bluuebunny/crossref_metadata_2025 huggingface dataset:
Synergy of water soluble prodrug triptolide (minnelide) with gemcitabine and nab-paclitaxel in pancreatic cancer.
Authors: Dudeja Vikas , Modi Shrey , Giri Bhuwan , Majumder Kaustav , Banerjee Sulagna , Saluja Ashok
Published: February 2017

259

Background: Gemcitabine with nab-paclitaxel is the standard of care for metastatic Pancreatic Ductal Adenocarcinoma (PDAC). Addition of nab-paclitaxel to gemcitabine improves the survival of patients with metastatic pancreatic cancer by only 6 weeks while increasing toxicity. Meaningful combinations that reduce the doses while improving efficacy are required. Water soluble prodrug of triptolide (Minnelide) is effective against PDAC in preclinical studies and has demonstrated activity in the ongoing phase I trial. We have evaluated the combination of low dose triptolide prodrug with lowered doses of Abraxane and gemcitabine in PDAC. Methods: Pancreatic cancer cell lines S2-013 and S2-VP10 were xenografted both subcutaneously as well as orthotopically in athymic nude mice. Efficacy of a combination of triptolide prodrug (Minnelide: 0.21mg/kg) with reduced dose of gemcitabine 100mg/kg + Abraxane 10mg/kg (~40% of the clinically effective dose) was evaluated and compared with both standard of care gemcitabine 250mg/kg + Abraxane 25mg/kg as well as reduced dose of gemcitabine + Abraxane in animal models. We also used the immunocompetent model where murine PDAC cell line KPC001 implanted subcutaneously in C57/bl6 mice. Results: In subcutaneous syngeneic model, combination of triptolide prodrug and paclitaxel significantly inhibited tumor growth (tumor volumes expressed as % of Control, Mean±SEM: triptolide prodrug: 75.4±25, paclitaxel: 50.0 ±3, triptolide prodrug + paclitaxel: 11.0 ±1). In metastasis model combination therapy markedly improved survival (median survival in days: Vehicle-13, triptolide prodrug -20, standard of care -45, reduced dose standard of care-30, and Minnelide + reduced dose standard of care (all mice alive at 90 days). Combination of triptolide prodrug and low dose gemcitabine + nab-paclitaxel decreased tumor size, increased survival, reduced metastases and malignant ascites in orthotopic model of PDAC. Conclusions: Triptolide prodrug synergizes with reduced dose standard of care (gemcitabine and nab-paclitaxel) and helps in reducing the doses of these toxic drugs all the while achieving same or better efficacy in animal models of PDAC.
Precision cancer therapy through nanoparticle delivery of siRNA against KRAS.
Authors: Strand Matthew S. , Pan Hua , Grossman Julie G. , Goedegebuure Peter S. , Fleming Timothy , Wickline Samuel A. , Fields Ryan C.
Published: February 2017

260

Background: Small interfering RNA (siRNA) has potential for highly specific gene manipulation, making it attractive for delivering precision therapy to cancer patients. However, efforts to employ siRNA therapeutically have been limited by its short half-life in circulation, low target tissue specificity, and cellular entrapment within endosomes. We utilized serum-stable, cell-penetrating, and endosomolytic peptide-based nanoparticles (NPs) to overcome these obstacles and deliver siRNA against KRAS to KRAS-mutant human and mouse pancreas and colorectal cancers. Methods: Human and mouse pancreas and colorectal cancer cell lines were tested for NP uptake in vitro utilizing fluorescent siRNAs. Uptake was assessed via fluorescent microscopy and flow cytometry (FC). Mice bearing tumors from these cells were injected IV with the same NP, and uptake was assessed with an in vivo imaging system (IVIS), and FC. Cell lines were treated with KRAS-siRNA NP and KRAS knockdown was assessed by real-time PCR. Results: Mouse and human pancreas and colorectal cancer cell lines took up NP in vitro, with signal detected within > 93% of cells at 24 hours. Tumors from these cells grown in mice were strongly fluorescent after IV injection of fluorescent NP within 2 hours, and until at least 30 hours. FC of a tumor treated with fluorescent NP showed that 86% of tumor cells expressed fluorescent signal 24 hours post-injection. IVIS revealed signal in mouse liver and kidneys, but when assessed by FC, only 17.8% and 13.5% of cells from these tissues were fluorescent, respectively. The brain, heart, lungs, spleen, and pancreas of mice receiving injections were negative. Cancer cell lines exposed to KRAS-siRNA NP for 48 hours express KRAS at levels that are 4.5 to 15.1% of untreated cells. Conclusions: Human and mouse pancreas and colorectal cancers efficiently and specifically take up NP in vitro and in vivo. Selected limitations of siRNA are overcome with this NP delivery system, and NP-packaged siRNA effectively inhibits KRAS. This platform represents a highly specific approach to targeting tumor genes of interest, which may ultimately enable selective knockdown of putative drivers of tumor progression.
Retrospective study of non-mucinous appendiceal adenocarcinomas: Role of systemic chemotherapy and cytoreductive surgery.
Authors: Uemura Marc Isamu , Qiao Wei , Fournier Keith F. , Morris Jeffrey , Mansfield Paul F. , Eng Cathy , Royal Richard Eldon , Wolff Robert A. , Raghav Kanwal Pratap Singh , Overman Michael J.
Published: February 2017

