Bone metastases in biliary cancers: A multicenter retrospective survey.

•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.

Capecitabine with/without mitomycin C: results of a randomized phase II trial of second-line therapy in advanced biliary tract adenocarcinoma.

PURPOSE: 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. METHODS: Patients aged 18-75 years and with KPS >50, with pathological diagnosis of BTA stratified based on site and stage of disease, were randomized to receive capecitabine 2000 mg/m(2) day 1-14 alone (ARM A) or in combination with mitomycin C 6 mg/m(2) day 1 (ARM B) as second-line therapy. Cycles were repeated in both arms every 3 weeks. Tumor assessment was performed every 2 months. The primary endpoint was the probability of being progression free at 6 months (PFS-6) from treatment start. According to the Fleming design, the study aimed to enroll 26 pts per arm. An exploratory endpoint was to assess thymidylate synthase (TS) and thymidine phosphorylase (TP) expression, as biomarkers predictive for clinical outcomes of capecitabine treatment. RESULTS: Between October 2011 and 2013, 57 metastatic pts were enrolled: ARM A/B 28/29. Accordingly, 55 (26/29) pts were assessable for the primary endpoint: 2 (8%) ARM A and 3 (10%) ARM B pts were PFS-6. Main G3-4 toxicities were: hand-foot syndrome and transaminitis in 4/0%, and thrombocytopenia, diarrhea and fatigue in 0/3% of pts. No statistically significant correlation was found between TS or TP expression and pts' outcome. CONCLUSIONS: Since capecitabine yielded a disappointing outcome and the addition of mitomycin C did not improve the results, new therapeutic strategies need to be explored to improve survival in this disease setting.

Multivariate prognostic factors analysis for second-line chemotherapy in advanced biliary tract cancer.

BACKGROUND: 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. METHODS: Baseline clinical and laboratory data of 300 consecutive aBTC patients were collected and association with overall survival (OS) was investigated by multivariable Cox models. RESULTS: 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). CONCLUSIONS: 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.

A first principles based polarizable O(N) interatomic force field for bulk silica.

We present a reformulation of the Tangney-Scandolo interatomic force field for silica [J. Chem. Phys. 117, 8898 (2002)], which removes the requirement to perform an Ewald summation. We use a Yukawa factor to screen electrostatic interactions and a cutoff distance to limit the interatomic potential range to around 10 Å. A reparametrization of the potential is carried out, fitting to data from density functional theory calculations. These calculations were performed within the local density approximation since we find that this choice of functional leads to a better match to the experimental structural and elastic properties of quartz and amorphous silica than the generalized gradient approximation approach used to parametrize the original Tangney-Scandolo force field. The resulting O(N) scheme makes it possible to model hundreds of thousands of atoms with modest computational resources, without compromising the force field accuracy. The new potential is validated by calculating structural, elastic, vibrational, and thermodynamic properties of α-quartz and amorphous silica.

Outcome of upfront combination chemotherapy followed by chemoradiation for locally advanced pancreatic adenocarcinoma.

PURPOSE: The role and timing of chemotherapy and radiation for treating stage III pancreatic adenocarcinoma remains controversial. METHODS: Treatment-naive patients with stage III non-resectable pancreatic adenocarcinoma were treated with PEFG/PEXG (cisplatin, epirubicin, 5-fluorouracil (F)/capecitabine (X), gemcitabine) or PDXG (docetaxel substituting epirubicin) regimen for 6 months followed by radiotherapy (50-60 Gy) with concurrent F or X or G. RESULTS: Ninety-one patients were registered between April 1997 and December 2007. Forty-three patients (47%) had a partial remission and 38 (42%) had a stable disease. Thirteen patients (14%) were radically resected yielding one pathologic complete remission. Median survival (OS) was 16.2 months. Median progression-free survival was 9.9 months. Pattern of failure consisted of isolated local failure (N = 26, 35%); both local and systemic failure (N = 14, 19%); isolated systemic failure (N = 35, 47%). CONCLUSION: Combination chemotherapy with four-drug regimens followed by chemoradiation was a feasible strategy showing relevant results in stage III pancreatic adenocarcinoma.

