bluuebunny/crossref_metadata_2025 huggingface dataset:
Serum adiponectin and overall survival in a prospective cohort of patients with hepatocellular carcinoma.
Authors: Siegel Abby B. , Goyal Abhishek , Hidalgo Rosa Denisse , Wang Shuang , Neugut Alfred I. , Brown Robert S , Emond Jean , Kato Tomoaki , Samstein Benjamin , Dove Lorna , Santella Regina
Published: February 2017

205

Background: Hepatocellular carcinoma (HCC) is one of the most rapidly increasing causes of cancer death in the United States. Adiponectin, a regulator of glucose metabolism, is reduced in those with diabetes and obesity. Serum adiponectin levels have been shown to correlate with prognosis in several types of cancers, but have not been well studied in patients with HCC.

Methods: We have an ongoing prospective study evaluating fasting adipokines and clinicopathological features in patients with newly-diagnosed HCC. We excluded patients who had any previous malignancy, and those with uncompensated Child Pugh (CP) B or C disease. We evaluated common non-pathological prognostic variables in uni- and multivariable models as predictors of all-cause mortality.

Results: Of our first 82 patients, median age was 60, 82% were men and 63% had underlying hepatitis C. 65% had a Body Mass Index (BMI)>25, and 33% had diabetes. We found that CP class, AJCC stage, adiponectin and IGF-1 levels were all significantly associated with survival, while age, AFP, etiology of liver disease, leptin and insulin levels were not in univariable analyses. We then created a Cox model which included age, CP class, AJCC stage, AFP>400 ng/mL, serum adiponectin, and IGF-1, and found that stage, adiponectin, and IGF-1 levels were all independently predictive of overall survival. Increased AJCC stage had the highest HR for death (3.9), while increased adiponectin levels (>12,000 ng/mL) led to a 3-fold increased risk of death. IGF-1 was protective, with higher levels (>40 ng/mL) leading to about a 3-fold decreased risk of death.

Conclusions: Novel predictive and prognostic biomarkers in patients with HCC are badly needed. We found serum adiponectin to be a robust predictor of all-cause mortality in a diverse prospective cohort of HCC patients in uni-and multivariable analyses. Adiponectin deserves further study as a simple and practical biomarker to assess outcomes in patients with HCC.
Platinum-based chemotherapy (Pt-chemo) in pancreatic adenocarcinoma (PC) associated with BRCA mutations: A translational case series.
Authors: Tran Ben , Moore Sara , Zogopoulos George , Borgida Ayelet , Holter Spring , Gallinger Steven , Moore Malcolm J.
Published: February 2017

217

Background: Prognosis of PC is poor and responses to chemotherapy are minimal and short lived. In prior randomized studies, cisplatin and gemcitabine provided no additional benefits over gemcitabine alone. Preclinical data and case reports suggest BRCA cancers have increased sensitivity to Pt-chemo. Our case series characterizes the benefits of Pt-chemo in germline BRCA mutated PC.

Methods: Patients with PC and deleterious germline BRCA mutations treated with Pt-chemo were identified using the Ontario Pancreatic Cancer Study and pharmacy databases. Review of clinical records provided demographic, treatment and survival data. Radiology review assessed responses to Pt-chemo. RNA was extracted from tumor samples for gene expression studies using a panel of DNA repair genes and Nanostring technology. BRCA loss of heterozygosity (LOH) was also investigated.

Results: We identified 5 PC patients with BRCA mutations (4 BRCA2, 1 BRCA1) who were treated with Pt-chemo: 1 had resectable disease, 1 locally advanced (LA) and 3 metastatic. The resectable patient (T1N0) had 3 cycles of neoadjuvant Pt-chemo, achieving a partial response (PR) and normalization of CA19-9; curative resection and adjuvant Pt-chemo (3 cycles) followed and the patient remains disease free after almost 3 years. The LA patient (T4N0) had 2 cycles of Pt-chemo, achieving a PR and becoming resectable; curative resection and adjuvant Pt-chemo (4 cycles) followed and the patient remains disease free for over 3 years. One metastatic patient remains on Pt-chemo (5 cycles) having achieved a PR and normalization of CA19-9. The other 2 metastatic patients completed 6 and 22 cycles of Pt-chemo, achieving best response of PR and complete response respectively, with progression free survival of 12 and 45 months. Gene expression and LOH results will be presented.

Conclusions: Survival and responses to Pt-chemo observed in our case series of BRCA mutant PC adds to existing data supporting the use of Pt-chemo in this subgroup. Although the incidence of BRCA mutations in PC is small, potential survival benefits gained from personalizing treatment using Pt-chemo supports BRCA testing in selected patients.
Disease control rate at 8 weeks as a predictive marker for long-term clinical outcomes in patients with advanced gastric cancer.
Authors: Yi Junho , Kim Gun Min , Kim Hyo Song , Rha Sun Young , Chung Hyun Cheol
Published: February 2017

22

Background: Survival is the ultimate end-point in field of medical oncology. Although tumor response has been used as surrogate end-point in early phase clinical trial in patients with gastric cancer, clear correlation between tumor response and long-term survival has not been established yet. The objective of the current study is to determine whether early assessment could predict survival in patients with AGC.

Methods: A total of 337 patients with AGC who had participated one of the three first-line, prospective, investigator-initiated, randomized trials carried out in Yonsei Cancer Center were included in the analysis. 238 had received fluoropyrimidine (F) + platinum (P), 61 had received F + taxane (T), 38 had received T + P. Response was assessed according to RECIST 1.1 at 8, 14 and 20 weeks after initiation of treatment. The correlation between response at each time point and the OS was evaluated using logistic regression test.

