bluuebunny/crossref_metadata_2025 huggingface dataset:
Who is receiving survivorship care plans? Findings from the 2012 LIVESTRONG survey.
Authors: Rechis Ruth , Nutt Stephanie , Bann Carla , Squiers Linda , Rao Naveen
Published: February 2017

26

Background: There are more than 14 million cancer survivors in the US – a number that is on the rise. Care coordination resources will be essential to provide support to this growing population. Key stakeholders, including the Commission on Cancer (CoC) and the Institute of Medicine, have proposed survivorship care plans (SCPs) as a way to extend support. However, limited research has been conducted to date on SCPs. Methods: In 2012, the LIVESTRONG Foundation (LIVESTRONG) administered a survey to understand the role of a treatment summary (TS) and SCPs and how they fit into survivors’ care. Logistic regression models were conducted to identify factors associated with receiving SCPs or TS. Results: 5,303 survivors responded to these questions. While 92% of these respondents received information about where to return to for cancer check-ups, only 51% reported receiving a TS and 17% reported receiving a SCP. Survivors who were more likely to receive SCPs if they had a navigator (p<.001) and if they were male, black, had finished treatment within the past year, or received care at a university-based medical center or community cancer center (p < 0.05). Also, those receiving a SCP were significantly more likely to have had a detailed discussion with a provider regarding long-term side effects, emotional needs, and lifestyle recommendations. Specifically, 60% of those with a SCP discussed long-term effects compared to 39% who did not. Conclusions: Results here indicate that few survivors receive SCPs but survivors reported benefits from receiving them. Currently many workflow barriers impede delivering SCPs, and LIVESTRONG is working with key stakeholders including the CoC to automate the LIVESTRONG Care Plan powered by Penn Medicine’s OncoLink through a registry and EMR system to understand how to address this issue.
Payer current and future utilization of pathways: A research study.
Authors: Greenapple Rhonda
Published: February 2017

273

Background: Clinical pathways are a growing payer management technique for controlling costs and standardizing care. Their use in other therapeutic areas has helped payers control costs and standardize care; however, use of pathways in oncology has not been assessed. Methods: There were a total of 49 respondents, including 19 Medical Directors and 30 Pharmacy Directors, covering 100 million lives in the US across all channels (Medicare, Commercial, and Medicaid). Approximately 39% of respondents were from small plans (covering less than 750,000 lives), 28% were from medium-sized plans (covering 750,000 – 2.5 million lives), and 33% of respondents represented large plans (covering more than 2.5 million lives). About 33% of respondents were from national plans, while 67% were from regional plans. Results: Only 39% of payers have actually implemented pathway programs in oncology. Of the payers surveyed that did not already have a clinical pathway, 59% said they are not currently implementing pathways. However, among those who are using pathways, a disproportionate share is commercial plans (42%) and Medicaid (40%), not Medicare (25%). Only 25% of Medicare-focused plans anticipate implementing clinical pathways in the future, while more than 40% of commercially-focused plans intend to do so. About half of plans (53%) anticipate that pathways also will be integrated into provider ratings, and a minority, (42%), see a role for pathways in product formulary placement or tier status. When payers have implemented pathways, the tumor types with the highest costs have been initial targets, with breast (84%), lung (63%), colorectal (63%), and prostate (37%) with the highest penetration of pathway implementation. Conclusions: Payers view clinical pathways as an important tool for reducing drug costs, especially with respect to tumor types that carry high treatment costs. Near-term strategies like step edits and coverage via the pharmacy vs. medical benefit will continue to play a significant role in oncology reimbursement decisions, but product companies need to understand how existing clinical pathway programs will impact provider access to products to more accurately forecast their future impact as the concept gains national traction.
The clinical significance of SWI/SNF complex in pancreatic cancer.
Authors: Numata Masakatsu , Morinaga Soichiro , Watanabe Takuo , Tamagawa Hiroshi , Yamamoto Naoto , Shiozawa Manabu , Yoichi Kameda , Ohkawa Shinichi , Oshima Takashi , Yukawa Norio , Rino Yasushi , Akaike Makoto , Masuda Munetaka , Miyagi Yohei
Published: February 2017

149

Background: Chromatin remodeling factors have been the subject of great interest in oncology. However, little is known about their role in pancreatic cancer. The objective of this study is to clarify the clinical significance of SWI/SNF complex, one of the major chromatin remodeling machineries, in patients with pancreatic cancer. Methods: 68 cases with pancreatic cancer who underwent R0, 1 resection were enrolled. Cancer tissues were processed to tissue microarray, then stained immunohistochemically by using antibody of SWI/SNF components; BRM, BRG1, BAF250a, BAF180, and BAF47. The correlation of expression level and clinicopathological outcome including overall survival were analyzed. Results: Expression level of the SWI/SNF components was categorized as low or high according to the median value of Histo score. Statistical analysis revealed that related factors were tumor size, T factor, M factor, lymphatic invasion, and Stage in BRM, histology and Stage in BRG1, tumor size in BAF180, lymphatic invasion in BAF47, respectively. Multivariate Cox propotional hazard analysis showed high-BRM and low-BAF180 expression level were independent predictors of worse survival in patients with pancreatic cancer. The hazard analysis was also examined in the patients treated with adjuvant gemcitabine, indicating that high-BRM, and low-BAF180 were independent prognostic factors for poor survival. Conclusions: These results suggest that the specific cofactors of SWI/SNF chromatin remodeling complex certainly have roles in pancreatic cancer. High-BRM, and low-BAF180 are useful markers for prognosis of pancreatic cancer.
Blood cell-derived nanovesicles as biomarkers of homeostasis in gastrointestinal cancer.
Authors: Jansa Rado , Stukelj Roman , Sustar Vid , Bedina Zavec Apolonija , Stabuc Borut , Kralj Iglic Veronika
Published: February 2017