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Background: The majority of studies evaluating appendiceal epithelial neoplasms have focused on those with mucinous histology. Few studies have reported on non-mucinous appendiceal adenocarcinomas. We performed the largest single-center study to investigate this histologic subtype, in order to describe the natural history and impact of both cytoreductive surgery (CRS) and systemic chemotherapy. Methods: We retrospectively reviewed 172 pts with non-mucinous appendiceal adenocarcinoma evaluated at the UT-MD Anderson Cancer Center between 1990 and 2015. Patient demographics, tumor characteristics, therapy received, and outcomes were recorded. Response assessment was semi-quantitative (response vs. no response) according to the treating physician. Overall survival (OS) and time to progression (TTP) were calculated using Kaplan Meier product-limit method and survival rates compared using the log rank test. Results: Median age at diagnosis was 52.9 yrs (M:F 1:1). Most pts presented with advanced stage: stage I (1.7%), stage II (32.5%), stage III (14.5%), and stage IV (51.2%). No patient had well-differentiated histology. 56% had moderate and 44% poor histology. Median OS by stage was 90.9m [95% CI: 70.8 to 172.9] for stage II, 52.1m [95% CI: 28.9 to NA] for stage III and 28.3m [95% CI: 22.9 to 31.9] for stage IV, (p < 0.0001). In pts with metastatic disease (n = 128) CRS was attempted in 20 (15.6%) and was complete (CCS 0/1) in 12. The median OS for pts achieving complete CRS was 48.6m. Systemic chemotherapy was administered to 92% (118/128) of metastatic pts. The median TTP was 9.4m [95% CI: 8.0 to 11.5] and semi-quantitative response rate was 54%. The majority of pts received either oxaliplatin-based, 57%, or irinotecan-based, 23%, first-line chemotherapy regimens. No statistical difference in TTP (p = 0.9) or OS (p = 0.07) between different chemotherapies was seen. Conclusions: In contrast to mucinous appendiceal neoplasms, non-mucinous appendiceal adenocarcinomas rarely present with low-grade (well-differentiated) histology. Treatment approaches appear more akin to colorectal cancer with most metastatic pts undergoing systemic chemotherapy and a minority undergoing CRS.
Sarcopenia with modified Glasgow prognostic score as a predictor of long-term survival in patients with gastric cancer.
Authors: Nishi Masaaki , Shimada Mitsuo , Yoshikawa Kozo , Higashijima Jun , Nakao Toshihiro , Kashihara Hideya , Takasu Chie
Published: February 2017

27

Background: Recent reports suggested that the Glasgow prognostic score (GPS), which is a preoperatively determined inflammation-based score, correlated with long -term survival in several types of cancers. The aim of this study is to create new prognostic index which is superior to modified GPS (mGPS) in gastric cancer. Methods: Seventy five patients with gastric cancer who underwent gastrectomy were enrolled in this study. Prognostic factors were searched for among clinocopathological factors and nutritional- or immune- parameters, including mGPS (J Gastoenterol 2011), neutrophil lymphocyte ratio (NLR), prognostic nutritional index (PNI), or sarcopenia. Cut of value were 3.0: NLR, 40: PNI, respectively. Sarcopenia was assessed by the following CT-based methods (Lancet 2011). Sarcopenia with mGPS (SarcoGPS) were defined as CRP was changed to sarcopenia. Results: The overall survival (OS) rate was significantly lower in mGPS:0 group than in mGPS:1,2 group (p < 0.05). The disease-free survival (DFS) rate didn’t differ in mGPS (N.S). The OS and DFS rate of high NLR group or sarcopenia group were significantly lower than those of low NLR group or non- sarcopenia group (p < 0.05). PNI did not differ significantly both in OS and DFS. SarcoGPS was the poor prognostic factor both in OS and DFS (p < 0.01) Conclusions: SarcoGPS is the new prognostic index, which is superior to mGPS, in gastric cancer.
Molecular prescreening (MP) to treat patients (pts) with advanced pancreatic cancer (PC) in early clinical trials.
Authors: Sauri Tamara , Macarulla Teresa , Cabrera Guadalupe , Verdaguer Helena , Zeron-Medina Jorge , Vivancos Ana , Capdevilla Jaume , Elez Elena , Alsina Maria , Argiles Guillem , Hierro Cinta , Grasselli Julieta , Matos Ignacio , Rodon Jordi , Nuciforo Paolo , Dienstmann Rodrigo , Tabernero Josep
Published: February 2017

272

Molecular prescreening (MP) to treat advanced pancreatic cancer (PC) patients (pts) in early clinical trials Background: Advanced PC has a dismal prognosis, with conventional therapies having poor impact on disease course. The aim of this study was to investigate the impact of a MP program to identify potentially targetable alterations (PTa) in PC pts eligible for clinical trials with matched targeted therapies. Methods: From Jan 2011 to June 2015, a total of 86 chemorefractory PC pts were referred to MP at the VHIO Phase I Unit. Archived tumor samples were analyzed for selected gene mutations (mut) in using mass spectrometry (MassARRAY, Sequenom) until June 2014 or next-generation sequencing (Amplicon, MiSeq) thereafter. PTEN and PDL1 expression levels were measured with immunohistochemistry. All demographic, treatment and survival data were extracted retrospectively from electronic medical records. Results: Median age was 61 years (range 29-78) and 64% were male. Median treatment lines before MP was 2 (range 1-5). Tissue used for MP was primary tumor in 74% and metastatic lesion in 26%. In total, 29% of the samples did not have enough material for mut analysis. The most common PTa were KRAS mut (20/35 with Sequenom, 57%; 22/26 with Amplicon, 85%; p = 0.02), PTEN low (9/22, 41%), PTEN null (4/22, 18%) and CDKN2A mut (2/26, 8%). RNF43 mut, STK11 mut, BRAF V600E and BRAF G469A were found in one sample each. A total of 30 pts were enrolled in Phase I trials following MP, 10 of them with a direct matched therapy (5 with PI3K pathway inh - PTEN low/null, 3 with PI3K + MEK inhibitor - KRAS mut, 1 anti-PDL1 therapy - PDL1 high, 1 HDM2 inh - TP53 wild-type). Partial response was observed in 1 case (PI3K inh + chemotherapy, PTEN null) and stable disease in additional 4 pts (3 with PI3K inh +/- chemotherapy, PTEN low/null; 1 PI3K + MEK inh, KRASmut). Median time on treatment with matched therapy was 2.5 months (CI95% 1.8 – not reached). Conclusions: Genomic/proteomic characterization of PC is able to identify a subpopulation eligible for matched therapy in early clinical trials, with rare cases presenting a clear treatment benefit. Low recruitment can be linked to lack of enough material for MP, low prevalence of PTa and patient characteristics
Blood neuroendocrine tumor gene cluster analysis to predict somatostatin analog response.
Authors: Kidd Mark S. , Drozdov Ignat , Modlin Irvin Mark
Published: February 2017