Results: The median OS was 13.7 months. (95% CI 11.8 – 15.6) In terms of confirmed tumor response, 1 CR, 84 PRs, 104 SDs and 148 PDs were observed. At every landmark period, disease control rate (DCR, CR + PR + SD) was superior in predicting OS comparing with response rate. (RR, CR + PR) (Table). Among them, 8-week DCR was the most powerful predictor for OS. (HR 0.18, p< .001) There was no significant OS difference between patients with (13.7 months) vs. without (13.9 months) measurable lesions (p = .705) and between patients with 8-week response of PR (18.1 months) vs. SD (15.3 months) (p = .522).

Conclusions: Disease control was a better predictor for OS in patients with AGC who had received first-line chemotherapy than response, with disease control at 8 week being the most powerful predictor. This could be used as a surrogate marker for long-term survival in early phase clinical trials.

[Table: see text]
A phase I study of MEK inhibitor MEK162 (ARRY-438162) in patients with biliary tract cancer.
Authors: Finn Richard S. , Javle Milind M. , Tan Benjamin R. , Weekes Colin D. , Bendell Johanna C. , Patnaik Amita , Khan Gazala Naaz , Laheru Dan , Anderson Lisa , Christy-Bittel Janna Lynn , Barrett Emma , Guthrie Kari , Litwiler Kevin S. , Bekaii-Saab Tanios S.
Published: February 2017

220

Background: The RAS/RAF/MEK/ERK pathway plays a major role in cell growth and survival and is aberrantly activated in many cancers. MEK162 (ARRY-438162) is a potent, selective, ATP-uncompetitive inhibitor of MEK1/2. The objectives of this Phase 1 expansion study were to characterize the safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary efficacy of MEK162 in patients (pts) with biliary tract cancer (BTC).

Methods: Pts with unresectable, locally advanced or metastatic BTC who had received ≤ 1 prior systemic therapy received oral MEK162 at 60 mg twice daily (BID). Mutation status of RAS, BRAF and other relevant genes were assessed from tumor samples. Tumor response was assessed every 6 weeks.

Results: Twenty-eight pts, median age 64 years (range 30-86) with gallbladder (7), intrahepatic (14) or extrahepatic (7) cholangiocarcinoma (CC) were enrolled. All pts were ECOG 0-1 and 43% received previous first-line therapy (primarily gemcitabine combinations). Of the 23 tumors assessed, 17 were wild type (WT) on all loci tested and 6 had mutations (1 MET, 1 PIK3CA, 2 KRAS, 2 PTEN null). The most common treatment-related AEs were rash, nausea, vomiting, diarrhea, peripheral edema, fatigue and central serous-like retinopathy, and most were Grade (G) 1 or 2. G3/4 treatment-related AEs were anasarca, hypokalemia, hyponatremia, upper/lower gastrointestinal hemorrhage and mucositis (1 each). Thirteen pts were dose reduced for AEs, of which, G1/2 central serous-like retinopathy was the most frequently reported event (6). Three pts were discontinued for treatment-related AEs (G2 central serous-like retinopathy, G1 nausea, G4 anasarca). Of the 26 pts evaluable for response, 1 CR, 1 PR and 11 SD (≥ 6 weeks) were observed. Of note, both responders were WT on all loci tested and had extrahepatic CC. The PK in this population was equivalent to that observed in prior studies. A consistent mean reduction (40-60%) of circulating TNFα was observed.

Conclusions: MEK162 has an acceptable safety profile and desirable PK properties at 60 mg BID and RECIST responses were observed in pts with BTC. Additional expansion cohorts are ongoing in pts with KRAS- or BRAF-mutant metastatic colorectal cancer.
An experimental model of FOLFOX-induced sinusoidal obstruction syndrome.
Authors: Robinson Stuart M. , Mann Jelena , Manas Derek M , Burt Alastair D , Mann Derek A , White Steve A
Published: February 2017

222

Background: Sinusoidal obstruction syndrome (SOS) following oxaliplatin based chemotherapy is a cause for major concern when undertaking liver resection for colorectal liver metastases. To date no relevant experimental models of oxaliplatin induced SOS have been described limiting our ability to understand the pathogenesis of this condition.

Methods: C57Bl/6 mice were treated with intra-peritoneal FOLFOX (n=10), or vehicle (n=10), weekly for five weeks and culled one week following final treatment. Organs were harvested for subsequent histological and biochemical analysis.

Results: Mice treated with FOLFOX developed peri-venular sinusoidal dilatation and hepatocyte atrophy in keeping with features of SOS seen in patients treated with this regimen. In addition we noted up-regulation of genes within the liver associated with matrix remodelling such as MMP2 (p<0.001), pro-collagen I (p<0.001) and TGFβ (p<0.001). We also demonstrated up-regulation of pro-thrombotic genes PAI-1 (p<0.001) and vWF (p<0.001) and genes involved in angiogenesis e.g. VEGFA (p<0.01).

Conclusions: We have provided the first direct evidence that FOLFOX directly results in the development of SOS in an experimental model. This system will enable us to gain a detailed understanding of the pathogenesis of this condition and provide a means to explore various strategies to prevent its development making major liver resection much safer after down-staging chemotherapy.
Effect of 2G8, a TGF-beta-R2 inhibitor, on TGF-beta signaling and migration in an immunocompetent pancreatic cancer model.
Authors: Ostapoff Katherine , Cenik Bercin , Schwarz Roderich , Brekken Rolf A.
Published: February 2017

230

Background: TGF-beta functions as a tumor suppressor early in the development of pancreatic ductal adenocarcinoma (PDAC) but during tumor progression after undefined molecular changes TGF-beta switches to a promoter of metastasis, tumor angiogenesis and epithelial to mesenchymal transition (EMT.) A potential strategy is to target TGF-beta-R2, one of the major signaling receptors for TGF-beta. 2G8 is a anti-rat monoclonal antibody that binds specifically to and blocks murine TGF-beta-R2.

Methods: Protein expression was analyzed using Western Blot. Cell proliferation was analyzed using Cell Titer Blue Assay and migration was determined using transwell migration assay. EMT protein expression was determined by ICC. PanO2-HY cells were used to establish an orthotopic and splenic metastasis model. In an orthotopic model, mice received saline, gemcitabine (Gem), 2G8 or 2G8 + Gem. For splenic metastasis model,mice received 2G8 on post injection day −1, +1 or +7 days or control IgG.

