bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of FOLFIRINOX with PEG-G-CSF for unresectable/recurrent pancreatic cancer.
Authors: Moriyama Ichiro , Sonoyama Hiroki , Kawabata Yasunari , Ikejiri Fumiyoshi , Inoue Masaya , Takahashi Fumimasa , Matsuda Shinichiro , Ugata Norimi , Shimasaki Yasumasa , Fujimoto Ayumi , Okada Yusuke , Ito Shunsuke , Okada Takahiro , Jo Yumi , Takahashi Tsutomu , Miyake Takaaki , Kodama Tatsuo , Suzuki Ritsuro , Tajima Yoshitsugu , Suzumiya Junji
Published: January 2019

411

Background: FOLFIRINOX (FFX) is a standard therapy for unresectable/recurrent pancreatic cancer, but it is associated with a high frequency of severe adverse events, especially blood toxicity. Human pegylated granulocyte colony-stimulating factor (PEG-G-CSF) can reduce the outpatient frequency during outpatient chemotherapy. However, there are few reports on the effectiveness of PEG-G-CSF in preventing febrile neutropenia during FFX. We retrospectively investigated the usefulness of PEG-G-CSF in reducing the incidence of FN during FFX. Methods: From June 2014 to January 2017, 40 patients with unresectable pancreatic cancer received FFX (including modified FFX) at our hospital. Twenty-three patients were administered PEG-G-CSF as primary/secondary preventive therapy (G group) and 17 were not administered any G-CSF (NG group). Results: The median patient ages in the G and NG groups were 65 (range, 48-78) and 63 (range, 42-81) years, respectively, and the male to female ratios were 13:10 and 11:6, respectively. There were 13 and 10 patients, respectively, in the G group with performance statuses of 0 and 1 and 8 and 9 such patients, respectively, in the NG group. Seventeen and five patients in the G and NG groups, respectively, had metastatic disease and six and two patients, respectively, had locally advanced disease. The respective response rates (RRs) in the G and NG groups were 30% and 6% (p = 0.0608), and the respective disease control rates (DCRs) were 30% and 41% (p = 0.0407). The median progression-free survivals in the G and NG groups were 7.3 (95% confidence interval [CI], 3–9.4) and 4.5 (95% CI, 1.9–8.5) months, respectively (p = 0.173), and the respective overall survivals were 16.9 (95% CI, 10.2–NA) and 14.2 (95% CI, 7.8–20.5) months (p = 0.302). Conclusions: The DCR was significantly greater in the G group than in the NG group, and the RR tended to be greater in the G group than in the NG group. A high tumor shrinking effect of FFX with PEG-G-CSF indicated that it might be useful as a neoadjuvant chemotherapy. A prospective study is needed to examine first-line chemotherapy in unresectable/recurrent pancreatic cancer and neoadjuvant chemotherapy in borderline/locally advanced pancreatic cancer.
Hypofractionated radiation therapy for unresectable/locally recurrent intrahepatic cholangiocarcinoma.
Authors: Smart Alicia , Hong Theodore S. , Petkovska Natasa , Noe Bridget N. , Zhu Andrew X. , Ferrone Cristina , Tanabe Kenneth , Allen Jill N. , Drapek Lorraine C. , Qadan Motaz , Murphy Janet E. , Goyal Lipika , Wo Jennifer Yon-Li
Published: January 2019