276

Background: Defining therapeutic efficacy in NETs is problematic. We have identified circulating NET transcripts that accurately reflect tumor tissue levels and are sensitive measures of tumor biology. We also identified gene clusters that define NET activity e.g., proliferation. We hypothesized that targeted treatment would alter cluster expression and these could predict treatment response. We evaluated this using somatostatin analogs since they effectively ameliorate symptoms and inhibit tumor growth. Methods: We prospectively evaluated GEP-NETs (n=35) [M:F 12:23; median age: 58 years, small intestine: n=29, pancreas n=3, rectum n=3]. Circulating NET gene expression was assessed (qRT-PCR, normalized gene expression) and imaging (CT/MRI: disease status–RECIST criteria) undertaken. Treatments included: sandostatin (n=32), octreotide (n=2) and pasireotide (n=1); median dose 20mg (range 20-60mg). Gene clusters e.g., proliferation (Ki67, NAP1L1, NOL3, TECPR2) were evaluated as predictive “neoplasia hallmarks” using 2-tailed non-parametric and ROC analyses. Cluster expression is expressed as mean±SEM. Results: Imagery identified25 (71%) patients with stable disease; 10 were progressing. Expression of genes associated with secretory regulation, the “secretome” was significantly down-regulated in the disease-stabilized versus progressive group (2±0.5 vs. 30±25, p<0.001). Individuals with disease progression on SSA therapy exhibited both a significantly elevated proliferation-associated gene cluster (65±15 vs. 16±1, p<0.001) and an epigenetic remodeling cluster (44±6 vs. 32±10, p<0.005). ROC analysis confirmed these accurately identified therapy response (AUC: 0.86-0.97, p<0.0001). Other gene clusters e.g., metabolism (10±1.2 vs. 15.4±3) and apoptosis (1.3±0.2 vs. 1.1±0.8) were not different. Conclusions: SSA therapy alters circulating transcript measurements. Disease stabilization is associated with downregulation of genes linked to tumor secretion while progression is associated with elevation in gene clusters that define tumor proliferation and epigenetic reprogramming. Blood transcript measurements provide an accurate tool to predict the efficacy of SSA therapy.
The Know Your Tumor (KYT) initiative: A national program of multi-omic molecular profiling (MoP) for patients (Pts) with pancreatic cancer (PDA).
Authors: Engebretson Anitra , Brody Jonathan Robert , Rahib Lola , Matrisian Lynn , Hendifar Andrew Eugene , Hoos William Arthur , Mikhail Sameh , Chung Vincent M. , Picozzi Vincent J. , Heartwell Craig , Mason Kimberly , Varieur Katelyn , Madhavan Subha , Petricoin Emanuel , Pishvaian Michael J.
Published: February 2017

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Background: There has been a significant increase in the utilization of MoP to facilitate the selection of therapies for pts with advanced cancers. However, coordinated efforts to perform uniform MoP and collect clinical outcomes data have only successfully been executed in limited academic settings. In an effort to “democratize” the availability of MoP for PDA patients in a broad spectrum of clinical settings, The Pancreatic Cancer Action Network (PanCAN) and Perthera initiated the KYT initiative, an academic, industry, and advocacy group collaboration. Methods: PDA pts self-referred to the Patient Central call center at PanCAN. Pts interested in enrolling in an IRB-approved registry trial were then referred to Perthera to facilitate consent, tissue acquisition, and commercial MoP of the pt’s tumor. Test results were reviewed by a team of PDA specialists in the context of the pt’s treatment (tx) history. A report detailing tx options was delivered to the pt’s oncologist. Pts are being actively followed longitudinally to assess physician acceptance of the tx options and to track outcomes. Results: From 06/2014 to 09/2015, 382 pts were enrolled into KYT. Of these, 273 pts from 192 physicians (community and academic) in 38 states were enrolled. Reasons for non-enrollment were: pts no longer interested (67%); pts too ill or not appropriate for KYT (17%); the pt’s physician would not sanction MoP (16%). To date, 162 pt tumor samples have been obtained, and 117 reports delivered. 75% of samples had adequate tissue for genomic profiling (NGS), with 87% of samples harboring a KRAS mutation. Actionable findings (i.e. linked to a specific tx option) identified by NGS included mutations in BRCA2 (5%), PALB2 (1%), ATM (4%); BRAF (2%), PIK3C/PIK3R (7%), STK11 (5%), amplification of ERBB2 (3%), FGFR (2%), PDGFR (2%); and RET fusions (2%). Of the 117 profiles, 43% revealed actionable findings; 58% presented off-label therapy options; and 48% led towards high priority clinical trials. Conclusions: MoP of pts with PDA is feasible irrespective of their geographical location or access to an academic center. Updated information on tx selection and patient outcomes will be provided.
Angiogenesis polymorphisms profile in the prediction of clinical outcome of advanced HCC patients receiving sorafenib: Combined analysis of VEGF and HIF-1α—Final results of the ALICE-2 study.
Authors: Faloppi Luca , Casadei Gardini Andrea , Masi Gianluca , Silvestris Nicola , Loretelli Cristian , Ulivi Paola , Vivaldi Caterina , Bianconi Maristella , Giampieri Riccardo , Bittoni Alessandro , Andrikou Kalliopi , Del Prete Michela , Scartozzi Mario , Cascinu Stefano
Published: February 2017