Results: At baseline, PanO2-HY cells express TGF-beta-R2, alk5 and alk1 and express high levels of zeb1 and beta-catenin. 2G8 inhibits phosphorylation of smad2, ERK1/2 and p38 but not smad1/5 in vitro. 2G8 did not inhibit cell proliferation but did inhibit cell migration in vitro. After 7 days of treatment with 2G8, PanO2-HY cells had reduction in nuclear zeb1 staining by ICC. In the orthotopic model, 2G8 significantly inhibited metastasis to liver, peritoneum and gastrointestinal tract(p=0.02). In splenic metastasis assay, 2G8 treated mice livers weighed significantly less than control treated mice (p=0.0005). In the group of mice treated prior to tumor cell injection, none of them developed a primary tumor.

Conclusions: Inhibition of TGF-beta-R2 with 2G8, results in inhibition of smad2 dependent pathways as well as non-canonical TGF-beta signaling in vitro. By inhibiting tumor cell migration in vitro and reducing EMT transcription factors, 2G8 may result in delayed tumor progression. In vivo data in both orthotopic and metastatic models suggest that inhibition of TGF-beta signaling via TGF-beta-R2 inhibits tumor cell metastasis. Further analysis are being conducted to understand changes within primary tumor and metastasis within this model.
Validating the woodchuck model for studying antiangiogenic therapies for human hepatocellular carcinoma (HCC).
Authors: Reddy Kaunteya , Ashton Edward , Buitrago Sandra , Hutson Alan , Tennant Bud Christopher , Iyer Renuka V.
Published: February 2017

239

Background: Anti-angiogenic agents have become the backbone of advanced HCC treatment and provide clinical benefit despite infrequent radiographic response. Animal models that mimic human HCC and treatment response are greatly needed. The laboratory woodchuck (Maramota monax) is a unique animal model that replicates the complex human liver milieu of HCC in the context of chronic hepatitis B viral infection and was selected for this translational study.

Methods: Humans: Patients with inoperable HCC were consented and prospectively treated with sunitinib 37.5mg PO qd for one week prior to liver directed therapy(chemoembolization). Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) was done pre-sunitinib and after one week as part of the trial. Woodchucks: Laboratory bred eastern woodchucks were inoculated at birth with known titers of sera from a chronic infectious pool of chronic woodchuck hepatitis virus (WHV), confirmed by ultrasound exam at 12-18 months to have developed HCC. Methods for assessment of woodchuck HCC blood flow using DCE-MRI were optimized. Woodchucks received sunitinib 12mg/kg/day poQD and identical image acquisition and analysis techniques were used for both species and identical parameter sets were obtained for cross comparison done by Dr. Ashton in a blinded fashion.

Results: A total of seven patients and eight woodchucks with HCC were included (2 scans per patient/woodchuck, pre and post sunitinib). The “Exact Wilcoxon rank-sum test” was used for statistical analysis. Comparison between median Ktrans, AUCBN(90), necrotic and total volumes of the tumors in both groups revealed all parameters to be similar and only total tumor volume reached statistical significance (P=0.002).

Conclusions: Our data indicate similarities between human and woodchucks in the tumor histology, blood flow and baseline and post antiangiogenic therapy functional imaging assessment by DCE-MRI. The current sample size of n=7+8 can detect large differences of roughly 1.5 standard deviation units between humans and woodchucks for our measures at alpha=0.05 and power=0.80. Further studies that explore the translational potential of this unique animal model are warranted.
Development of a tissue-equivalent human liver phantom for 90Y-microsphere dosimetry studies and testing of other local ablation therapies.
Authors: Kennedy Andrew S. , McNeillie Patrick , Dezarn William
Published: February 2017

244

Background: 90Y-microsphere brachytherapy for unresectable hepatic cancers is an increasingly popular therapy. The beta radiation dosimetry involved is not well understood and there is lack of pre and post treatment planning capabilities.

Methods: A phantom was developed with tissue equivalent electron density, accurate anthropomorphic size, shape and volume to an adult human liver, with similar properties in response to heat, cold, radiation and diagnostic imaging as human liver tissue. Space-occupying masses were created to accommodate implantation of microspheres to simulate a human treatment. Imaging included MRI, CT and SPECT gamma scans pre and post implantation of 90Y-microspheres.

Results: A phantom was produced that was shaped from a mold of an adult human liver. A mass with a different density than the liver was created in the right lobe that had a 3mm – 6mm rim for microsphere implantation. A known quantity of 99mTc was implanted into the left lobe. 90Y-microspheres of known activity were implanted in the periphery of the right lobe tumor. CT contrast was mixed with the microspheres to improve localization on subsequent CT scans. The electron density of the phantom was identical to human liver. Microsphere implantation was limited to the outer 6 mm of the right lobe tumor and 99mTc limited to the left lobe. Spatial resolution in 3D was excellent on all three modalities (MRI, CT and SPECT gamma).

Conclusions: A human liver phantom as described will be a useful tool in future studies of beta radiation dosimetry, cross sectional and nuclear imaging and tissue responses. The next generation phantom is being developed with blood vessel-like branching channels to allow fluids to pass into and through the phantom similar in scale and diameter to hepatic vessels and tumors.
Selective reoperation for locally recurrent or metastatic pancreatic ductal adenocarcinoma following primary pancreatic resection.
Authors: Thomas Ryan Michael , Truty Mark Joseph , Fleming Jason B. , Pisters Peter W. T. , Lee Jeffrey Edwin , Rice David C. , Hofstetter Wayne Lewis , Wolff Robert A. , Varadhachary Gauri R. , Wang Huamin , Katz Matthew H.G.
Published: February 2017

252

Background: Resection of recurrent disease in malignancies such as colorectal cancer has been shown to prolong survival but resection for recurrent pancreatic ductal adenocarcinoma (PDAC) is viewed as futile. We sought to identify factors that may be associated with prolonged survival following resection of recurrent PDAC.