412

Background: Our objective was to evaluate outcomes for patients with unresectable/locally recurrent intrahepatic cholangiocarcinoma (ICC) treated with hypofractionated proton or photon radiation therapy (HF-RT). Methods: We retrospectively identified 66 patients with ICC who were treated with HF-RT from 2008-18. 51 patients had intrahepatic disease only, and 15 patients had extrahepatic disease at time of RT but received RT for biliary control. Median age at RT was 76 years (range: 30-92), including 27 patients (41%) ≥ 80 years. Median RT dose was 58.05 Gy (range: 37.5-67.5), delivered in 15 daily fractions. 32 patients received proton RT, and 34 patients received photon RT. Rates of local control (LC), progression-free survival (PFS), and overall survival (OS) were calculated by the Kaplan-Meier method. Univariate and multivariate analyses were conducted using the Cox proportional hazards method. For multivariate analyses, variables with p < 0.5 on univariate analysis were evaluated by backwards selection. Results: Median follow-up times from diagnosis and RT start were 21 and 14 months, respectively. In total, 5 patients (7.6%) developed local failure. Only 1 patient developed isolated local failure. The 2-yr outcomes were 93% LC, 37% PFS, and 55% OS. Among the 51 patients treated with definitive intent, the 2-yr LC was 96%, PFS 35%, OS 60%. Receipt of protons was significantly associated with younger age (p = 0.02), but not gender, race, ECOG status, metastatic disease at presentation, mean liver dose, cumulative GTV, or number of lesions. There were no significant predictors of LC or PFS, including RT dose. On UVA for OS, younger age, female gender, prior chemotherapy, prior surgery, and proton RT were associated with improved OS (p < 0.05). On MVA, female gender (HR: 0.33, p = 0.001), prior chemotherapy (HR: 0.38, p = 0.002), and proton vs. photon RT (HR: 0.50, p = 0.05) remained significantly associated with OS. Conclusions: HF-RT yields high rates of local control and is an effective modality to optimize biliary control for unresectable/locally recurrent IC. HF-RT should be considered for elderly patients who are considered medically inoperable. Proton RT and chemotherapy may further improve outcomes.
Pathologic outcomes of systemic therapy followed by stereotactic body radiation therapy (SBRT) for pancreatic cancer (PC) in a novel lateral decubitus treatment position.
Authors: Song Ethan , Frakes Jessica , Latifi Kujtim , Malafa Mokenge Peter , Hodul Pamela Joy , Pimiento Jose Mario , Kim Dae Won , Kim Richard D. , Hoffe Sarah E.
Published: January 2019

415

Background: Outcomes of multi-fraction stereotactic body radiotherapy (SBRT) for PC report low rates of toxicity and high local control, improving feasibility for combination with more aggressive systemic therapy regimens. However, SBRT in the ablative range poses risk to adjacent normal structures, excluding this option for tumors within 1 cm of a mucosal organ. In this study, we report our initial experience with treatment in the lateral decubitus position. Methods: An IRB retrospective query identified patients with pancreatic body adenocarcinoma treated with systemic chemotherapy followed by SBRT in the lateral decubitis position. SBRT was delivered to the entire gross disease with 30 Gy in 5 fractions with focal dose escalation up to 40 Gy to the tumor/vessel interface (TVI) as long as constraints were met. Patients were explored for resection if no metastasis or progression on restaging scans. The primary endpoints were pathologic response and margin status. Descriptive analysis was performed with SPSS 24. Results: The median age of the cohort was 68.6 (range, 50-83 yrs), with a white (94%) and male (59%) predominance. Initial staging of the 17 patients who met criteria included 10 (59%) patients diagnosed with borderline resectable disease (BRPC) and 7 (41%) with locally advanced disease (LAPC). 7 (41%) patients were treated with FOLFIRINOX, 5 (29%) with gemcitabine/nab-paclitaxel, 4 (24%) with gemcitabine/capecitabine/docetaxel, and 1 (6%) with gemcitabine/paclitaxel preceding SBRT. A median dose of 40 Gy (range, 33-40 Gy) was delivered to the TVI for all patients. 5 BRCP (29%) and 2 LAPC (12%) patients went to surgery, with 6 of these patients undergoing an R0 resection (86%) and 1 BRPC patient with an R1 resection. Pathologic tumor regression grades by the College of American Pathologists guidelines were 14% Grade 1, 71% Grade 2, and 14% Grade 3. Conclusions: Lateral decubitus treatment expands inclusion of pancreatic body patients for SBRT with focal TVI dose escalation leading to margin negative resection and significant partial tumor response, warranting future studies exploring ablative dosing in this position.
Prognostic factors associated with long term survival in chemotherapy-treated advanced pancreatic cancer: A Canadian multicenter analysis.
Authors: Kim Christina , Ahmed Shahid , Armstrong Dawn Elizabeth , Baig Tayyba , Cardoso Miguel , Ko Yoo-Joung , Kong Shiying , Mackinnon Madison , Meyers Brandon Matthew , Pratt Michelle , Ward Julie , Xu Yuan , Cheung Winson Y.
Published: January 2019