Weekly docetaxel as salvage therapy in patients with gemcitabine-refractory metastatic pancreatic cancer.

Gemcitabine-based chemotherapy provides very limited disease control in the treatment of advanced pancreatic cancer. Approximately half of the patients failing upfront treatment present good performance status and are willing to undergo further treatment. Docetaxel activity against pancreatic cancer is reported both in the preclinical and clinical setting. Between November 2004 and November 2005, 10 patients (median age 59; median KPS 80) with metastatic pancreatic adenocarcinoma, progressive disease after gemcitabine-containing chemotherapy, KPS >50, adequate organ function, were treated with weekly docetaxel at 30 mg/m-(2) until progressive disease. Docetaxel dose intensity was 100% of the intended dose. No grade >2 toxicity was observed. No objective response to treatment was obtained. Median progression-free survival was 1.5 months (range 1-3.5 months); median survival was 4.0 months (range 2.0-7.5). Weekly administration of single-agent docetaxel does not seem to have any activity in the treatment of gemcitabine-resistant metastatic pancreatic cancer.

PEFG (cisplatin, epirubicin, 5-fluorouracil, gemcitabine) regimen as second-line therapy in patients with progressive or recurrent pancreatic cancer after gemcitabine-containing chemotherapy.

OBJECTIVE: The therapeutic arsenal for salvage therapy in pancreatic cancer is limited. PEFG (cisplatin, epirubicin, 5-fluorouracil [FU], gemcitabine) regimen is an effective upfront treatment in advanced pancreatic cancer. The activity and safety of this combination regimen were assessed by means of an observational study in a population of patients with progressive or recurrent pancreatic adenocarcinoma after gemcitabine-containing chemotherapy. METHODS: Patients with age <76 years, Karnofsky performance status >50 were treated with either classic PEFG (until April 2004: cisplatin and epirubicin 40 mg/m day 1, gemcitabine 600 mg/m day 1 and 8, FU 200 mg/m/d continuous infusion day 1-28) or dose-intense PEFG (since May 2004: cisplatin and epirubicin 30 mg/m, gemcitabine 800 mg/m every 14 days; FU 200 mg/m/d continuous infusion day 1-28) until progressive disease or a maximum of 6 cycles of 28 days. RESULTS: Forty-six patients (37 metastatic) received 69 cycles of classic PEFG (18 patients) or 104 cycles of dose-intense PEFG (28 patients) as second-line therapy. Prior treatment consisted of single agent gemcitabine (N = 17), gemcitabine-based chemotherapy (N = 4), or PEFG regimen (N = 25). Median previous progression-free survival was 7.6 months. Dose intensity (mg/m/wk) with classic PEFG was cisplatin and epirubicin 8.5; gemcitabine 230; FU 1035 and with dose-intense PEFG was cisplatin and epirubicin 11.5 (+36%); gemcitabine 259 (+13%); FU 1046 (+1%). Main grade >2 toxicity consisted of neutropenia in 26 patients (56%), thrombocytopenia in 10 (22%), anemia in 11 (24%), fatigue and stomatitis in 4 (9%), vomiting, diarrhea and hand-foot syndrome in 2 (4%). Partial response was observed in 11 patients (24%) (5 classic PEFG 28% + 6 dose-intense PEFG 21%). Median and 1-year survival was 8.3 months (8.0 vs. 9.0 months) and 26% (17% vs. 32%). Median and 6-months progression-free survival was 5.0 months (4.5 vs. 5.0 months) and 34% (33% vs. 38%). CONCLUSIONS: PEFG regimen in gemcitabine refractory pancreatic cancer had an acceptable toxicity profile and interesting activity, and may constitute a treatment option in this setting.