152

Background: Nanovesicles (NVs) are membrane-enclosed fragments of cell interior which are pinched off from membranes of cells of all types (including cancer) in the last stage of the budding process. They are involved in cell-cell communication and can promote tumor growth and invasion. Interactions of tumor-derived NVs with blood cells, especially platelets are hypothetically reflected in vesiculability of platelets by means of concentration of NVs in blood isolates. Also we hypothesized that in patients whose plasma mediates stronger attractive interaction between membranes the concentration of NVs in blood isolates would be lower. Methods: NVs were isolated from 2.7 ml samples of blood of 29 patients with gastrointestinal cancer, 44 patients with other gastrointestinal diseases, additional 13 patients who were treated by imatinib due to gastrointestinal stromal tumor (GIST) and 50 healthy volunteers, by repeated centrifugation and washing, and counted by flow cytometry. We followed patients with GIST for 32 months. Ability of blood plasma to mediate attractive interaction between membranes was assessed by the angle of contact between giant phospholipid vesicles prepared by electroformation, which adhered due to addition of plasma to the suspension of NVs. Results: The concentration of NVs was considerably (44%, p = 0.0005) higher in the blood isolates of patients with gastrointestinal cancer than in the population of healthy volunteers and considerably (34%, p = 0.025) higher in patients with gastrointestinal cancer than in patients with other gastrointestinal diseases. We observed a considerable (average 13 fold peak) but transient (about one month within 32 montth follow up interval) increase of concentration of NVs in blood isolates due to treatment with imatinib.We found a negative correlation between the concentration of NVs and the average contact angle between adhered giant phospholipid vesicles (r = –0.50, p = 0.031). Conclusions: Concentration of NVs is increased while the ability of plasma to mediate attractive interaction between membranes is decreased in patients with gastrointestinal cancer. Treatment with imatinib caused transient increase of concentration of NVs in isolates from blood.
Hepatocellular cancer tumor growth and metabolic risk factors.
Authors: Miksad Rebecca A. , Goyal Rohit , Wei Jesse , Shaikh Raja , Halpern Elkan F. , Gazelle G. Scott
Published: February 2017

162

Background: Understanding hepatocellular cancer (HCC) tumor growth patterns is important for determining optimal treatment strategy. However, growth of untreated HCC tumors is unclear and prior studies are limited by older imaging technologies and small samples. We evaluated HCC growth patterns and predictors in a cohort of patients with serial modern computed tomography (CT) and magnetic resonance imaging (MRI). Methods: Two radiologists retrospectively evaluated CT and MRI imaging for 56 patients with 83 HCC tumors with at least two images. Tumor Volume (TV) = 4/3* π *average short axis (X)*average long axis (Y)*X. To assess the relative change in size, normalized tumor volume (NTV) = TV/ baseline TV. Growth curves were fitted using an exponential growth model for tumor >2 observations. Univariate analysis explored clinical and pathologic predictors of NTV. A multivariate model was built by backward elimination of significant univariate variables. Results: Among 56 patients: 77% male, 96% cirrhotic, 50% Child-Pugh Class (CPC) B, 59% Hepatitis C, 32% obese, 37% diabetic, and 12% used metformin. Mean baseline and end TV were 98.8 cm3 and 213.0 cm3, respectively. Mean follow-up=8.3 months and mean number of serial images=3. Exponential TV growth was observed on visual inspection. Diabetes predicted lower NTV (i.e. slower TV growth) in univariate and multivariate analysis (Table). Obesity decreased the impact of diabetes. Conclusions: Diabetic patients had slower growing tumors than non-diabetics, even when clinical and pathologic factors were controlled. Tumor growth fit an exponential pattern. Further study of the impact of metabolic conditions on HCC tumor growth may provide insights into growth factors and identify potential treatment targets. [Table: see text]
Pretreatment plasma concentrations of YKL-40 and IL-6 in patients with pancreatic cancer: Potential diagnostic and prognostic biomarkers.
Authors: Schultz Nicolai Aagaard , Christensen Ib Jarle , Werner Jens , Giese Nathalia , Jensen Benny Vittrup , Larsen Ole , Bjerregaard Jon Kroll , Pfeiffer Per , Calatayud Dan , Nielsen Svend Erik , Yilmaz Mette , Hollander Niels Henrik , Wøjdemann Morten , Bojesen Stig E. , Nielsen Kaspar , Johansen Julia S.
Published: February 2017