416

Background: The outcomes of patients (pts) with advanced pancreatic cancer (APC) are poor. With the use of currently available multi-agent regimens, median overall survival (mOS) remains < 12 months. Select pts, however, experience a protracted survival. Little is known about the clinical, pathologic and treatment characteristics associated with long term survival (LTS) in APC. Methods: Pooled individual level data from six Canadian cancer centers of pts diagnosed with APC from 2012 to 2016 who received at least one cycle of chemotherapy (CT) were analyzed. Clinical, pathologic and treatment characteristics, as well as survival, were compared between pts who lived < and ≥ 18 months. Multivariable logistic regression was used to identify independent predictors of survival. Results: Of 455 pts, 96% had metastatic disease and 88 (19%) survived ≥ 18 months. Compared to pts who survived < 18 months, those with LTS had lower WBC (p = 0.0025), CA 19-9 (p < 0.001), ALP (p < 0.001) and LDH (p = 0.007) at baseline. Pts with LTS also had higher albumin (p < 0.001) and BMI (p = 0.0268). In addition, they had better ECOG (p < 0.001) and were more likely to have tumors in the head of the pancreas (p = 0.0204). LTS pts were more likely to have a complete response (CR) or partial response (PR) to 1L CT (p < 0.001). The mOS seen with LTS was 29.2 months, compared to 4.3 months (p < 0.001). On multivariable logistic regression, independent predictors of LTS included: primary tumor in the head of the pancreas (OR 3.42 95% CI 1.2-9.76); experiencing a CR or PR to 1L CT (OR 9.19 95% CI 3.78-22.32); and receipt of 2L doublet CT (OR 2.72 95% CI 1.05 to 7.08). Conversely, factors associated with lower likelihood of LTS included: ECOG ≥ 2 (OR 0.32 95% CI 0.11-0.95); and elevated CA 19-9 (OR 0.43 95% CI 0.21-0.9). Conclusions: A select proportion of pts with APC experience LTS and have clinical features which differentiate them from those without LTS. The use of performance status, primary tumor location, pre-treatment CA 19-9, 2L CT type and radiologic response may help identify LTS and inform discussions regarding treatment and prognosis.
Impact of hospital volume and type on survival in hepatocellular carcinoma: Results from the National Cancer Database.
Authors: Uhlig Johannes , Sellers Cortlandt , Khan Sajid A. , Cha Charles , Kevin Kim Hyun S.
Published: January 2019

417

Background: To assess the impact of hospital volume and type on survival in patients with hepatocellular carcinoma (HCC). Methods: Patients with histopathological or imaging-based diagnosis of HCC were identified from the 2003-2015 National Cancer Database (NCDB). First-line treatment was stratified as liver transplant, surgical resection, interventional oncology (IO) and chemotherapy. Hospital volume was stratified as high (ranking among top 10% in case numbers) and low volume, separately for each treatment modality. Hospital type was categorized as academic and non-academic. Overall survival was assessed using multivariable Cox proportional hazards models. Results: A total of 63,877 patients were included (transplant n = 10,596, surgical resection n = 11,132, IO n = 12,286, chemotherapy n = 29,863). Of 1,261 hospitals systems which treated HCC, 226 (17.9%) were academic centers and 1,035 (82.1 %) were non-academic centers. Mean number of cases treated annually was higher in academic centers (55.2; 34.6; 40.7; 79.9) versus non-academic centers (10.7; 6.25; 6.6; 11.9 for transplant; surgical resection; IO and chemotherapy; p < 0.001, respectively). Young African American patients and those with private insurance, high income and education were more likely to receive treatment at academic centers. Geographical difference were evident among US regions, with highest proportion of HCC treated at academic centers in New England states (83.6%) and lowest in South Atlantic states (48.6%). Overall survival was superior for academic versus non-academic centers (HR = 0.89, 95% CI: 0.87-0.91, p < 0.001) and high versus low volume centers (HR = 0.79, 95% CI: 0.77-0.81, p < 0.001), after multivariable adjustment for potential confounders. These effects were evident among all HCC treatment modalities. Conclusions: HCC treatment in academic centers shows distinct patterns according to patient demographics and US geography. Among all treatment modalities, both academic setting and hospital volume independently affected HCC outcomes, with highest patient survival observed in high-volume academic centers.
The impact of histology (adenocarcinoma vs. SCC) on outcomes in nonmetastatic pancreatic cancer.
Authors: Gruhl Joshua , Francis Samual Roberts , Tao Randa , Solomon Benjamin Lev , Nevala-Plagemann Christopher Duane , Garrido-Laguna Ignacio , Lloyd Shane
Published: January 2019