Thermal-hydrogen promoted selective desorption and enhanced mobility of adsorbed radicals in silicon film growth.

Car-Parrinello simulations and static density-functional theory calculations reveal how hydrogen promotes growth of epitaxial, ordered Si films in plasma-enhanced chemical vapor deposition at low-temperature conditions where the exposed Si(001)-(2x1) surface is fully hydrogenated. Thermal H atoms, indeed, are shown to selectively etch adsorbed silyl back to the gas phase or to form adsorbed species which can be easily incorporated into the crystal down to T approximately 200 degrees C and start diffusing around T approximately 300 degrees C. Our results are well consistent with earlier experiments.

A multi-centre retrospective review of second-line therapy in advanced pancreatic adenocarcinoma.

INTRODUCTION: Limited information on second-line treatment in patients with pancreatic adenocarcinoma is available. At time of first-line treatment failure, approximately half of the patients are candidates for further treatment. MATERIAL AND METHODS: A retrospective review of 183 patients submitted to second-line therapy has been performed to identify prognostic factors, provides useful information for patients counseling and generates hypotheses for future studies. Inclusion criteria were: cytological or histologic diagnosis of pancreatic adenocarcinoma and prior gemcitabine-including chemotherapy. Any age, performance status (PS) and chemotherapy regimen were considered. RESULTS: One hundred and eighty-three patients (106 males; 168 metastatic; median age 62 years; median PS 1; 63 submitted to prior curative surgery, 32 to prior radiotherapy) with a median previous progression-free survival (PFS) of 6.7 months were included. Median and 6-month PFS after initiation of salvage therapy were 3.0 months and 20%. Median, 1 and 2 years, overall survival after initiation of salvage therapy were 6.2 months, 17 and 4%, respectively. Previous PFS, CA19.9 levels and age independently predicted OS. CONCLUSION: Re-challenge with gemcitabine and 5-fluorouracil administration may have a role in selected patients.

Dose-intense PEFG (cisplatin, epirubicin, 5-fluorouracil, gemcitabine) in advanced pancreatic adenocarcinoma: a dose-finding study.

The aim of this study was to assess the maximum tolerated dose (MTD) of an intensified PEFG regimen administered every 14 days to patients with Stage III or metastatic pancreatic adenocarcinoma. Twenty-nine patients received fixed doses of both epirubicin (30 mg/m2) and 5-fluorouracil (200 mg/m2/day on Days 1-14) and of escalating doses of cisplatin and gemcitabine. The MTD was cisplatin 30 mg/m2 and gemcitabine 800 mg/m2. With respect to classical PEFG, intensified regimen potentially improved the dose-intensity of both cisplatin and epirubicin by 50 percent and of gemcitabine by 33 percent, reduced Grade 3-4 haematological toxicity and the number of outpatient accesses.

Venous thromboembolism predicts poor prognosis in irresectable pancreatic cancer patients.

BACKGROUND: The aim was to investigate the outcomes associated with venous thromboembolism (VTE) among irresectable pancreatic cancer patients. METHODS: This is a follow-up study of consecutive irresectable cancer patients, treated and followed up in clinical trials between December 2001 and December 2004 in order to evaluate the prognostic impact of symptomatic VTE on clinical outcomes, such as response to treatment, progression-free survival (PFS) and overall survival (OS). RESULTS: Among 227 irresectable pancreatic cancer patients, with Eastern Cooperative Oncology Group performance status (ECOG-PS) < or = 2, 59 (26.0%) patients developed a VTE. A synchronous VTE occurred in 28 (12.3%) patients, while a VTE during chemotherapy was observed in 15 (6.6%) patients, and 16 (7.0%) patients experienced both events. Presence of synchronous VTE was associated with a higher probability of not responding to treatment (odds ratio 2.98, 95% CI 1.42-6.27, P = 0.004), but showed no effect on both PFS and OS at least at multivariate analysis. Occurrence of a VTE during chemotherapy showed a statistically significant effect on PFS (hazard ratio [HR] 2.59, 95% CI 1.69-3.97, P < 0.0001) and OS (HR 1.64, 95%CI 1.04-2.58, P = 0.032). CONCLUSIONS: Our data suggest that the occurrence of VTE may be associated with a reduced response rate and a shorter PFS and OS among patients with irresectable pancreatic cancer. In these patients the development of VTE may reflect the presence of a biologically more aggressive cancer that in turn leads to a worse prognosis.