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Background: To test the hypothesis that high pretreatment plasma YKL-40 and IL-6 associate with pancreatic cancer (PC) and short overall survival (OS). Methods: 556 patients with PC from Denmark (N=445) and Germany (N=111) were included in the present prospective biomarker study. 152 (27%) patients were operated and treated postoperative with adjuvant gemcitabine. 404 (73%) had locally advanced or metastatic PC and received palliative chemotherapy (primarily gemcitabine). Pretreatment plasma YKL-40 and IL-6 were determined by ELISA with known reference intervals in healthy subjects. Results: The OR for prediction of PC in the whole study population was significant for all 3 biomarkers with CA 19-9 having the highest AUC (YKL-40: OR=4.50, 95% CI 3.99-5.08, p<0.0001, AUC=0.87; IL-6: OR=3.68, 3.08-4.44, p<0.0001, AUC=0.87; CA 19-9: OR=2.28, 1.97-2.68, p<0.0001, AUC=0.93). YKL-40, IL-6 and CA-19-9 increased with more advanced stage (YKL-40 median (IQR): Stage IA-IIA 100 (68-157), IIB-III 101 (59-179), IV 166 (89-296) μg/L, p<0.0001; IL-6: Stage IA-IIA 4.2 (1.9-8.9), IIB-III 4.0 (2.1-8.2), IV 7.4 (3.6-18) ng/L, p<0.0001); CA-19-9: Stage IA-IIA 58 (10-622), IIB-III 209 (54-856), IV 1041 (146-9178) ng/L, p<0.0001). Univariate Cox analysis in resected patients showed that only pretreatment IL-6 and CA 19-9 (dichotomized according to normal values) were associated with short OS (YKL-40: HR=1.38, 0.87-2.18, p=0.17; IL: HR=2.23, 1.41-3.52, p=0.0006; CA 19-9: HR=2.80, 1.54-5.09, p=0.0007). In non-resectable patients all 3 biomarkers were associated with short OS (YKL-40: HR=1.54, 1.23-1.93, p=0.0001; IL: HR=1.63, 1.29-2.06, p<0.0001; CA 19-9: HR=1.48, 1.02-2.15, p=0.039). Multivariate Cox analysis in non-resectable patients (YKL-40, IL-6, CA 19-9 (log transformed base 2), age, sex, and stage) demonstrated that YKL-40 (HR=1.12, 1.02-1.23, p=0.021), IL-6 (HR=1.20, 1.09-1.31, p=0.0001) and CA 19-9 (HR=1.10, 1.07-1.14, p<0.0001) were independent biomarkers for short OS. This was not found in resected patients. Conclusions: Pretreatment plasma concentrations of YKL-40 and IL-6 may be new diagnostic and prognostic biomarkers in patients with PC.
SMAD4 gene mutation and prognosis of pancreatic adenocarcinoma.
Authors: Derbel Olfa , de la Fouchardière Arnaud , Peron Julien , Desseigne Francoise , Heudel Pierre , Guibert Pierre , Rivoire Michel , Meeus Pierre , Peyrat Patrice , Lemaistre Anne-Isabelle , De La Fouchardiere Christelle
Published: February 2017

180

Background: Pancreatic adenocarcinoma remains resistant to many key cytotoxic chemotherapeutic agents and novel targeted therapies. The molecular heterogeneity of this cancer may account for therapy failures to date, although the growing arsenal of novel targeted agents could translate into patient survival. A better understanding of the cellular and molecular features of advanced disease will afford new opportunities for investigation, therapeutic intervention and clinical management of patients afflicted with pancreatic cancer. Methods: Data of 46 patients with pancreatic adenocarcinoma were analyzed. The clinicopathological parameters, the histologic features were determined and correlated to the stage at initial diagnosis and patterns of failure (locally advanced v metastatic disease). Using tissue microarray, we assessed the relationship of SMAD4 expression with the overall survival of patients. Results: Among the 46 treated patients, 32 underwent pancreaticoduodenectomy. 40% of patients died with metastatic disease and 15 % died with locally advance evolution. Loss of SMAD4 expression was found in 22% of patients and seems to be correlated with a high grade histologic features and progression to metastasis disease. Complementary data about correlation between the mutational status of SMAD4 and survival will be presented during congress. Conclusions: SMAD4 gene inactivation seems to be associated with poorer prognosis and disease progression. Prospective validation of SMAD4 as a predictive biomarker may personalize treatment strategies for patients with pancreatic cancer.
Phosphorylated Akt expression as a favorable prognostic factor for patients undergoing curative resection and adjuvant chemoradiotherapy for proximal extrahepatic bile duct cancer.
Authors: Kim Kyubo , Min Hye Sook , Chie Eui Kyu , Jang Jin-Young , Kim Sun-Whe , Han Sae-Won , Oh Do-Youn , Im Seock-Ah , Kim Tae-You , Bang Yung-Jue , Ha Sung W.
Published: February 2017

182

Background: To evaluate the prognostic significance of phosphorylated Akt (p-Akt), phosphorylated mammalian target of rapamycin (p-mTOR), and total phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression in patients undergoing adjuvant chemoradiotherapy for proximal extrahepatic bile duct (EHBD) cancer. Methods: Sixty-three patients with proximal EHBD cancer who underwent curative resection followed by adjuvant chemoradiotherapy were enrolled into this study. Postoperative radiotherapy was delivered to tumor bed and regional lymph nodes up to a median of 40 Gy (range; 40-54). Fifty-nine patients also received fluoropyrimidine chemotherapy as a radiosensitizer. p-Akt, p-mTOR, and PTEN expression were assessed with immunohistochemical staining on the tissue microarray. Results: p-Akt, p-mTOR, and PTEN were expressed in 23 (36.5%), 17 (27.0%) and 25 patients (39.7%), respectively. p-Akt expression was associated with distant metastasis and overall survival, but not with loco-regional recurrence. The 5-yr distant metastasis-free and overall survival rates were 25.8% vs. 58.2% (p = 0.007), and 27.5% vs. 50.2% (p = 0.0167) in patients with negative and positive expression, respectively. On multivariate analysis, nodal involvement was the only significant prognosticator predicting inferior distant metastasis-free survival (p = 0.0105), while p-Akt expression had a borderline significance (p = 0.0541). As for overall survival, p-Akt expression was a marginally significant prognosticator (p= 0.0635), whereas other risk factors lost the statistical significance. Conclusions: p-Akt expression was a favorable prognostic factor for patients undergoing curative resection followed by adjuvant chemoradiotherapy for proximal EHBD cancer.
Effect of trametinib in combination with panitumumab and trastuzumab on tumor growth in an orthotopic xenograft model of human pancreatic cancer.
Authors: Lindberg James M. , Adair Sara J , Newhook Timothy E. , Kim Alison , Parsons J Thomas , Bauer Todd W.
Published: February 2017