419

Background: Outcomes in squamous cell carcinoma (SCC) of the pancreas are generally thought to be poor compared with adenocarcinoma; however, this has not been sufficiently demonstrated in prior studies. This is the first NCDB analysis of the prognostic role of SCC histology in non-metastatic pancreatic cancer. Methods: We analyzed patients with non-metastatic pancreatic cancer using the National Cancer Database (NCDB) diagnosed from 2006-2014. Patients were analyzed according to histology—only adenocarcinoma, adenosquamous carcinoma, or SCC were selected for. The primary endpoint was overall survival (OS) from the time of diagnosis. Kaplan-Meier and Cox proportional hazard modeling were used to analyze OS. Results: A total of 94,928 patients were included; 94,016 in the adenocarcinoma group, 757 in the adenosquamous group, and 155 in the SCC group. There was a statistically significant decrease in median OS for patients with SCC (MS = 8.67 months, 95% CI: 7.23–9.92 months), compared to patients with adenosquamous carcinoma (MS = 12.7 months, 95% CI: 11.9–13.7 months) and adenocarcinoma (MS = 14.0 months, 95% CI: 13.86–14.06 months, p < .001). On multivariate Cox regression, both adenocarcinoma and adenosquamous carcinoma were associated with a longer OS compared with SCC (for adenocarcinoma, HR 0.45, 95% CI: 0.31–0.66, p < .001; for adenosquamous carcinoma, HR 0.60, 95% CI: 0.39–0.92, p = 0.02). On subgroup analysis, this OS improvement for adenocarcinoma histology was seen for patients with resectable/borderline resectable disease (HR 0.50, 95% CI: 0.32–0.79, p =.003) and for those with unresectable disease (HR 0.39, 95% CI: 0.19–0.77, p = 0.01). Conclusions: In patients with non-metastatic pancreatic cancer, there was a statistically significant detriment in OS for those with SCC histology compared with adenosquamous carcinoma or adenocarcinoma histology. On subgroup analysis, this difference persisted for those with resectable/borderline resectable disease and for those with unresectable disease. [Table: see text]
Evaluation of disease-specific and functional symptom items on carcinoid tumor patients treated with telotristat ethyl.
Authors: Hudgens Stacie , Lapuerta Pablo , Floden Lysbeth
Published: January 2019

427

Background: Within the pivotal, phase III TELESTAR trial, telotristat ethyl significantly reduced bowel movement (BM) frequency compared to placebo ( P < 0.001) (NCT01677910). Assessing patient-related outcomes can help understand the impact of changes in BM frequency on patient lives. An analysis was done to determine whether individual items on patient-reported outcome measures show relevant patterns over the course of treatment for patients with carcinoid syndrome (CS). Methods: The TELESTAR study was a phase III, double-blind, parallel-group, randomized, placebo-controlled study comparing placebo (PBO) to telotristat ethyl (TE) in 135 patients with Carcinoid Syndrome (CS). Clinical quality of life (QoL) measurements included the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and European Organisation for Research and Treatment of Cancer (EORTC) GI.NET21 scales. Analyses on identified individual gastrointestinal (GI) symptom and role function items were conducted using longitudinal generalized estimation equations (GEE; reference=PBO) to characterize the likelihood of a 1-grade categorical improvement (e.g., improvement by one category on the verbal response scale). Forest plots of odds ratios (OR) and associated confidence intervals (CI) on individual items are presented. Results: At week 12, the likelihood of patients experiencing a 1-grade improvement on most GI symptoms were equivalent (OR approx. 1.0). The highest odds ratios observed with TE were for improvement in diarrhea (OR=1.86, CI=0.848-4.090) and a reduction in weight bother (OR=2.95, CI=0.713-12.199), in parallel to TELESTAR results for bowel movement frequency reduction and weight gain. Interference with daily activities (IADL) and limitations in doing work demonstrated similar outcomes (IADL OR=1.63, CI=0.617,4.288; Work OR=1.97, CI=0.722,5.376). Conclusions: The overall pattern of item level change on telotristat suggested clinical relevance for bowel movement frequency reduction and weight gain, and it was consistent with symptomatic and functional benefit in CS. Clinical trial information: NCT01677910.
Stereotactic body radiation therapy for hepatocellular carcinoma with macrovascular invasion.
Authors: Munoz-Schuffenegger Pablo , Barry Aisling S , Atenafu Eshetu G. , Kim John , Brierley James D. , Ringash Jolie , Brade Anthony M. , Dinniwell Robert Edward , Wong Rebecca , Cho Charles , Sapisochin Gonzalo , Dawson Laura A.
Published: January 2019