Methods: A retrospective review of a prospectively-maintained pancreatic tumor database was performed to identify all patients from 1992-2010 who developed recurrent PDAC after intended surgical cure. The group was screened for those who underwent a second operative procedure with curative intent. Clinicopathologic features were correlated with disease-free interval (DFI) and survival to identify factors that may be associated with prolonged survival in patients undergoing reoperation for PDAC.

Results: Of 700 patients who underwent resection for PDAC, 426 (61%) recurred after a median of 8mo and 21 (5%) of those had a locoregional [pancreas (n=5), other (n=2)] or distant [lung (n=7), liver (n=6), brain (n=1)] recurrence that were selected for a second, potentially curative operation. Sixteen of 21 patients received chemotherapy prior to reoperation. Those selected had a single, technically resectable lesion, good performance status, and prolonged median DFI compared to patients not selected (22mo v. 8mo, p<0.01). The median DFI from initial resection to recurrence for those with lung (52mo) or locoregional (41mo) recurrence was longer than those with liver recurrence (10.5mo, p=0.03). The interval between reoperation and second recurrence in patients with lung metastasis (NR) was longer than for liver (6mo) or locoregional recurrence (7.5mo, p=0.02). Patients still alive include 4/7 of lung, 3/7 of locoregional, and 1/6 of liver recurrences with a median follow-up after reoperation of 30mo, 14mo, and 18.5mo, respectively.

Conclusions: Patients who develop a solitary recurrence of PDAC in the lung after a long disease-free interval should be considered for reoperation. Those with recurrence in other sites are likely to re-recur relatively quickly after reoperation regardless of disease-free interval.
Phase I trial of radiotherapy with concurrent bevacizumab, erlotinib, and capecitabine for locally advanced pancreatic cancer (LAPC).
Authors: Skinner Heath Devin , Javle Milind M. , Wolff Robert A. , Clemons Marilyn V. , Munsell Mark F. , Delclos Marc E. , Fleming Jason B , Das Prajnan , Crane Christopher H. , Krishnan Sunil
Published: February 2017

254

Background: The addition of bevacizumab to capecitabine-based chemoradiotherapy (CRT) for LAPC has been shown to be safe. The aim of this study was to determine the safety, tolerability and maximum tolerated dose (MTD) of the addition of erlotinib to this treatment regimen.

Methods: Seventeen patients with CT-staged biopsy-proven non-metastatic unresectable LAPC were enrolled between March 2008 and October 2010. Prior chemotherapy was permitted. All patients received 50.4 Gy (GTV only) in 28 fractions with concurrent capecitabine, bevacizumab and erlotinib. Dose was escalated using a continual reassessment method. Two patients each were enrolled at dose levels (DLs) 1-4 and 9 patients at DL 5. Bevacizumab was escalated from 5mg/Kg every two weeks (DLs 1-4) to 10mg/Kg (DL 5); erlotinib from 100 mg/day (DLs 1-2) to 150 mg/day (DLs 3-5); and capecitabine from 400mg/m2 twice daily on days of radiation (DL 1) to 600mg/m2 (DLs 2-3) to 825 mg/m2 (DLs 4-5). Reassessment for potential resection was performed 6-8 weeks later.

Results: With a median follow-up of 10 months (range 3-23), no grade 3 toxicities were observed in DLs 1-4. Three (33%) patients at DL 5 developed a grade 3 acute toxicity (2 diarrheas and 1 rash). No grade 4 or 5 toxicities were seen. DL 4, with a posterior probability of 0.122 of dose limiting toxicity, was selected as the MTD. Median survival was 19.4 months and time to distant progression was 9.8 months. Patients treated at DLs 4 and 5 had a median survival of 24 months. Of 5 patients who underwent margin-negative resections, 4 were originally deemed unresectable and 1 was borderline; 4 were treated at DLs 4 or 5 (36% of patients treated at these DLs); 3 patients had excellent pathological responses (complete response, 5% viable tumor, and 20% viable tumor) at pancreatectomy and are alive at 13, 21 and 22 months respectively with no local or distant failures.

Conclusions: The combination of erlotinib, bevacizumab and capecitabine with radiotherapy for LAPC is safe and tolerable. Both the promising survival and the high rate of resectability at the higher dose levels suggest that this strategy of dual inhibition of growth factor receptor pathways during CRT warrants continued evaluation.
Efficacy of belinostat in advanced hepatocellular carcinoma (HCC): Phase I and II multicentered study of the Mayo Phase 2 Consortium (P2C) and the Cancer Therapeutics Research Group (CTRG).
Authors: Chan Stephen Lam , Chung Hyun Cheol , Wang Ling-Zhi , Lim Robert S. C. , Picus Joel , Boyer Michael J. , Erlichman Charles , Chan Anthony T. C. , Goh Boon C. , Yeo Winnie
Published: February 2017

259

Background: Belinostat is a novel histone deactylase inhibitor which demonstrates preclinical activity in HCC. We report the results of a phase I/II study on belinostat in patients (pts) with unresectable HCC.

Methods: Major eligibility criteria included histologically confirmed HCC not amenable to curative treatment; PS ≤ 2; adequate organ function; prior systemic therapy was allowed. In the phase I portion, belinostat was given i.v. on D1-5 every 3 weeks with dose levels of 600, 900, 1200 and 1400 mg/m2/day. In the phase II portion, belinostat was tested at the MTD. Primary endpoint was PFS and secondary endpoints were RR according to RECIST and OS. CT assessment was done every 8 weeks.