280

Background: HIF-1α plays a crucial role in tumour angiogenesis triggering the transcription of several genes including VEGF. The overexpression of HIF-1α in HCC is associated with tumour angiogenesis, invasion, metastasis, treatment resistance and poor prognosis. The therapeutic stronghold of advanced HCC is the TKI sorafenib. In our previous report (ALICE-1 study) SNPs rs2010963 and rs4604006 of VEGF have been shown to predict clinical outcome in HCC patients treated with sorafenib. Methods: 210 patients from a multicentre database were eligible for our analysis. Tumour samples were tested for 8 HIF-1α SNPs. Patients PFS and OS were analysed. Results: At univariate analysis CC > AA+AC of rs1951795, TT > CC+CT of rs10873142, AA+AG > GG of rs12434438 SNPs of HIF-1α were statistically significant for PFS and OS. The extended analysis of VEGF and VEGFR SNPs confirms the results of ALICE-1 study. At multivariate analysis rs12434438 of HIF-1α, rs2010963 of VEGF-A and rs4604006 of VEGF-C have been confirmed as independent factors. At the combined analysis of significant SNPs the presence of 2 favourable alleles of rs2010963 and rs4604006 of VEGF compared to only 1 or to none favourable alleles, identifies three populations with different PFS (respectively: 10.8 vs. 5.6 vs. 3.7 months, p < 0,0001) and OS (respectively: 19.0 vs. 13.5 vs. 7.5 months; p < 0,0001). Furthermore the presence of GG genotype of rs12434438 (HIF-1α) select a population with a particularly poor outcome independently from the clinical effect of the two VEGF SNPs (PFS: 2.6 months, p < 0,0001; OS: 6.6 months, p < 0,0001). Conclusions: This investigation on HIF-1α SNPs, following our previous discoveries on VEGF and VEGFR, may represent a clinical tool to identify patients with favourable response to sorafenib. In the presence of a favourable genotyping, clinicians would administer sorafenib as soon as clinically indicated, instead of delaying it with other treatments. Conversely patients with unfavourable genotyping may not be optimal candidates for sorafenib. These patients should be preferably included in clinical trials exploring new treatment options.
Effect of adjuvant (AD) radiotherapy (RT) on outcomes following pancreaticoduodenectomy (PD) for pancreatic adenocarcinoma (PDA): A margin-stratified analysis.
Authors: Ocuin Lee Mayer , Miller Jennifer Lee , Zenati Mazen S , Steve Jennifer , Singhi Aatur D. , Burton Steven A. , Bahary Nathan , Bartlett David L , Hogg Melissa Ellen , Zeh Herbert J. , Zureikat Amer H.
Published: February 2017

311

Background: The role of RT following PD for PDA remains controversial due to ambiguity in the definition of R0/R1 margin status in existing clinical trials. Recent data suggest that increased margin clearance (MC) is associated with improved survival after PD for PDA, however the role of adjuvant radiotherapy (ADRT) in patients with known MC is undefined. We sought to analyze the influence of ADRT on outcomes of PD for PDA based on MC data. Methods: We retrospectively identified 326 patients with MC data (in mm) who underwent PD between 2002-2014. Recurrence-free (RFS) and overall survival (OS) was determined by Kaplan-Meier analysis. Hazard ratios (HR) were calculated by Cox multivariate regression analysis on significant variables. Results: Mean age was 68 yrs and 55% were male. Median follow-up was 21 mos (IQR 12-34 mos). ADRT was administered to 87 patients (27%). Median RFS and OS for the entire cohort was 14 mos and 25 mos. On univariate analysis, ADRT was not associated with improved median RFS (13 vs. 14 mos; p = NS) or OS (23 vs. 27 mos; p = NS), but increasing MC was associated with prolonged median RFS [10 (0mm) vs. 13 (0-1mm) vs. 23 mos ( > 1mm); p < 0.02 for all pairs] and OS [16 (0mm) vs. 23 (0-1mm) vs. 40 mos ( > 1mm); p < 0.01 for all pairs]. After controlling for sex, BMI, neoadjuvant therapy, LVI, PNI, lymph node ratio > 0.2, tumor size > 2.5cm, and adjuvant chemotherapy, increasing MC was independently associated with improved OS [HR 0.680; p = 0.034 (0-1mm); HR 0.451; p < 0.001 ( > 1mm), compared to 0mm]. Patients were subsequently stratified into 3 groups based on MC [0mm (n = 73); 0-1mm (n = 118); > 1mm (n = 135)]. ADRT was administered less frequently to patients with greater MC [0mm (n = 29; 41%); 0-1mm (n = 36; 31%); > 1mm (n = 22; 16%); p < 0.001]. Even when stratified by MC, ADRT was not associated with improved RFS [10 vs. 9 mos (0mm); 13 vs. 12 mos (0-1mm); 21 vs. 23 mos ( > 1mm); p = NS for all pairs] or OS [16 vs. 18 mos (0mm); 24 vs. 23 mos (0-1mm); 33 vs. 42 mos ( > 1mm); p = NS for all pairs]. Conclusions: ADRT is not associated with improved RFS or OS following PD for PDA regardless of MC. The use of RT following PD for PDA should be re-examined.
Utility of a multidisciplinary tumor board in the management of pancreatic diseases.
Authors: Brauer David G. , Strand Matthew S. , Sanford Dominic E. , Doyle Maria Majella , Murad Faris , Mullady Daniel , Kushnir Vladimir M. , Ruzinova Marianna , Olsen Jeffrey R. , Parikh Parag J. , Lim Kian-Huat , Tan Benjamin R. , Edmundowicz Steven Alphonse , Wang-Gillam Andrea , Hawkins William G. , Chapman William C. , Strasberg Steven M. , Fields Ryan C.
Published: February 2017

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Background: Multidisciplinary Tumor Boards (MTBs) are a requirement for comprehensive cancer centers and are routinely used to coordinate multidisciplinary care in oncology. Despite their widespread use, the impact of MTBs is not well characterized. We studied the outcomes of all patients presented at our pancreas MTB, with the goal of evaluating our current practices and resource utilization. Methods: Data were prospectively collected for all patients presented at a weekly pancreas-specific MTB over the 12-month period at a single-institution NCI-designated cancer center. The conference is attended by surgical, medical, and radiation oncologists, interventional gastroenterologists, pathologists, and radiologists (diagnostic and interventional). Retrospective chart review was performed at the end of the 12-month period under an IRB-approved protocol. Results: A total of 470 patient presentations were made over a 12-month period. Average age at time of presentation was 61.5 years (range 17 – 89) with 51% males. 61.7% of cases were presented by surgical oncologists and 26% by medical oncologists. 174 cases were the result of new diagnoses or referrals. 78 patients were presented more than once (average of 2.3 times). Pancreatic adenocarcinoma was the most common diagnosis (37%), followed by uncharacterized pancreatic mass (16%), and pancreatic cyst (7%). The treatment plan proposed by the presenting clinician was known or could be evaluated prior to conference in 402 cases. Presentation of a case at MTB changed the plan of management 25% (n = 100) of the time, including MTB recommendation against a planned resection in 46 cases. When the initial plan changed as a result of MTB discussion, the most common new plan was to obtain further diagnostic testing such as biopsy and/or endoscopy (n = 24). Conclusions: MTBs are required and resource-intensive but offer the opportunity to discuss a wide array of pathologies and influence management decisions in a sizable proportion of cases. Additional investigations evaluating adherence rates to MTB decisions and to published guidelines (i.e. National Comprehensive Cancer Network) will further enhance the assessment and utility of MTBs.
Adjuvant therapy in pancreatic adenocarcinoma: A systemic review and meta-analysis.
Authors: Nahar Kazi Jannatun , Chan David , Mittal Anubhav , Samra Jaswinder S. , Hugh Thomas , Diakos Connie Irene , Clarke Stephen John , Pavlakis Nick
Published: February 2017