428

Background: In patients with hepatocellular carcinoma (HCC), macrovascular invasion (MVI) is associated with a poor prognosis. This study describes long-term outcomes of patients with HCC and MVI treated with stereotactic body radiation therapy (SBRT). Methods: Patients with HCC and MVI who were treated with SBRT from January 2003 to December 2016 were eligible for analysis. Patients who had extrahepatic disease or who had prior liver transplant were excluded. Demographical, clinical, and treatment variables were collected, under IRB approval. The degree of vascular invasion was quantified into two categories: main portal vein branch/IVC and distal portal/hepatic vein. Results: 128 eligible pts with HCC and MVI were treated with SBRT ( > 4.5 Gy/fraction). The median age was 61 yrs (range: 39 to 90 yrs). Underlying liver disease was hepatitis B in 23%, hepatitis C in 45%, other in 20%; no known liver disease in 12%. Baseline Child-Pugh (CP) score was A5 in 67%, A6 in 20%, B7 or higher in 13%. 35% received previous liver-directed therapies. Median HCC volume was 153.7 mL (range: 3.9 to 1,813.5 mL). Median AFP was 205 ug/L (range: 1 to 171,154 ug/L). Median SBRT dose was 33.3 Gy (range: 27 to 54 Gy) in 6 fractions. Local control at 1 year was 87.4% (95% CI 78.6 to 96.1%). SBRT dose or HCC volume were not significant on univariate analysis. Median overall survival was 18.3 months (95% CI 11.2 to 21.4 months). ECOG PS > 1 (HR:1.73, p = 0.03), CP score (HR: 1.67, p = 0.04), and treatment between 2004 and 2010 (HR: 2.28, p = 0.0009) were significant on multivariable analysis, while SBRT dose, HCC volume, and degree of vascular invasion were not. In 35 patients who received sorafenib following SBRT, median survival was 38.5 months (95% CI 17.23 to 43.16 months). 4/128 pts. developed GI bleeding and 35/112 patients with liver function evaluable at baseline and 3 months had a deterioration in CP class. Conclusions: SBRT was associated with excellent outcomes for patients with HCC and MVI. Randomized phase III trials of SBRT are warranted and ongoing.
DNA methylation signature predictive of benefit from neoadjuvant chemotherapy in esophageal adenocarcinoma: Results from the MRC OEO2 phase III trial.
Authors: Sundar Raghav , Ng Alvin , Zouridis Hermioni , Sheng Taotao , Zhang Shenli , Lee Ming Hui , Padmanabhan Nisha , Ooi Wen Fong , Qamra Aditi , Nankivell Matthew Guy , Langley Ruth E. , Allum William H. , Cunningham David , Grabsch Heike I , Tan Patrick
Published: January 2019