Results: Phase I portion: a total of 18 pts were accrued; no DLTs were observed at 1400mg/m2/day for 5 days, and this dose was selected for phase II development. Phase II portion: 42 pts were accrued; Median age = 57.5 years; 41 had Child’s A function, and 24 pt had ECOG 0. Sixteen (38%) had previous systemic therapy, and 21 (50%) had previous transarterial therapy. Median follow-up was 20.0 months. The PR and SD rate was 2.4% (1/42) and 45.2% (19/42). Median PFS was 2.64 months (95%C.I. 1.55-3.17) and OS was 6.60 months (95%C.I. 4.53-11.60). Grade 3 or higher toxicities (>5% rate) were abdominal pain (9.5%), (9.5%) hyperbilirubinemia (9.5%), raised ALT (9.5%); anemia (7.1%) and vomiting (7.1%).

Conclusions: Belinostat demonstrates disease stabilization in a predominantly pretreated population of pts with unresectable HCC with an acceptable safety profile. Further randomized studies are warranted.Supported in part by N01-CM-62205.
Cholangiocarcinoma: A joint cancer database analysis.
Authors: Deutsch Yehuda Ethan , Sleeman Danny , Ribeiro Afonso , Franceschi Dido , Hosein Peter Joel , Akunyili Ikechukwu Immanuel , Macintyre Jessica , Soares Heloisa P. , Herna Stuart , Lally Brian E. , Levi Joe U , Rocha Lima Caio Max S.
Published: February 2017

268

Background: Cholangiocarcinoma is an uncommon malignancy. In addition, only 10-30% of patients are eligible for curative surgical resection due to advanced disease at diagnosis. The role of adjuvant therapy is not yet established. The objective of this analysis is to assess the outcome of patients with cholangiocarcinoma managed with surgery, chemotherapy, radiation, and/or chemo-radiation.

Methods: From 1997 to 2007, patients with biliary cancer from the joint tumor registry database at UMH, SCCC, and JHS had their demographics, stage, pathology, treatment (surgical management, adjuvant and palliative therapy) and survival collected. A total of 800 patients with the diagnoses of biliary cancer were reviewed. The site of cancer was the bile duct in 351 patients, gallbladder in 173, and ampulla of vater in 239 patients.

Results: Cholangiocarcinoma - adenocarcinoma of the bile duct – in 334 patients of the 351 with bile duct tumors were analyzed. The mean age at diagnosis was 65 (range 26-92) and 55% of patients were male. Stage at presentation was as follows: 22% of patients presented with stage I, 18% with stage II, 21% with stage III, 26% with stage IV, and 13% were unknown. Potentially curative surgical resection was performed in 45% of the patients. 24% received chemotherapy, 20% received radiation, and 14% received chemo-radiation in combination. The overall median survival (MS) of all patients was 13 months - 22, 16, 14, and 10 months for stages I, II, III, and IV respectively. Surgery provided an overall survival benefit for all stages (24 vs. 9 months, p<.001), including stage III (n=31/71; 20 vs. 10 months, p=.026) and stage IV (n=28/88; 23 vs. 6 months, p<.001). Chemotherapy offered a trend to survival benefit for patients with stage IV (13 vs. 6 months, p=.06) and combined stages III and IV (13 vs. 10 months, p=.07). Combination chemo-radiation had a significant survival benefit in stage IV (19 vs. 6 months, p=.022) and in combined stages III and IV (14 vs. 10 months, p=.026).

Conclusions: Chemotherapy and chemo-radiation had a positive impact on survival in patients with late stage cholangiocarcinoma. Surgery improved survival in both early and advanced stages. The lack of data on performance status and organ function did not allow factoring these variables in the analysis.
Efficacy of infusional 5-fluorouracil, doxorubicin, and mitomycin-C (iFAM) chemotherapy and analysis of prognostic factors in previously treated advanced hepatocellular carcinoma.
Authors: Lim Kyu-Hyoung , Han Sae-Won , Oh Do-Youn , Im Seock-Ah , Kim Tae-You , Bang Yung-Jue
Published: February 2017

269

Background: In advanced HCC, the role of salvage chemotherapy after failure of prior chemotherapy including sorafenib has not been fully studied. The aims of this study were to evaluate the efficacy of infusional 5-fluorouracil (5-FU), doxorubicin, and mitomycin-C (iFAM) as salvage regimen in advanced HCC and to identify the prognostic factors in a salvage setting.

Methods: Eligibility included the following: 1) age > 18 years; 2) Diagnosed as HCC; 3) previously treated with palliative chemotherapy; 4) ECOG PS 0-2; 5) Child-Pough Class A or B; and 6) adequate BM and renal function. iFAM consisted of 5-FU 800 mg/m2 over 10 hours on days 1-5, doxorubicin 30 mg/m2 on day 1 and mitomycin-C 8 mg/m2 on day 1, every 4 weeks. Response evaluation was done every 8 weeks with RECIST criteria.

Results: A total of thirty-five patients were enrolled. The median age was 50.2 years (range: 23.3-74.7). ECOG PS was; PS 0-1 (80%) and PS 2 (20%). The etiology of HCC was; HBV (82.8%), HCV (2.9%) and others (14.3%). Liver function was; Child Pough A (91.4%) and B (8.6%). Nine patients had macrovascular invasion and all had extrahepatic metastatic lesion. Prior chemotherapies were sorafenib or 5-FU based regimens. A total of 94 cycles of iFAM were delivered (median 2: range 1-7). There were 2 PR and 6 SD, resulting in RR 5.7% (95% CI, 1.6-18.6%) and DCR 22.9% (95% CI, 12.1-39%). The PFS and OS were 2.4 months and 8.6 months, respectively. The 6- and 12-month survival rates were 67.7% and 35.3%, respectively. Grade 3/4 hematologic toxicity was neutropenia (14.3%). Frequent non-hematological toxicities were; anorexia (45.7%), alopecia (40%), stomatitis (20%), all of which were grade 1/2. In multivariate analysis, PS and serum α-FP were significantly associated with OS. Patients were classified into 3 risk groups based on the number of prognostic factors (0 vs. 1 vs. 2). This classification was well-correlated to OS (16.1 months vs. 10.5 months vs. 3.8 months, respectively; p < 0.0001).