190

Background: Aberrant MAPK and EGFR family signaling are key drivers of pancreatic ductal adenocarcinoma(PDAC). We hypothesized that combination trametinib(MEK1/2 inhibitor), panitumumab(EGFR inhibitor) and trastuzumab(Her2 inhibitor) would more effectively suppress tumor growth than any of these monotherapies. Methods: Patient-derived PDAC cell line MAD09-366 was exposed to trametinib, panitumumab, trastuzumab, and combination therapies in vitro. Western blot analysis was performed on treated cell lysates. Athymic, nude mice were orthotopically implanted with patient-derived PDAC xenografts(MAD09-366, 08-608, and 08-738). Established murine tumors were treated with control, trametinib (0.3mg/kg, qDay), panitumumab (500ug, BIW), trastuzumab (200ug, BIW) or in combination. MRI was used to assess tumor response. Results: Two of 3 PDACs were Kras mutant, 2 of 3 demonstrated increased Her2 activity, and all 3 showed increased EGFR activity. In vitro studies showed increased growth inhibition of triple-therapy-treated cells relative to control or each inhibitor alone. Western blot analysis revealed that EGF stimulation increased Ras pathway signaling in this Kras-mutant cell line. With EGF stimulation, the greatest Ras pathway signaling inhibition was seen in triple-therapy-treated cells. In vivo studies in all PDAC xenografts revealed that triple therapy significantly decreased tumor growth rate relative to control, trametinib alone, panitumumab alone, or panitumumab plus trastuzumab. In 2 of 3 PDACs assessed, triple therapy was superior to trametinib plus panitumumab. Average tumor size in MAD08-738 triple-therapy-treated mice decreased by 9.3%. Conclusions: Triple therapy with trametinib, panitumumab, and trastuzumab demonstrated the greatest in vitro Ras signaling blockade. In vivo, this combination produced significant tumor growth inhibition or regression in all PDAC tumors studied. This regimen should be considered for a future clinical trial in pancreatic cancer patients.
Diagnostic utility and prognostic performance of a 92-gene cancer classifier to molecularly profile periampullary adenocarcinomas.
Authors: Overman Michael J. , Wang Huamin , Schnabel Catherine A. , Anderson Jeff , Erlander Mark G. , Wolff Robert A. , Varadhachary Gauri R.
Published: February 2017

197

Background: Due to the small anatomic size, multiplicity of epitheliums, and suboptimal diagnostics determining the site of origin of periampullary adenocarcinomas (PAA) is a challenge. We investigated the ability of a 92-gene RT-PCR assay (CancerTYPE ID) to categorize PAA and to prognostically stratify ampullary adenocarcinomas. Methods: 45 PAA patients who underwent pancreaticoduodenectomies were included; samples were histopathologically verified for tumor subtype determination (pancreatic, extrahepatic biliary, ampullary, or duodenal). Blinded FFPE tumor sections underwent molecular testing and were compared for concordance to histopathological tumor types and prognostic performance. 28 of these samples had previously undergone whole-genome RNA profiling (Overman et al. GI ASCO 2011 a161). Results: Molecular classification of 43 (96%) evaluable samples (13 ampullary, 10 pancreatic, 10 biliary, 10 duodenal) showed 91% concordance: ampullary [5 intestinal (int), 7 pancreaticobiliary (pb)], pancreatic [10 pb], duodenal [3 int, 7 gastroesophageal (ge)], biliary [7 pb]. The 92-gene assay was prognostic with a median OS of 70 m for ge/int cases vs. 32 m for pb cases, P=0.05. Discordant classifications were ge for 1 ampullary and 2 biliary samples, and ovary for 1 biliary case. Previous unsupervised RNA hierarchical clustering of all 13 ampullary cases had identified two prognostic groups (a good-prognosis int-like and a poor-prognosis pb-like), which were identical to the 92-gene classification for 12 cases (5 int and 7 pb). These two ampullary subgroups were prognostic with median OS of 63 vs. 24 m, P=0.07, respectively. Conclusions: The 92-gene assay demonstrated diagnostic utility for molecular site-of-origin classification of PAA. These results support exploration of this approach for the management of metastatic PAA (in which pathologic review of a primary resection specimen is not an option). Molecular classification of ampullary adenocarcinomas into intestinal and pancreaticobiliary subgroups is prognostically relevant; these and the gastric-like molecular profile of duodenal adenocarcinomas may have therapeutic implications.
Circulating tumor cells (CTC) in metastatic hepatocellular carcinoma (HCC): Comparison to control patients with nonmalignant liver diseases (NMLD) and exploratory characterization by next generation sequencing (NGS).
Authors: Kelley Robin Katie , Magbanua Mark Jesus Mendoza , Butler Timothy M , Sidiropoulos Nikoletta , Hwang Jimmy , Evason Kimberley , Hameed Bilal , Wayne Elizabeth M , Yao Francis Y , Siah Iche , Park John W. , Venook Alan Paul , Collisson Eric Andrew
Published: February 2017