330

Background: The “optimal” adjuvant treatment in pancreatic cancer remains undetermined. Chemotherapy (chemo) such as gemcitabine (Gem), 5-fluorouracil (5-FU) and chemo-radiotherapy (chemoRT) with either Gem or 5-FU have been investigated in trials. We performed a systematic review and meta-analysis to determine the overall efficacy of adjuvant treatment. Methods: We searched databases (PubMed, Medline, Cochrane database) and major conference proceedings up until August 2015 for randomized trials comparing chemo or chemoRT versus (vs) observation, two different chemo regimens and chemoRT vs chemo. Primary end point was overall survival (OS); secondary end points were relapse free survival (RFS), grade 3/4 toxic effects and quality of life (QoL). We performed meta-analysis as per the PRISMA guidelines; hazard ratios (HR) for OS and RFS were pooled with random-effects modelling. Results: Fifteen trials were identified evaluating 4348 patients. For trials comparing chemo to observation (7 trials, n = 1383) the OS HR was 0.77 (95% CI 0.67-0.89, p = 0.001) and PFS HR 0.73 (95% CI 0.53-1.01, p = 0.06) both favouring chemo. For trials investigating Gem (2 trials, n = 472), OS was improved with HR 0.76 (95% CI 0.63 -0.92, p = 0.006) as was RFS (HR 0.56, 95% CI 0.46-0.68, p < 0.00001). For trials investigating agents other than Gem (5 trials, n = 911), OS was improved with HR 0.79 (95% CI 0.63-0.99, p = 0.04), but RFS was not (2 trials only, HR 1.00, 95% CI 0.73-1.37, p = 0.99). Five trials (n = 1832) compared different chemo regimens to Gem in each case; pooled OS HR was 0.90 (95% CI 0.65-1.25, p = 0.54) and RFS HR 0.88 (95% CI 0.67-1.15, p = 0.35). Insufficient data was available to pool grade 3/4 toxicity for chemo vs observation trials; no significant difference was found in incidence of overall grade 3/4 toxicity for trials comparing two chemo regimens (OR 0.98, 95% CI 0.39-2.47, p = 0.96). QoL data was available in 3 trials (ESPAC-1, ESPAC-3, CapRi) with no significant differences noted. Conclusions: Adjuvant chemo vs no chemo for resected pancreatic adenocarcinoma improves OS and RFS. Adjuvant ChemoRT vs no treatment is not beneficial. Overall, novel chemo regimens have not been shown to be superior to Gem. Reporting of QoL is inadequate to make any conclusion.
Treatment patterns and clinical outcomes of patients with metastatic gastroenteropancreatic neuroendocrine tumors (mGEP-NETs).
Authors: Jiao Xiaolong , Pulgar Sonia J. , Boyd Marley , Braiteh Fadi S. , Lowenthal Susan Pitman , Cox David , Fox Patricia S. , Paulson Andrew Scott
Published: February 2017

331

Background: mGEP-NETs are rare and heterogeneous tumors. Limited data has been published on real world clinical management of these tumors. This study was conducted to understand the treatment patterns and clinical outcomes of patients with mGEP-NETs treated in the community oncology setting. Methods: A retrospective study was conducted using US Oncology’s (USON) iKnowMed electronic health record (EHR) database with supplemental chart review. The first diagnostic record of mGEP-NET in the EHR system was defined as the date of diagnosis of mGEP-NET. Inclusion criteria: ≥ 18 years of age at diagnosis; diagnosis of mGEP-NET between 1/1/2008 to 12/31/2012. Patients in clinical trials or with poorly differentiated tumors were excluded. Results: 229 patients were included with a median age of 64.0 years. Primary tumor site included small bowel (47.6%), pancreas (31.4%), and other (21.0%). Tumor grade was available for 134/229 (58.5%) patients, and the majority was reported as well-differentiated (52.8%). Chromogranin A (CgA) and urinary 5-HIAA were reported for 34.9%, and 32.8% of patients respectively. 37 (16.2%) of patients were under observation only. For those receiving systemic treatment, median time to first systemic treatment after diagnosis was 2.7 weeks, with 75% of patients starting therapy by 9.4 weeks. 120 (52.4%) patients received only somatostatin analogs (SSAs) during the study period, and 72 (31.4%) patients received chemotherapy, and/or targeted therapy. In the 1st line setting (n = 192), 148 (77%) patients received SSAs, 23 (12%) chemotherapy, and 21 (10.9%) targeted therapy. The most common AEs for SSAs were diarrhea (18.2%), abdominal pain (16.9%), and fatigue (13.5%). The median OS from diagnosis was 84.2 months [95%CI 70.9, 108.0 months] for the overall cohort. OS was longer in small bowel NETs than in pancreatic or other NETs (median OS 108.0 vs 69.9 vs 84.2 months, p = 0.017). Conclusions: Most of the patients with mGEP-NETs received systemic treatment soon after diagnosis and referral to USON. The OS and AEs were consistent with other studies. Low reporting of CgA, 5-HIAA, and tumor grade reflected variability of clinical practice in the community setting.
Outcome of second-line treatment (2L Tx) following nab-paclitaxel (nab-P) + gemcitabine (G) or G alone for metastatic pancreatic cancer (MPC).
Authors: Goldstein David , Chiorean E. Gabriela , Tabernero Josep , El-Maraghi Robert Hassan , Ma Wen Wee , Reni Michele , Harris Marion , Whorf Robert C. , Coughlin Susan , Li Jack , Manax Victoria G. , Lu Brian D. , Romano Alfredo , Von Hoff Daniel D.
Published: February 2017