Conclusions: iFAM is an effective and tolerable treatment option in advanced HCC and could be considered as salvage regimen. PS and α-FP are significant prognostic factors in a salvage setting.
Evaluation of venous thromboembolism (VTE) risk among ambulatory patients with pancreatic cancer in a real-world setting.
Authors: Lin Jay , Dalal Mehul R. , Connolly Gregory Clayton , Khorana Alok A.
Published: February 2017

273

Background: Patients with cancer are at high risk for VTE, and risk varies by cancer type, patient demographics/history, chemotherapy regimen, and hospitalization status. This retrospective cohort analysis examined the incidence of and risk factors for VTE in a cohort of ambulatory cancer patients with primary pancreatic tumors who were starting chemotherapy.

Methods: Data were extracted from the IMS Patient-Centric Database, a large administrative database of real-world US healthcare claims. Demographics/clinical characteristics of cancer patients with pancreatic and other solid tumors and a matched control cohort of patients without cancer were evaluated. The incidence of deep vein thrombosis (DVT), pulmonary embolism (PE), and DVT+PE was recorded during a follow-up period of 3-12 months after chemotherapy initiation in the group with pancreatic cancer.

Results: Women composed 47% (632/1,336) of the pancreatic cancer and 51% (8,831/17,284) of the control cohort; mean age was 63 years in the pancreatic cancer cohort and 64 years in the control cohort. Mean Charlson Comorbidity Index scores were 6.8 and 0.6 respectively. VTE occurred in 19.2% of the pancreatic cancer cohort (odds ratio [OR], 5.39; 95% confidence interval [CI], 4.26, 6.80) compared with 1.4% in the control cohort (P<0.0001). The incidence of DVT, PE, and DVT+PE was 12.6%, 2.3%, and 4.4%, respectively, in the group with pancreatic cancer vs 1.0%, 0.2%, and 0.2% in the control cohort (P<0.0001 for all comparisons). The use of erythropoiesis-stimulating agents (ESAs) was associated with an increased incidence of VTE (OR, 1.71; 95% CI, 1.27, 2.31; P=0.0004 vs no ESA). Bleeding occurred in 23.4% of the pancreatic cancer cohort and 7.0% of the control cohort (P<0.0001).

Conclusions: In a real-world setting, nearly 20% of this cohort of ambulatory cancer patients receiving chemotherapy experienced VTE. The presence of primary pancreatic cancer was associated with a 5-fold increase in VTE risk compared with controls. Use of ESA was associated with significant incremental risk of VTE.
Advanced hepatocellular carcinoma (HCC) treated with sunitinib (Su) and transarterial chemoembolization (TACE): Phase II trial final report.
Authors: Iyer Renuka V. , Tomaszewski Garin , Wu Yuhsin V , Kuvshinoff Boris W. , Groman Adrienne E. , Khushalani Nikhil I. , Grande Catherine , Zagst Patricia D. , Clark Kimberly , Fetterly Gerald J.
Published: February 2017

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Background: TACE and anti-angiogenic agents have individually been effective in inoperable HCC. In this prospective phase 2 study, the effects and PFS of Su+TACE was evaluated.

Methods: Eligibility: ECOG PS 0, 1, inoperable HCC, Child Pugh (CP) A/B, platelets >100K, bilirubin < 2 and no contraindications to TACE. Treatment: Cycle (C) 1 -Su 37.5mg po days (d)1-7; - TACE with doxorubicin in lipodiol on d8;- Su 37.5mg po qd d15-36; - 2 wks off C2 onwards - Su 4 wks on (dose escalation to 50mg in pts without grade 3 toxicities);- 2 wks off DCE-MRI, sVEGFr, monocytes, and Su PK were assessed at d0, 8, 10, and 36.

Results: Characteristics of the 16 pts were: median age 74 yr (range 40-86), all with CP A cirrhosis (etiology: hepB: 2, hepC: 6, ETOH: 1, unknown: 7), and PS 0: 12, PS 1: 4. 10 pts had liver only and 6 pts had extrahepatic disease. Median PFS was 8 mo (95% CI 4.3-9.3) and OS was 14.9 mo (95% CI 6.3-27.1) with a median follow up of 12.8 mo (5 pts still alive) receiving a median of 3 cycles (range 1-7). Responses by RECIST criteria were PR: 2, SD: 11 and PD: 3 for total clinical benefit of 81%. DCE-MRIs pts (8) showed median Ktrans change of -20% after d7 of Su and a further 7% after TACE+Su. There was concurrent decrease in viable tumor, 3% (d8) and 15% (d36) respectively. Steady-state Su concentration ranged from 20-150 ng/ml, which is above the IC50 values of 4-30 ng/ml for VEGF inhibition. PK/PD modeling estimated a Su IC50 values of 15 and 10 ng/ml to modulate Ktrans and AUC90. sVEGFR2 levels change with Ktrans and AUC90. Median monocyte counts of 0.4x109/L decreased by 50% on d36 after TACE. 11 pts (69%) had grade 3/4 toxicities attributable to Su. Of a total of 57 events, the most frequent (n>5) were thrombocytopenia (10), amylase/lipase increase (9), lymphopenia (7), and fatigue (6). Dose delays and dose reductions occurred in 13 and 3 pts respectively. Reasons for discontinuing therapy were toxicity (7), progression of disease (7), and withdrawal of consent (2).

Conclusions: Improvement in PFS and OS was seen with acceptable toxicity in the first study of Su + TACE in HCC. In addition, it shows a relationship between Su concentration and Ktrans, AUC90, sVEGFR2 and monocytes; with additional decrease seen after TACE.
Efficacy of transcatheter arterial chemoembolization (TACE) in combination with sorafenib for the treatment of unresectable hepatocellular carcinoma in Chinese patients.
Authors: Qu Xudong , Wang Jianhua , Yan Zhiping
Published: February 2017

279

Background: The purpose of this prospective trial is to evaluate the efficacy and safety of the concurrent use of TACE and sorafenib in a group of patients with unresectable HCC.The treatment outcomes of this group of patients were also compared in a retrospective fashion with a group of HCC patients with similar characteristics of patient and disease in a case controlled setting.