207

Background: Noninvasive biomarkers are urgently needed to improve diagnosis, prognosis, and molecular characterization in HCC. Detection of CTC by EpCAM-enrichment methods is associated with poor outcomes in other tumors. Approximately 35% of HCC are EpCAM+. We hypothesized that CTC are detectable in a subset of metastatic HCC but not in NMLD and that CTC DNA might serve as a source of tumor DNA for biomarker detection and discovery. Methods: Whole blood was obtained from (1) patients with metastatic HCC and (2) NMLD controls. CTC were enumerated using CellSearch by blinded investigators. If > 10 CTC/7.5 mL, immunomagnetic enrichment for EpCAM followed by fluorescence-activated cell sorting (FACS) was also performed to collect highly purified CTC for whole genome amplification (WGA) by GenomePlex WGA4 kit. NGS using 46-gene AmpliSeq Cancer Panel (Ion Torrent) was performed on DNA from CTC, formalin-fixed paraffin embedded tumor (FFPE), and peripheral blood mononuclear cells (PBMC) if available. Results: 20 HCC and 10 NMLD were enrolled. FFPE was available in 7 HCC. In HCC cohort, median alpha-fetoprotein (AFP) was 492 ng/mL (range: 3.8-587,134) and vascular invasion (VI) was present in 13/20 (65%). CTC ≥ 3/7.5 mL were detected in 6/20 (30%, 95% CI: 0.08, 0.52) HCC and 0/9 (95% CI: 0, 0) eligible NMLD (p=0.07). One NMLD had CTC > 3/7.5 mL but was found to have HCC on surveillance ultrasound and excluded. CTC ≥ 3/7.5 mL were associated with AFP ≥ 400 (p=0.01) and VI (p=0.05) by Fisher’s exact test. NGS identified mutations listed in COSMIC in the majority including TP53 and CTNNB1. Variants appeared more frequent in CTC than FFPE in this small sample. Coverage was significantly lower in CTC than FFPE (coverage 20x mean 50% vs 93%, p < 0.02 by unpaired t-test). Conclusions: CTC are a promising biomarker in metastatic HCC and merit further study, including non-EpCAM methods. CTC were associated with AFP and VI. NGS of CTC WGA DNA is feasible and identified characteristic mutations but was limited by coverage bias. Updated NGS findings including 5 cases with paired CTC, FFPE, and/or PBMC will be presented.
Microwave ablation for hepatic malignancies: A multi-institutional analysis.
Authors: Groeschl Ryan Thomas , Pilgrim Charles Henry Caldow , Hanna Erin Marie , Simo Kerri A , Swan Ryan Z , Sindram David , Martinie John B , Iannitti David A , Bloomston Mark , Schmidt Carl Richard , Khabiri Homan , Shirley Lawrence Andrew , Martin Robert C. G. , Christians Kathleen K. , Rilling William S , Gamblin T. Clark
Published: February 2017

218

Background: Although many hepatobiliary centers have moved from radiofrequency ablation to microwave ablation (MWA), the factors that influence local control with MWA are not well described. We hypothesized that tumor size, number of tumors, and tumor histology significantly affected MWA success and recurrence-free survival (RFS). Methods: Consecutive patients with hepatic malignancy treated by MWA were included from 4 high-volume institutions (2003-2011), and grouped by histology: hepatocellular cancer (HCC), colorectal metastases (CM), neuroendocrine metastases (NM), and other cancers. Independent significance of variables was established with logistic regression and Cox proportional hazards models. Results: Four-hundred seventy three ablation procedures were performed (139 HCC, 198 CM, 61 NM, and 75 other) for a total of 875 tumors. Median follow-up was 18 months. Complete ablation was confirmed for 839 of 865 tumors (97.0%) on follow-up cross-sectional imaging (Table). NM had greater odds of an incomplete ablation compared to other histologies (odds ratio: 3.07, 95% confidence interval [CI]: 1.08-8.67, p=0.035), however this was not significant in adjusted models. The local recurrence rate was 6.1% overall, and was highest for HCC tumors (10.3%, p=0.051). RFS did not vary significantly between histologies. In adjusted models, tumor size ≥3cm was the only variable predicting poorer RFS (hazard ratio: 1.60, 95% CI: 1.02-2.50, p=0.039). Independent predictors of poorer OS included age, number of tumors ablated, and tumor size ≥3cm. Conclusions: In this large dataset, patients with ≥3cm tumors showed a propensity for early recurrence, regardless of histology. Higher rates of local recurrence were noted in HCC patients, which may reflect underlying liver disease. Accounting for recurrence at any site, however, there were no significant differences in RFS between tumor histologies. [Table: see text]
Phase I trial of chemoradiation with capecitabine and vorinostat in pancreatic cancer.
Authors: Chan Emily , Arlinghaus Lori R. , Cardin Dana Backlund , Goff Laura Williams , Yankeelov Thomas E. , Berlin Jordan , McClanahan Pamela , Holloway Melanie , Parikh Alexander A. , Abramson Richard G. , Merchant Nipun B. , Hiebert Scott , Chakravarthy Anuradha Bapsi
Published: February 2017

225

Background: Histone deacetylase inhibitors (HDACi) and fluoropyrimidines are synergistic and are radiation (R) sensitizers. The combination of the fluoropyrimidine capecitabine ( C) and the HDACi vorinostat (V) with R was evaluated in the treatment (tx) of non-metastatic pancreatic cancer (NMPC). Methods: Patients (Pts) with NMPC were treated with C + V + R. C dose was 1000 mg q12 Monday (M) - Friday (F) on the days of R. R was given via 3D conformal therapy to a total dose of 3000 cGy in 10 fractions over 2 weeks (wk). V dose was given daily M-F x 4 wk. V doses evaluated were: 100, 200, 300, and 400 mg. Resectability assessment occurred within 6 wk after completion of tx. Diffusion weighted- MRIs (DW-MRIs) were obtained pre tx and one wk after tx initiation to assess tumor cellularity. Peripheral blood mononuclear cells (PBMCs) were collected pre tx, during tx, and after completion to assess whole cell HDAC activity. Unresectable pts could opt for continuation of C and V (CCV) at systemic doses (C 1000 mg q12 x 14 days and V 300 mg QD x 14 days of every 21 day cycle) or come off study. Results: 18 pts were enrolled and evaluable. Disease statuses pre-tx were: resectable (n=1), borderline resectable (n=9), and unresectable (n=8). One DLT occurred at dose levels 1, 3, and 4, 2 GI toxicities and one thrombocytopenia. Most common adverse events were lymphopenia, GI toxicity, and fatigue. On MRI, the apparent diffusion coefficient (ADC) increased in most, but not all, tumors after one wk of tx but did not correlate to change in tumor size at completion. PBMC histone acetylation increased in some pts. Eight pts (Pre-tx status: 1 resectable and 7 borderline resectable) underwent exploration with 4 undergoing tumor resection. No unresectable pt converted to resectable. Four of ten potential pts opted for CCV after being deemed unresectable, 2 with stable disease for 6 cycles. Conclusions: C + V + R is feasible with no unexpected toxicity. HDAC inhibition and ADC decrease on DWI-MRI was seen. Accrual to the final cohort (V 400 mg) is ongoing. This study was approved and funded by the National Comprehensive Cancer Network (NCCN) from general research support provided by Merck & Co., Inc. Study was also supported by the Vanderbilt-Ingram Center Support Grant P30CA68485. Clinical trial information: NCT00983268.
Comparison of investigator-delineated GTV in chemoradiotherapy (CRT) for locally advanced nonmetastatic pancreatic cancer (LANPC): Analysis of the pretrial test case for the SCALOP trial.
Authors: Mukherjee Somnath , Halle Charlotte , Spezi Emiliano , Joseph George , Branagan Jennifer Mary Rose , Hurt Chris , Falk Stephen , Nixon Lisette , Abrams Ross A. , Staffurth John
Published: February 2017

