PD) after induction chemotherapy (CT), using an observation only group (O) as calibration arm [Reni et al. Proc ASCO 2012]. The aim of this present study was to identify genetic polymorphisms related to pharmacokinetics and pharmacodynamics of sunitinib that are associated with outcome. Adult pts with pathologic diagnosis of MPA, performance status (PS) >50%, no PD after 6 months of CT were randomized to O (arm A) or MS at 37.5 mg daily until PD or a maximum of 6 months (arm B). Functional polymorphisms of 6 genes involved in sunitinib activity, metabolism and transport (VEGFA, VEGFR-2, CYP3A5, CYP1A1, ABCB1, ABCG2) were studied in genomic DNA from baseline blood samples, using PCR Taqman®-probes-based assays. Associations of genotypes with overall survival (OS) and progression-free survival (PFS) were evaluated by Log-rank test. Genotyping was successfully performed in all the DNA samples of 43 consenting pts of 55 enrolled in the trial (78%; arm A/B: 83%/73%; p = 0.39). Significantly longer OS was observed in 7 pts harbouring the ABCB1 3435TT genotype (group-1; median OS 20 months) as compared to 36 pts with 3435CC/CT genotype (group-2; median OS 7 months; p = 0.027). Median OS was 26 months in 4 group-1 arm B pts, 7 months in 15 group-2 arm B pts (p = 0.12); 16 months in 3 group-1 arm A pts and 9 months in 21 group-2 arm A pts (p = 0.67). No OS difference was observed in 28 pts harbouring the VEGFA -634GC-CC genotype (group-3; median OS 10 months) as compared to 15 pts with -634GG genotype (group-4; median OS 8 months; p = 0.15). However, median OS was 13 months in 13 group-3 arm B pts, 6 months in 6 group-4 arm B pts (p = 0.016); 9 months in 15 group 3 arm A pts and 11 months in 9 group 4 arm A pts (p = 0.67). These results suggest that polymorphisms of genes involved in expression of the main ligand for VEGFR2 (VEGFA 634G > C) and of efflux transporters (ABCB1 3435C > T) are promising candidates as predictive marker for selecting pts with MPA who may benefit of MS. Given the small sample size of these analyses, a larger confirmatory trial is necessary and appears worthwhile.