Methods: A total of 45 patients (BCLC stage B/C: 16/29) with unresectable HCC were enrolled between June 2008 and Feb 2011 as experimental group and were treated with combination of sorafenib and TACE according to an institutional protocol. To evaluate the efficacy of the combination therapy, a group of 45 HCC patients (n=45, BCLC stage B/C: 17/28) with comparable baseline characteristics who had been treated with TACE alone in our institute were retrospectively selected as control group to compare the treatment outcomes. Median overall survival was compared between the two groups. Adverse events related to sorafenib were assessed according to CTCAE3.0 to observe safety endpoints. The study was approved by the Institutional Ethics Committee at Zhongshan Hospital, Fudan University, China.

Results: The median follow-up time for the entire group of patients was 21 months (12.66 - 29.33). The median survival time for the TACE/sorafenib group was 27 months (21.89 - 32.10), and that for TACE alone group was 17 months (8.9 - 25.04) (P<0.05). The most common adverse events associated with sorafenib were hand-foot skin reaction (82.2%), rash (57.94%) and diarrhea (48.91%). Most of the drug-related adverse events were manageable with dose modification, and no CTCAE Grade 4 adverse event was observed.

Conclusions: The combination treatment of TACE and sorafenib significantly prolonged median survival in Chinese patients with unresectable HCC, with well tolerated safety profile.
Second interim analysis of the Global Investigation of Therapeutic Decisions in Unresectable HCC (uHCC) and of Its Treatment with Sorafenib (GIDEON): Differences in AE reporting across physician specialties.
Authors: Venook Alan Paul , Lencioni Riccardo , Marrero Jorge A. , Kudo Masatoshi , Nakajima Keiko , Ye Sheng-Long , Cihon Frank
Published: February 2017

286

Background: GIDEON is an ongoing, global, prospective, non-interventional study of patients (pts) with uHCC receiving sorafenib (Sor) in real-life practice. Differences in pt management across physician specialties can be explored.

Methods: The 2nd interim analysis was pre-planned when ~1500 treated pts were followed for ≥4 months. The predefined descriptive subgroup analysis by specialty is presented.

Results: Median days between visits varied across specialties: medical oncologists (Med Oncs) had the shortest. Sor dosing was broadly similar across specialties, with hepatologists/gastroenterologists (Hep/GIs) having the greatest incidence of dose reductions. Most commonly reported (>20% of pts) adverse events (AEs; e.g. diarrhea, hand-foot skin reaction [HFSR], fatigue) were similar across specialties, but the incidences varied. These AEs and grade 3/4 AEs were reported by more Hep/GIs and Med Oncs than by surgeons. The incidences of liver-related AEs varied across specialties. Interval-specific AE rates by specialty will be presented.

Conclusions: Interim data from GIDEON highlight variations in the assessment and management of uHCC pts across specialties. The reporting of AEs and dose reductions may reflect the frequency of visits with physicians. Findings support the importance of a multidisciplinary team approach to optimize pt care.

[Table: see text]
Biliary tract cancer: A large institutional experience.
Authors: McNamara Mairead , Horgan Anne M. , Walter Thomas , McKeever Elizabeth , Min Trisha , Hedley David W , Cleary Sean P , Gallinger Steven , Greig Paul David , Serra Stefano , Knox Jennifer J.
Published: February 2017

288

Background: Biliary tract cancers (BTCs) encompass both cholangiocarcinoma (CC), arising in the intrahepatic, perihilar (klatskin), or distal biliary tree, ampulla of vater and gallbladder carcinoma (GBC). The prognosis is poor for the majority of these patients (pts). Given the rarity of BTC compared with other solid tumours, there have been few large studies looking at long-term outcomes. The aim of this study was to retrospectively review outcomes of pts who presented to a multidisciplinary team at Princess Margaret Hospital, Toronto, with a diagnosis of BTC.

Methods: 950 pts with a diagnosis of BTC were followed from diagnosis to death between Jan 1987 and Sept 2011. Complete demographics, performance status, disease site, histological diagnosis, percentage receiving surgery with curative intent, other treatments and overall survival were analysed.

Results: The cohort includes 497 (52%) males, performance status of 0-1 in 781 (82%) and 2-3 in 68 (7%) pts. A histological diagnosis of adenocarcinoma was confirmed in 806 (85%), 104 (11%) were non diagnostic, 40 (4%) other. Definitive surgery was performed in 42% and adjuvant chemotherapy (CT) or concurrent CT/radiotherapy given in only 7% and 4% respectively. The overall survival for the entire cohort of 950 pts was 18 months (mo) with survival for breakdown of tumour type detailed in table. At this time 319 (34%) pts are still alive, 561 (59%) are deceased and status is unknown in 70 (7%). CT or concurrent CT/radiotherapy was given for unresectable or metastatic disease in the first line palliative setting in 332 (35%) and 23 pts (2%) respectively. The response to first line CT in GB was 46% vs. 31% in CC and med survival was 12.2 and 11.2 mo respectively.

Conclusions: This represents a large biliary cancer cohort with survival benchmarks obtained in the modern era of multidisciplinary care. The different sub-sites clearly have different prognosis. Responses and survival for advanced disease on CT are similar for GBC and CC. Updated data will be presented.

[Table: see text]
Fear of cancer recurrence and quality of life among survivors of pancreatic and periampullary neoplasms.
Authors: Petzel Maria Q. B. , Parker Nathan H , Valentine Alan D. , Simard Sebastien , Nogueras Gonzalez Graciela M , Fleming Jason B. , Lee Jeffrey Edwin , Pisters Peter W. T. , Vauthey Jean-Nicolas , Katz Matthew H.G.
Published: February 2017

289

Background: Fear of Cancer Recurrence (FCR) is well documented among survivors of breast, colon and prostate cancer. Incurable recurrence is common following resection of pancreatic and periampullary neoplasms. The incidence and significance of FCR in this population is unknown. We hypothesized that FCR represents an important source of psychosocial distress following resection of pancreatic neoplasms.