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Background: SCALOP, a randomized, multicenter, phase II trial, tested efficacy/toxicity of gemcitabine (Gem) versus capecitabine (Cap) based CRT following 4 cycles of induction chemotherapy. 114 patients from 28 centers were registered and 75 patients had CRT. The RT Quality Assurance included a test case. GTVs outlined by investigators were evaluated by the chief investigator (CI). We report analysis of the test case. Methods: The test case was LANPC of head of pancreas. The gold standard GTV (gsGTV) was outlined by the CI and trial radiologist. Protocol specified margins (GTV + 2cm sup-inf, 1.5 cm radial) were applied to generate the gold standard PTV (gsPTV). CT-DICOM dataset of the planning scan was sent to participating centers for tumor volume delineation by investigators and individualized feedback was provided by CI. CERR software was used to compare the investigator volumes (iGTV and iPTV) against the gold standard. Results: Volumes from 25 investigators were analyzed. The results are summarized below (Table). Slice-by-slice conformity indices and qualitative review showed that most variation occurred at the superior and inferior extremes of the tumor and a peri-tumoral node was frequently missed by investigators. Conclusions: SCALOP is the first trial in LANPC to test investigator-delineated volumes using conformity indices, and has demonstrated considerable variation in iGTVs. Trial workshops and real-time central review of tumor outlines are proposed. [Table: see text]
Duodenal sparing stereotactic body radiation therapy for the treatment of locally advanced pancreatic cancer.
Authors: Ghaly Maged , Montchal Elaine , Cao Yijan , Marrero Mihala , Vijeh Lili , Xanthopoulos Eric , Vinciguerra Vincent , Kaushik Neeraj , Sullivan James , Bloom Beatrice , Knisely Jonathan
Published: February 2017

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Background: The proximity of the pancreas to bowel presents a unique challenge for pancreatic cancer SBRT. This study explores the safety and effectiveness of a novel approach optimizing pancreatic tumor coverage and duodenal sparing. Methods: Eighteen patients with locally advanced pancreatic cancer (15 head/3 body) were treated with initial chemotherapy (Gemcitabine or 5-FU/Cisplatin) for 2- 6 months. All underwent endoscopic US-guided fiducial placement in and around the tumor and had a 4D treatment planning CT scan with oral contrast. This CT was used in conjunction with EUS findings, PET, and biphasic CT scans to identify the GrossTumorVolume (GTV) on the expiration phases. The planning target volume (PTV) was created by expanding the GTV by 2 mm. Dose-volume histogram (DVH) endpoints were constructed, keeping V7/15/20 (stomach/duodenum volumes that receive 7 Gy/15 Gy/20 Gy) <40%,/<25%/ <15% ;the dose to 1/3 of the duodenal circumference <20Gy and duodenal point max dose <23 Gy. Additional dose constraints included liver D50<5 Gy, ipsilateral kidney D25<5 Gy, cord Dmax<10Gy. Three 10 Gy fractions, normalized to the 85% isodose were delivered to the PTV on consecutive weekdays using fiducial-based respiratory motion tracking on a dedicated 6 MV linac-integrated stereotactic delivery system . The patients were then offered systemic therapy for 6 months or until tolerance or disease progression. Follow-up occurred at 4 weeks, 12 weeks, and every 3 months. Results: All patients completed SBRT and a median of 5 total cycles of pre-and post-SBRT chemotherapy. Gross target volumes ranged from 14.2-205.7cm3 (median 39.5cm3). With a median follow-up of 10 months, 1 patient developed transient gastroparesis, 1 G 2 abdominal pain;1 G 2 hematologic toxicity. No late toxicity was observed in 15 patients with longer follow-up (median 12 month). All patients were free of local progression at the last follow-up visit (range 3-12 months). Conclusions: Linac-delivered organ-sparing SBRT with chemotherapy in locally advanced pancreatic cancer resulted in excellent local control and also was well tolerated acutely and subacutely. Longer follow-up is warranted. A phase I dose-escalation study is underway.
Outcomes with FOLFIRINOX for locally advanced pancreatic cancer.
Authors: Boone Brian A. , Steve Jennifer , Krasinskas Alyssa M. , Zureikat Amer H. , Lembersky Barry C. , Gibson Michael K. , Stoller Ronald , Zeh Herbert J. , Bahary Nathan
Published: February 2017