PEFG (cisplatin, epirubicin, 5-fluorouracil, gemcitabine) for patients with advanced pancreatic cancer: the ghost regimen.

The consensus report of the International Society of Gastrointestinal Oncology on the therapeutic management of advanced pancreatic cancer is commented. In the context of the available literature, a critical and methodological analysis supporting the role of cisplatin, epirubicin, 5- fluorouracil, gemcitabine (PEFG) regimen in the treatment of unresectable and metastatic pancreatic cancer is provided. In particular, the clinical relevance of the outcome observed in the phase III trial comparing PEFG regimen to standard gemcitabine is highlighted. Results of other recent trials comparing gemcitabine-erlotinib, gemcitabine-capecitabine and gemcitabine-oxaliplatin combinations to single agent gemcitabine are briefly commented from a clinical perspective.

Dose-intense PEFG (cisplatin, epirubicin, 5-fluorouracil, gemcitabine) in advanced pancreatic adenocarcinoma.

BACKGROUND: PEFG regimen (cisplatin and epirubicin 40 mg/m2 day 1, gemcitabine 600 mg/m2 days 1 and 8, 5-fluorouracil (FU) 200 mg/m2/day continuous infusion) significantly improved the outcome of patients with advanced pancreatic adenocarcinoma (PA) with respect to standard gemcitabine in a previous phase III trial. This regimen was subsequently modified in a dose-finding study by increasing dose intensity of cisplatin and epirubicin (both at 30 mg/m2 every 14 days) and of gemcitabine (at 800 mg/m2 every 14 days). Results of a consecutive series treated by dose-intense PEFG regimen are herewith reported. MATERIAL AND METHODS: Dose-intense PEFG was administered to chemotherapy-naive patients with stages III-IV PA, < 75 years, performance status (PS) > 50, till progressive disease or for a maximum of 6 months. RESULTS: Between January 2004 and June 2005, 49 (31 or 63% metastatic) patients, median age 62 years, median PS 80, were treated with dose-intense PEFG. Partial response and stable disease was observed in 24 (49%) and 16 (33%) patients, respectively; 31 patients were progression-free at 6 months (PFS-6 = 63%). Median survival was 10.5 months and 1-year overall survival (OS) was 48% (95% confidence interval: 33-61%). Main grade 3-4 toxicity was: neutropenia in 26% of patients, stomatitis and fatigue in 8%, anaemia, diarrhoea, nausea/vomit in 6%, febrile neutropenia and thrombocytopaenia in 4%, hand-foot syndrome in 2%. CONCLUSION: When compared with 84 patients treated by classical PEFG at the same institution, dose-intense PEFG was not inferior in terms of PFS-6 (63 versus 57%), 1-year OS (48 versus 42%) and response rate (49 versus 49%); it allowed to increase dose intensity for gemcitabine by 32%, for cisplatin and epirubicin by 36% (FU reduced by 3%), to significantly reduce grade 3-4 hematological toxicity (neutropenia: 26 versus 86%; P < 0.00001; thrombocytopaenia: 4 versus 58%; P < 0.00001) and to reduce by one-third the number of outpatient accesses. The new PEFG schedule appears more suitable for clinical use and should be preferred as a basis for further development of therapeutic strategies against pancreatic cancer.