Methods: We conducted a cross-sectional study of patients with non-recurrent pancreatic ductal (PDAC), periampullary adenocarcinoma or pancreatic neuroendocrine tumor (PNET) treated with potentially curative surgery 1991–2011. We assessed 7 discrete dimensions of FCR using the Fear of Recurrence Inventory (FCRI) and evaluated quality of life (QOL) and psychosocial distress using the Functional Assessment of Cancer Therapy-Hepatobiliary Questionnaire and Hospital Anxiety and Depression Scale. Participants completed these validated instruments by mail.

Results: 188 (53%) of 355 eligible patients completed at least one instrument, a median of 49 months (range, 6–222 months) following potentially curative resection. Participants included 73 (39%) patients with PDAC, 55 (29%) with periampullary adenocarcinoma, and 60 (32%) with PNET. The median FCR severity score was higher than a previously established cutoff for clinical significance in 55%, 51% and 63% of patients with PDAC, periampullary adenocarcinoma and PNET, respectively. Older age, male gender, periampullary adenocarcinoma, negative lymph nodes, and longer interval since operation were clinical factors associated with lower total FCR score (all p<0.05). In multivariate analysis, only age (p=0.01) and gender (p=0.03) were independently associated with severity of FCR. A higher total FCR score was significantly associated with higher anxiety (r=0.64), depression (r=0.41) and lower QOL (r =−0.53), all p<0.001.

Conclusions: Fear of cancer recurrence is pervasive following resection of pancreatic neoplasms, regardless of survivors’ histopathologic diagnosis, disease severity, or time since resection. Given its association with anxiety, depression and lower QOL, FCR represents a critical therapeutic target.
Outcomes and efficiency of national gastric cancer screening program in Korea: Single-center, large-scale study.
Authors: Kim Beom Jin , Heo Chae , Cha Bong Ki , Kim Jae G. , Kim Sang-Jung
Published: February 2017

29

Background: Gastric cancer is a major cause of death and a substantial socioeconomic burden in Korea. The National Cancer Screening Program for Medicaid recipients was initiated in 1999 and has contributed to reduction of cancer-related mortality in Korea. Endoscopy may be cost-effective screening tool in Korea, where the cost of endoscopy and UGIS are similar and the incidence of gastric cancer is high. Most of Japanese studies on the efficiency of mass screening for gastric cancer have dealt with photoflurography as a screening tool. Although biennial gastric cancer screening by endoscopy has been increasing in Korea as part of the National Cancer Screening Program, few studies have evaluated its efficiency. Therefore, we analyzed the outcomes and efficiency of the National Gastric Cancer Screening Program using endoscopy in Korea.

Methods: We reviewed medical records from the National Gastric Cancer Screening Program at Chung-Ang University hospital in Korea from January 2007 to December 2010. The study population was comprised of Medicaid recipients ≥ 40 years of age who were taken from the National Health Insurance Corporation.

Results: A total of 41,150 asymptomatic subjects underwent endoscopy for gastric cancer screening. The mean age of the screened subjects was 56.3 years for men and 48.9 years for women. The male to female ratio of the screened subjects was 1.57:1. Gastric cancer was diagnosed in 102 (0.24%) of 41,150 subjects (60 men and 42 women). Their mean age was 54.4 years. Of these, 76 subjects (0.18%) were diagnosed as early gastric cancer and 26 subjects (0.06%) as advanced gastric cancer. The proportion of early gastric cancer among total gastric cancers was 74.5%. During the period, only 6,586 (16.0%) subjects participated in the biennial gastric cancer screening (59% for men and 49% for women).

Conclusions: Despite accomplishments of the National Gastric Cancer Screening Program in Korea, low compliance to the screening program remains an issue. Furthermore, its cost-effectiveness analysis will be needed for successful progression.
Associations between county-level general surgeon (GS) and gastroenterologist (GA) density and outcomes for hepatobiliary cancer (HBC).
Authors: Tsang Trevor C. , Cheung Winson Y.
Published: February 2017

292

Background: Surgical resection is the mainstay of treatment for early, localized HBC. Prior studies consistently show an association between procedure volumes and cancer outcomes, but the impact of surgeon and physician density is unclear. Our aims were to 1) examine the effects of GS and GA density on HBC mortality and 2) compare the relative importance of GS versus GA density on HBC outcomes.

Methods: Using county-level data from the Area Resource File, US Census, and National Cancer Institute, we developed both multivariate linear and logistic regression models to determine the effect of GS and GA density on overall HBC mortality between 2002 and 2006, while controlling for cancer incidence, county demographics and socioeconomic factors.

Results: In total, 793 counties were analyzed: mean HBC incidence and mortality were 5.89 and 5.34 per 100,000 persons, respectively; 77% were metropolitan; mean GS and GA densities were 10.6 and 3.5 per 100,000 people, respectively. When compared to counties with no GS, those with at least one had a statistically significant decrease in HBC-specific mortality (beta coefficient -.115; p=.001). In contrast, when compared to counties with no GA, those with at least one showed a trend towards lower mortality (beta coefficient -.0677; p=.065). Increasing the county-level density of GS and GA improved outcomes, but increases beyond 10 GS or 4 GA per 100,000 people did not continue to result in significant reductions in HBC mortality; rather, these showed an increase in HBC mortality.

Conclusions: Reductions in HBC mortality are more strongly influenced by increasing GS than GA density. There appears to be a ceiling effect at which point increasing GS and GA density does not appear to result in improvements in HBC outcomes. A strategy of allocating healthcare resources and distributing the workforce across counties will optimize outcomes at the population-level.