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Background: Trials examining the use of FOLFIRINOX in metastatic pancreatic ductal adenocarcinoma demonstrate significantly higher response rates compared to gemcitabine-based regimens. These high response rates may be particularly important for patients with locally advanced pancreatic ductal adenocarcinoma (LAPD), in which there is currently limited experience with FOLFIRINOX. We examined the outcomes of patients with LAPD treated with neoadjuvant FOLFIRINOX at our high volume clinic. Methods: Retrospective review of a prospectively maintained pancreatic cancer database was used to identify patients who were recommended neoadjuvant treatment with FOLFIRINOX. Clinical outcomes were reviewed. Resectability was determined using SSO criteria. Results: Between 2/2011 and 9/2012 FOLFIRINOX was recommended for 25 patients with LAPD, 13 (52%) unresectable (UR) and 12 (48%) borderline resectable (BR). Median age was 59. 4 patients (16%) either refused treatment or were lost to follow up. 21 patients (84%) were treated with a median of 4.7 cycles (Range: 2-8). 5 patients (24%) required dose reductions secondary to toxicity. 2 patients (9%) were unable to tolerate treatment and 3 patients (14%) had disease progression on treatment. Of the remaining 16 patients, 13 patients (62%) displayed a radiologic response allowing for surgical exploration, 4 (31%) of which were initially unresectable. 6 of these patients (29%) received additional chemotherapy and/or radiation therapy prior to surgery. Peritoneal metastases were discovered at surgery in 2 (8%) patients. Of the patients who were BR, 7/8 (88%) had a R0 resection. Of the 10 UR patients, 3 (33%) underwent surgical resection, with 2 (20%) R0 resections. Overall R0 resection rate was 43%. A total of 4 patients (19%) demonstrated a major pathologic response (2 complete responses and 2 near complete responses) and 8 other patients (73%) had some pathological response. Conclusions: FOLFIRINOX alone or as part of multimodality approach is a biologically active regimen in LAPD with encouraging R0 resection rates, especially in BR LAPD. Further research is needed to determine the utility of additional chemoradiotherapy with FOLFIRINOX and to identify predictors of response in UR patients.
Intravenous and intraperitoneal paclitaxel with S-1 for refractory pancreatic cancer with malignant ascites: An interim analysis.
Authors: Takahara Naminatsu , Isayama Hiroyuki , Nakai Yousuke , Sasaki Takashi , Ishigami Hironori , Yamaguchi Hironori , Kogure Hirofumi , Yamamoto Natsuyo , Sasahira Naoki , Hirano Kenji , Tada Minoru , Kitayama Joji , Watanabe Toshiaki , Koike Kazuhiko
Published: February 2017

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Background: Here we reported an interim analysis of feasibility and safety in the first 10 cases of 30 cases in a phase II trial of intravenous and intraperitoneal paclitaxel combined with S-1 for gemcitabine-refractory pancreatic cancer with malignant ascites. Methods: Paclitaxel was administered intravenous at 50 mg/m2 and intraperitoneal at 20 mg/m2 on days 1 and 8 every 3 weeks, and S-1 was administered at 80 mg/m2/day for 14 consecutive days, followed by 7 days rest. Results: Between April 2011 to February 2012, 10 patients were enrolled. A partial response was achieved in two (20%) and a disease control rate of 50%. The median time to progression and overall survival were 3.2 and 5.9 months, respectively. Malignant ascites was completely resolved in two (20%). Major grade 3/4 adverse events weremyelosuppression including neutropenia (50%) and catheter-related infection (10%). Conclusions: This novel combination chemotherapy was feasible and showed promising results in pancreatic cancer patients with malignant ascites. Clinical trial information: UMIN000005306.
A phase I study of hyperfractionated low-dose radiotherapy (RT) as a chemotherapy sensitizer in combination with gemcitabine (G) and erlobtinib (E) in advanced pancreatic cancer.
Authors: Konski Andre A. , Meyer Joshua E. , Philip Philip Agop , Shields Anthony Frank , Hall Michael J. , Choi Minsig , Duncan Gail , Adaire Beth , McSpadden Erin , Cohen Steven J.
Published: February 2017

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Background: G can sensitize pancreatic cancer (PC) to radiotherapy (RT). However, this approach requires lower doses of G and thus delays aggressive systemic treatment, which may lead to distant failure. In preclinical models, hyperfractionated low-dose RT sensitizes PC cells to G and erlotinib. We thus initiated a Phase I trial combining hyperfractionated low-dose RT combined with full dose G and a tyrosine kinase inhibitor, E, in the treatment of patients with advanced PC. Methods: Patients (pts) with locally advanced or metastatic PC confined to the abdomen and an ECOG performance status (PS) of 0-1, who had received 0-1 prior regimens (without G or E) and no prior RT were enrolled to successive cohorts in a 3+3 design. Patients were treated in 21 day cycles with G IV days 1 & 8, E once PO QD, and twice daily RT fractions separated by at least 4 hours on days 1, 2, 8, and 9. Whole abdominal RT fields were used. Dosing cohorts were as follows (G in mg per m2, E in mg, XRT/fraction in cGy): 1 (1,000, 100, 40), 2 (1,000, 100, 50), 3 (1,000, 100, 60), 4 (1,000, 150, 60). Primary endpoint was to define dose limiting toxicity (DLT) and the maximum tolerated dose (MTD). Results: A total of 27 pts, (median age 64 yrs and 15 male), were enrolled between 11/24/08 and 4/12/12. 17 patients had a PS of 1. The majority of patients were stage IV. Seven pts were enrolled in dose level 1, with 1 pt experiencing a DLT of grade 3 ileus, 3 pts enrolled each in dose levels 2-4 without DLT and 11 pts enrolled in the expanded portion of level 4. Best response by RECIST in 24 evaluable pts and was as follows: partial response 8, stable disease 15 and progressive disease 1. One pt initially found to be unresectable at surgery was subsequently resected with only minimal microscopic residual disease. The majority of grade 3 toxicities were hematologic with 1 grade 5 bowel perforation in dose level 1 in cycle 4. Conclusions: This phase I study combining low-dose hyperfractionated RT as a sensitizer to full dose G plus E was well tolerated with the majority of pts experiencing either a partial response or stable disease. This represents a novel strategy worthy of further investigation in pts with advanced PC. Clinical trial information: NCT00761345.
Local control in resectable and borderline resectable pancreatic cancer (PCa) treated with preoperative chemoradiation using IMRT or chemotherapy alone.
Authors: Kharofa Jordan , Kelly Tracy R. , George Ben , Ritch Paul S. , Tsai Susan , Christians Kathleen K. , Evans Douglas B. , Erickson Beth
Published: February 2017