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Background: The impact of 2L Tx in MPC is not well described. The phase III MPACT trial (N = 861) demonstrated superior efficacy for nab-P + G vs G alone for 1L Tx of MPC. This post hoc analysis examined 2L Tx use in pts in MPACT. Methods: OS was estimated by the Kaplan-Meier method, using the most updated information from MPACT. Data were summarized by type of 2L Tx. Results: 347 pts received 2L Tx. Baseline characteristics (at start of 1L) of those pts were balanced between arms and representative of the ITT population: median age, 61-62 years; 12% had > 3 metastatic sites, and ≈ 30% had Karnofsky PS 70-80 in each arm. 26% and 14% of pts in the nab-P + G and G arms, respectively, discontinued 1L Tx for adverse events. OS in the 347 pts was significantly longer for nab-P + G vs G (Table). The median time from the end of 1L Tx to death for pts receiving no 2L Tx was 2.5 and 1.6 mo in the nab-P + G and G arms, respectively (HR, 0.67; P < 0.001), less than half for those who received any 2L Tx (5.3 and 4.5 mo). 78% and 76% of pts received a 5FU/capecitabine (cape)–containing regimen as 2L Tx after nab-P + G and G and achieved 13.5 and 9.5 mo of median OS, respectively. Conclusions: 2L Tx after nab-P + G or G alone in MPC is feasible and may potentially improve pt outcomes. Clinical trial information: NCT00844649. [Table: see text]
Preoperative accuracy of gastric cancer staging in patient selection for neoadjuvant therapy.
Authors: Ikoma Naruhiko , Elimova Elena , Blum Mariela A. , Ajani Jaffer A. , Chiang Y. Sabrina , Fournier Keith F. , Mansfield Paul F. , Badgwell Brian D.
Published: February 2017

34

Background: Because gastric cancers stage ≥ T2 or ≥ N1 are considered for neoadjuvant treatment, accuracy of preoperative staging is critical. The purpose of this study was to identify preoperative staging accuracies of computed tomography scan (CT) and endoscopic ultrasound (EUS) in gastric cancer and their utilities in selecting patients for neoadjuvant therapy. Methods: Medical records of 8,260 patients with gastric or gastroesophageal adenocarcinoma (presented 1995-2013) were reviewed to identify those who underwent gastrectomy but not neoadjuvant treatment. We reviewed preoperative EUS reports and CT images to identify detailed T stage (based on AJCC 7thedition) and lymph node positivity (short axis diameter ≥ 6mm). T stage and N status were compared with those from the surgical pathology report. Clinicopathologic variables associated with incorrect preoperative staging were also examined. Results: We identified 187 patients who underwent preoperative staging by EUS (n = 145) and/or CT (n = 134) for gastrectomy. The accuracy, sensitivity, and specificity of EUS in distinguishing T1 from more advanced tumors were 82%, 78%, and 85%, respectively. In univariate analysis, tumor location and lymphovascular invasion were associated with incorrect EUS T staging. In multivariate analysis, variables associated with underestimation of EUS T stage was lymphovascular invasion (OR 7.51, 95% CI 1.91-29.5, p < 0.01) and Caucasian race (OR 3.75, 95% CI 1.31-10.75, p = 0.01). The accuracies, sensitivities, and specificities for N status were, respectively, 65%, 49%, and 79% with CT and 66%, 29%, and 95% with EUS. In univariate analysis, poor differentiation and lymphovascular invasion were associated with incorrect diagnosis of CT N status. In multivariate analysis, lymphovascular invasion was associated with false-negative (OR 3.79, 95% CI 1.34-10.7, p = 0.01), and differentiated histology was associated with false-positive CT N status (OR 7.14, 95% CI 2.00-25.44, p < 0.01). Conclusions: EUS has reasonable accuracy in T stage, while both CT and EUS have low sensitivities and high specificities in N status. These accuracies should be considered when selecting patients for neoadjuvant treatment.
An institutional analysis of gemcitabine and capecitabine for advanced biliary cancer.
Authors: Gandhi Shipra , Gabriel Emmanuel M. , Attwood Kristopher , Ma Wen Wee , Kuvshinoff Boris W. , Hochwald Steven N. , Iyer Renuka V.
Published: February 2017

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Background: The results of ABC-2 trial established gemcitabine and cisplatin (gem-cis) as a standard regimen for advanced biliary cancer. Although no randomized trial has been performed with gemcitabine and capecitabine (gem-cap), this regimen has reported benefits and has been a standard treatment at our institution. We report our experience with outcomes and toxicity. Methods: This is a single institution, retrospective study from 2005-2015 of patients with advanced biliary cancer, including intra and extrahepatic cholangiocarcinoma (IHCC/EHCC) and gallbladder carcinoma (GBC). Overall survival (OS) and progression-free survival (PFS) on gem-cap were reported using standard Kaplan-Meier methods. Comparisons were made using log-rank test. Results: A total of 372 patients were identified. Of these, 227 (61.0%) had chemotherapy data at our institution. A total of 153 patients (41.1%) received gem-cap, 133/153 (86.9%) received it in first line. The majority of patients (67.4%) had metastatic disease. Twenty-seven patients (17.6%) received it as adjuvant therapy, of which 16 (10.5%) also received adjuvant radiation. Forty-four patients (33.1%) received second line of chemotherapy and 12 (9.0%) received third line. Disease sites included 48.9% IHCC, 24.0% EHCC and 27.1% GBC. Median follow-up was 45.1 months (mo). The median OS and PFS for the entire cohort were 13.0 mo (95% CI 10.7-17.4) and 8.0 mo (6.0-9.3), respectively. Patients with metastatic disease had poorer OS and PFS compared to locally advanced disease: median OS – 11.4 vs 16.3 mo (p = 0.01); median PFS – 6.9 vs 10.4 mo (p < 0.001). There was no statistically significant differences in OS/PFS by disease site. Overall, 69 patients (55.6%) experienced grade 3/4 toxicity. The most common (35.7%) was hematologic toxicity (neutropenia/thrombocytopenia). Other adverse events included elevated LFT’s (9.3%) and non-hematologic events (22.5%), including fatigue (6.8%) and hand-foot syndrome (6.0%). Conclusions: Gem-cap provides a similar PFS to gem-cis based on historical comparison with ABC-2 trial. Gem-cap may offer the advantage of fewer adverse events (55.6%) compared to the 70.7% reported in ABC-2. Prospective comparison of these two regimens is warranted.
Intrahepatic cholangiocarcinoma: Ambitious operations and outcomes.
Authors: Raoof Mustafa , Dumitra Sinziana , Ituarte Philip HG , Melstrom Laleh , Warner Susanne , Fong Yuman , Singh Gagandeep
Published: February 2017