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Background: The primary objective is to review local control and failure patterns in PCa patients treated with preoperative chemoradiation (chemoXRT) using IMRT compared to patients treated with chemotherapy alone. Methods: All patients with resectable and borderline resectable PCa treated between 1/1/2009 -11/1/2011 were reviewed. During the study period, 68 patients (40 borderline resectable, 28 resectable) were treated with preoperative chemoXRT (50.4 Gy [1.8 Gy/fx] with concurrent gemcitabine [n=59] or capecitabine [n=7]). 12 patients with resectable tumors received gemcitabine based chemotherapy alone and did not receive radiation therapy due to enrollment on chemotherapy only protocols (n=10) or to patient preference (n=2). Radiation was delivered to a CTV that includes the primary mass, the SMA and SMV, +/- the celiac axis. A 4D-CT and daily image guidance were used in all patients. The local failure free interval was defined as the time from surgical resection to local failure or last documented CT scan of the abdomen with no evidence of local disease progression. Results: Following preoperative chemoXRT, 48/68 patients underwent resection with 47(98%) R0 resections. 11/12 patients in the No XRT group undwerent resection with 10 (91%) R0 resections. In the No XRT group, 8/11 (73%) patients failed locally at the SMA/SMV or resection bed as a component of first failure compared to 1/48 (2%) patients who received preoperative chemoXRT (p<0.001). Local failure was the sole site of first failure in 5/11 patients in the No XRT group and 0/48 patients who received preoperative chemoXRT. The actuarial rate of local failure 1 year from surgery was 5% in the preoperative chemoXRT group vs 27% in the No XRT group (p<0.001). All local failures in the No XRT group would have been encompassed using the CTV target volumes used in patients treated with preoperative chemoXRT. Conclusions: IMRT-based, conformal, preoperative chemoXRT for resectable and borderline resectable PCa may facilitate margin negative resection and increase local control. Omission of radiation therapy may result in high rates of local failures at the SMA/SMV vasculature or in the pancreatic bed.
High-volume centers for pancreatic cancer surgery: Does the media message matter?
Authors: Chau Zeling , Smith Jillian K , West James K. , Zhou Zheng , McDade Theodore P. , Ng Sing Chau , Whalen Giles Francis , Moser Arthur J. , Tseng Jennifer F.
Published: February 2017

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Background: Hospital procedure volume is associated with pancreatic cancer outcomes. However, differences between high-volume hospitals are less clear. Furthermore, consumers are barraged with grading systems for hospitals, whose relationship to volume and real outcomes are poorly delineated. Methods: Massachusetts Division of Health Care Finance and Policy Hospital Inpatient Discharge Database was queried to identify 5 highest-volume hospitals performing resection for pancreatic cancer 2005-2009. Primary outcomes included mortality, complications, median length of stay (LOS) and composite outcomes score (COS) including above. Ranks were determined for each outcome and compared to procedure volume order (highest to lowest), as well as ratings identified from popular media and internet-based hospital ratings including US News and World Reports (USN) Consumer Reports (CR), Healthgrades (HG) and Hospital Compare (HC). An inter-rater reliability analysis was performed with Spearman’s rank correlation coefficients calculated between outcomes and ratings. Results: 5 hospitals performing 82% (n=681) of statewide resections for pancreatic cancer were identified. In-hospital mortality ranged from 0-5.1%, complications 9.0-32.0%, median LOS 7-11 days. Within 5 highest-volume centers, outcomes did not improve in a consistent linear fashion with increased volume; however, volume remained more correlated with outcomes than consumer ratings. Of consumer ratings, HG ratings were most correlated with mortality, but had Spearman correlation coefficient of only 0.32. Complication measures were correlated with HG and USN equally at 0.22. USN rankings were highly correlated with LOS measures at 0.85. When all outcome measures were combined, HG was most correlated at 0.32. CR ratings were inversely correlated with all outcome measures. Conclusions: Between high-volume hospitals, outcome variation exists that does not completely correlate with either absolute volume numbers or by popular media grading systems, which can be discordant. Both consumer-directed ratings and volume data, where available, should be used only in appropriate contexts to direct patient care.
Analysis of recurrence after resection of pancreatic neuroendocrine tumors.
Authors: Newman Naeem A , Mann Gary N. , Shukla Mrinal , Swett Katrina R , Levine Edward A. , Bergquist John , Park James Oh , Pillarisetty Venu Gopal , Sham Jonathan G , Shen Perry
Published: February 2017

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Background: Outcomes after recurrence of resected pancreatic neuroendocrine tumors (PNETs) are not well described. Our aim is to assess the rate and sites of recurrence and its effect on clinical outcomes. Methods: Retrospective chart review of patients (n= 80) who underwent surgical resection of PNETs at two institutions. Patients were treated from September 2002 to July 2010. Charts were reviewed for disease recurrence, date, site, and treatment of recurrence. Results: There were a total of 14 (17.5%) recurrences. The most common site of recurrence was the liver (10 patients, 71.4%). The most common treatment of recurrences was chemotherapy (5 patients, 35.7%). The 1, 3, and 5 year disease-free survival (DFS) was 90.9%, 82.7%, and 72.5% respectively. Median recurrence free survival (RFS) was 127 months. The median follow-up for all PNET patients was 25.8 months (range 1 to 140 months). Three-year survival was 97%. Local, distant, and combined recurrences occurred in 7.5%, 12.5%, and 5% of all patients, respectively. Multivariate analysis found AJCC stage (p=0.03) to be an independent predictor for DFS. Median follow-up of patients after they were found to have a recurrence was 13.8 months. Three-year survival for those with and without recurrence was 96.3% and 100%, respectively (p=0.36). Conclusions: AJCC stage is a significant predictor of recurrence after resection of PNETs with hepatic metastases being most common. Survival of patients with recurrence is not significantly different from patients without recurrence and is likely due to the indolent nature of the disease.