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Background: Data from specialized institutions suggests that resection for large ( > 7cm) and mutifocal intrahepatic cholangiocarcinoma (ICC) is safe and feasible. We aim to study this hypothesis using a population-based dataset. Methods: This is a study of a contemporary cohort from California Cancer Registry database (2004-2011) that was merged with Office of Statewide Health Planning and Development inpatient database. All patients with ICC that underwent resection or ablation were included. Tumors were classified into two groups; intrahepatic, small ( < 7cm) & solitary (ISS) vs. extrahepatic extension, large or multifocal (ELM). Mortality was recorded at 90 days. Overall survival (OS) analysis was performed using the Kaplan-Meier and Cox-proportional hazard model. Results: Of the total 275 patients that met the inclusion criteria, 55% were female, 52% were white and median age was 65 years (IQR 55-72). Majority of patients had > 3 segment resection 59% (Ablation 10%, 1-3 segments 30%). Portal lymphadenectomy was performed in 45% of patients. Vascular Invasion was found in 22% of patients, 14% were bilobar and 20% were node positive. Median follow up was 23 months (IQR 13-40). Number of ISS tumors (139, 50.5%) and ELM tumors (136, 49.5%) was similar. The two groups were comparable in regards to age, sex, race, comorbidities, extent of surgery, portal lymphadenectomy, node positivity. ELM tumors were more likely to have vessel invasion (27% vs. 17%, p = 0.048) and be bilobar (26% vs. 2%, p < 0.001). There was no significant difference in overall complication rate (ISS 34%, ELM 27%, p = 0.19) and mortality rate (both groups < 1%, p = 0.32). A multivariate Cox-proportional hazard model demonstrated that age > 60 years, > 1 comorbidity, high grade tumors, ELM tumors (HR 1.63: 95%CI 1.11-2.40; p = 0.013) and LN positivity (HR 2.30: 95%CI 1.49-3.54; p < 0.001) are independently associated with worse OS. Conclusions: Surgical resection of tumors > 7cm, multifocal lesions involving contiguous extrahepatic organs is safe with acceptable morbidity and mortality. Age > 60 years, grade, comorbidity, ELM tumors and LN positivity are independent predictors of worse OS.
Role of adjuvant chemoradiotherapy for duodenal cancer: An update of the experience at a single institution.
Authors: Park Hae Jin , Kim Kyubo , Chie Eui Kyu , Jang Jin-Young , Kim Sun Whe , Oh Do-Youn , Bang Yung-Jue
Published: February 2017

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Background: The patterns of failure after resection for duodenal cancer are very limited, and the benefit of adjuvant chemoradiotherapy has not been proven. We compared the treatment outcomes of surgery alone to those of surgery followed by adjuvant chemoradiotherapy (CRT) for duodenal cancer. Methods: Forty-seven patients with duodenal cancer underwent pancreaticoduodenectomy between January 1991 and February 2013. There were 33 males and 14 females, and their median age was 62 years (range, 31-80). Twenty-two patients (47%) received adjuvant CRT, and 25 (53%) did not. Postoperative radiotherapy was delivered to tumor bed and regional lymphatics (dose range = 40-55.4 Gy). All the patients underwent CRT concurrently with 5-fluorouracil. Median follow-up period was 31 months (range, 6-286). Results: Nodal stage and stage group were more advanced in CRT(+) group (p = 0.003 and 0.002, respectively). Locoregional recurrence (LRR) occurred in 11 patients; 8 out of 25 in CRT(-) and 3 out of 22 in CRT(+) group. Distant metastasis (DM) occurred in 19 patients; 7 out of 25 in CRT(-) and 12 out of 22 in CRT(+) group. Five patients experienced LRR and DM, and 3 of them were synchronous. Five-year overall survival rates of CRT(-) and CRT (+) group were 50% and 47%, respectively (p = 0.794). Five-year locoregional relapse-free survival rates of CRT(-) and CRT(+) group were 68% and 80%, respectively (p = 0.267). On multivariate analysis, the addition of CRT after curative resection was the only prognostic factor predicting superior locoregional relapse-free survival (p = 0.049). No patient suffered from grade 3 or higher toxicity during or after CRT. Conclusions: The addition of CRT after pancreaticoduodenectomy was associated with improvement of local control in duodenal cancer. Given the high LRR in surgery alone group, adjuvant CRT should be considered.
Effect of metformin on survival in pancreatic ductal adenocarcinoma.
Authors: Amin Sunil , Mhango Grace , Lin Jenny J , Aronson Anne , Boffetta Paolo , Wisnivesky Juan P. , Lucas Aimee
Published: February 2017

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Background: Pancreatic ductal adenocarcinoma (PDAC) remains highly lethal. Diabetes mellitus (DM) is both a risk factor for and a sequela of PDAC. Metformin, a commonly prescribed biguanide oral hypoglycemic used for the treatment of type II DM, has been found to have a chemo-protective role in PDAC in some in-vitro and human-based studies; conflicting literature exists regarding its potential role as a therapeutic agent. We investigated whether metformin use prior to PDAC diagnosis is associated with improved survival of patients with DM. Methods: We used the Surveillance, Epidemiology, and End-Results (SEER) linked Medicare database to identify diabetic patients with PDAC diagnosed between 2007-2011. Information regarding use of anti-hyperglycemic drugs prior to cancer diagnosis was extracted from Part D claims. The diabetic severity comorbidity index (DCSI) was used to control for DM severity. Logistic regression was used to calculate propensity scores for metformin use based on each patient’s sociodemographic characteristics, diabetic severity, and co-morbidity status. Inverse propensity weighted Cox Proportional-Hazard Models were subsequently used to assess the association between metformin use and overall survival adjusting for measured confounders. Results: We identified 1916 patients with PDAC and a diagnosis of DM on hypoglycemic medications at least one year prior to cancer diagnosis. Of these, 1098 (57.3%) were treated with metformin and 818 (42.7%) with other DM medications. Mean survival for those on metformin was 5.5 months compared with 4.2 months for those not on metformin (p < 0.01). After adjusting for confounders, patients on metformin had a 12% decreased risk of mortality compared to patients on other medications (hazard ratio [HR]: 0.88, 95% confidence interval [CI]: 0.81-0.96, P <.01). In stratified analysis, differences persisted for those with Charlson score 0-1 vs > 2, DCSI 0-1 vs > 2, and for those treated with insulin vs other hypoglycemic medications (p < 0.01 for all). Conclusions: Metformin is associated with increased survival among diabetics with PDAC. If confirmed in prospective study, these results suggest a possible role for metformin use in diabetics with PDAC.
JASPAC 06: Observational study of FOLFIRINOX therapy for unresectable and recurrent pancreatic cancer—Preliminary report on serious adverse events.
Authors: Ozaka Masato , Todaka Akiko , Mori Keita , Boku Narikazu , Mizuno Nobumasa , Ueno Hideki , Kobayashi Satoshi , Uesugi Kazuhiro , Kobayashi Noritoshi , Hayashi Hideyuki , Sudo Kentaro , Okano Naohiro , Horita Yosuke , Kamei Keiko , Yukisawa Seigo , Nakamori Shoji , Yachi Yutaka , Henmi Toshiyuki , Kobayashi Marina , Fukutomi Akira
Published: February 2017

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Background: In Japan, indication of FOLFIRINOX for unresectable and recurrent pancreatic cancer was approved in 2013. Because clinical data of FOLFIRINOX in Japanese patients based on only one exploratory trial is limited, this observational study was conducted to survey practical use of FOLFIRINOX and to evaluate incidences of adverse events in Japanese patients. Methods: The subjects were patients with unresectable or recurrent pancreatic cancer who received FOLFIRINOX therapy during one year from Dec. 20, 2013 (approval date of this study). All the subjects were registered and their clinical data were sent to the data center. In this preliminary report, we analyzed patients’ characteristics related to serious adverse event (SAE). This study was approved by the IRB in each institution. Results: Four hundred patients (pts) were registered from 27 institutions in Japan. Median age was 63 years (range 27-80). Sixty-four percent (n = 254) had no prior treatment and 254 pts (60%) had distant metastatic lesions. The UGT1A1 genotype was wild-type in 56.8% of the subjects, heterozygous (*1/*6, *1/*28) in 39.3%, and homozygous (*6/*6, *6/*28, *28/*28) in 3.9%. One hundred forty-one SAEs in 115 pts (28.8％) were reported until Aug. 10, 2015. Most common SAEs were febrile neutropenia (n = 26), neutrophil count decreased (n = 26), anorexia (n = 21) and biliary tract infection (n = 18). Of these 141 events, five events were results in death. The proportion of patients who met the inclusion criteria (as follows: ECOG PS of 0 or 1; age 20-75 years; adequate hematological, liver and renal functions) used in the phase II trial of FOLFIRINOX for Japanese patients was significantly lower in the subjects with SAEs than those without SAE (60.5% vs. 72.4%, p = 0.023). Four of the 5 pts who resulted in death did not fulfill the inclusion criteria; C-reactive protein in 4, platelet count in 1 and hemoglobin in 1. Conclusions: This is a first report to evaluate the safety profile of FOLFIRINOX in Japanese pancreatic cancer patients. These data highlight the importance of patient selection for FOLFIRINOX. The final safety and efficacy results of this study will be reported at the coming meeting. Clinical trial information: UMIN000014658.
The association between sarcopenia and treatment outcomes in patients with pancreatic cancer undergoing chemoradiation.
Authors: Patel Kajal , Shaikh Talha , Wang Lora S , Hoffman John Parker , Cohen Steven J. , Meyer Joshua E.
Published: February 2017

415

Background: Sarcopenia (Sp) or severe loss of muscle mass is a prognostic factor in cancer patients. We assessed the association between Sp and outcomes in borderline resectable or locally advanced/unresectable pancreatic cancer patients undergoing chemoradiation (CRT). Methods: We reviewed all patients who underwent CRT at an NCI-designated cancer center between 2007-2012. Patients with available pre-treatment imaging were included in the analysis. Sp was defined as a lumbar skeletal muscle area/height of < 55.4 cm2/m2 for males and < 38.9 cm2/m2for females. Sp was correlated to treatment toxicity, cause specific survival (CSS), and overall survival (OS). Analysis was performed using chi-square test for categorical variables and Mann-Whitney U test for continuous variables. Kaplan-Meier method and Cox regression was used for survival analysis. Results: A total of 86 patients met the inclusion criteria with 32 (37%) patients being sarcopenic. The median age was 70 (range 46-91) with a median follow-up of 14 months (3-68). The majority of patients were male (57%), had T3 disease (47%), or were borderline resectable (63%). Twenty nine (33.7%) patients underwent surgery. Sarcopenic patients were less likely to undergo surgery (p = 0.024) versus non-sarcopenic patients. Otherwise there was no difference in clinical or treatment factors. The 12-month actuarial OS for patients with and without Sp was 47.9% and 70.7%, respectively (p = 0.047). The 12-month actuarial CSS for patients with and without Sp was 48% and 76%, respectively (p = 0.007). On multivariable analysis, after controlling for T-stage, N-stage, resectability, gender, pre-treatment CA 19-9, and surgery, Sp was no longer associated with CSS (HR 0.284 95% CI 0.774-2.398) or OS (HR 1.077 95% CI 0.626-1.853). Surgery remained associated with CSS (HR 0.205 95% CI = 0.102-0.412) and OS (HR 0.187 95% CI 0.096-0.363). T-stage also remained associated with both CSS (HR 0.616 95% CI 0.410-0.925) and OS (HR 0.649 95% CI 0.440-0.957). Conclusions: The presence of Sp decreases the likelihood of undergoing curative surgery for pancreatic cancer. This may be another useful tool to identify poor prognosis patients.