43

Background: Platinum and 5-Fluorouracil (5FU) neoadjuvant chemotherapy followed by surgery is one of the standard approaches for patients with resectable EAC. To date, there are no predictive biomarkers of chemotherapy benefit. We hypothesize that DNA methylation of genes in key biologic and oncogenic pathways predict for chemotherapy benefit in EAC. Methods: In the OE02 trial, 802 patients with resectable esophageal carcinoma were randomised to surgery alone (S) versus two cycles of cisplatin and 5FU chemotherapy followed by surgery (CS). DNA was extracted from 213 EAC resection specimens (110 from the (CS) arm, 103 from the (S) arm). DNA methylation was analyzed at 1505 CpG sites within 807 genes using the Illumina GoldenGate platform. Cox proportional hazard analysis was performed to identify predictive markers of survival in (CS) arm; non-negative matrix factorization (NMF) was used to delineate methylation signatures. Results: Methylation status of 1505 CpG sites had no statistical difference between the (CS) and (S) arms. In the (CS) arm, 87 (5.7%) CpG sites were initially identified as promising candidates in univariate analysis (p < 0.05 cutoff). NMF generated a 4 CpG site signature which divided patients into poor risk and good risk. Genes involved in the signature include RUNX1T1, CCND2, MST1R and MMP14. Survival was significantly different between poor risk and good risk in (CS) arm (HR 0.32, 95% CI: 0.21 to 0.52, p < 0.0001). No difference in survival was detected in the surgery arm (HR 1.12, 95% CI: 0.76 to 1.80, p = 0.48), suggesting the signature served as a predictive and not prognostic biomarker. Methylation signature remained an independent predictor of survival in multivariate analysis with clinicopathologic factors (along with age and vascular invasion). Conclusions: Chemotherapy does not appear to change methylation status of EAC. Hypermethylation of RUNX1T1, CCND2 and hypomethylation of MST1R and MMP14 leads to significantly decreased benefit from chemotherapy in EA. We describe an epigenetic signature which may serve as a predictive biomarker for chemotherapy benefit using data form the largest bank of DNA methylation in EA reported to date.
A retrospective study of hepatic arterial infusion (HAI) FUDR/Dex and mitomycin C (MMC) for chemotherapy refractory unresectable intrahepatic cholangiocarcinomas (ICC).
Authors: Fernandes Gustavo Dos Santos , Kemeny Nancy E. , Hauser Haley , Harding James J. , Boerner Thomas , Varghese Anna M. , Kingham Peter , D'Angelica Michael Ian , DeMatteo Ronald P. , Drebin Jeffrey A. , Balachandran Vinod P. , Jarnagin William R. , Cercek Andrea
Published: January 2019

432

Background: ICC are aggressive tumors with approximately 6,000 cases a year in US. The 5-year survival rate is less than 30% even for localized disease. There is only one approved line of systemic (SYS) treatment and further treatment options are necessary. HAI chemotherapy is an option to treat liver predominant cancers. Methods: After obtaining IRB approval, we retrospectively reviewed patients (pts) with ICC chemo refractory unresectable liver limited (LL) or liver dominant (LD) disease who received intrahepatic chemotherapy with HAI MMC. Baseline characteristics, previous lines of therapy, toxicity profile, combinations and radiographic responses were reviewed. Tumor genomic analyses were performed on samples using an on-site next generation sequencing (NGS) assay. Results: Between January 2011 and October 2018, 19 patients ICC with LL or LD disease were treated with HAI FUDR/Dex/MMC at Memorial Sloan Kettering Cancer Center. Disease was confined to the liver in 58% of the pts. All pts had previous chemotherapy (1-4 lines) and 14 (74%) previously had HAI FUDR/Dex. Of the 19 pts, 56% had HAI with FUDR/Dex and MMC, 43% had FUDR/Dex, MCC and SYS and 5% had HAI MMC and SYS. Seventeen patients were evaluable for response, two are being treated and will have response assessment for the meeting. Response was noted in 4 (23.5%), stable disease in 6 (35.5%) and progressive disease in 7 (41%) pts. Median overall survival from treatment was 6.1months (0.36-26). Median progression free survival was 3.65 months (0.36-9.53). Four patients had dose reductions. Common toxicity attributed to MMC was grade (G) one fatigue (32%), thrombocytopenia G1(16%) and G2 (5%). Of the 12 tumors analyzed to date the most 92% of tumors harbored at least one (0-10) genomic alteration. Common genomic alterations were ARID1 (25%), RASA1 (25%), IDH1(16.6%), NTRK (16.6%), TERT (16.6%), NRAS (16.6%), CDKN2 (16. 6%). FGFR2-FOXP1 and GTL2MEt fusions were found in one patient each. Conclusions: HAI FUDR/Dex/MMC containing regimens are active in pts with heavily pretreated refractory unresectable ICC. This strategy should be further investigated. Translational data will be presented.
Clinical outcomes of hepatocellular carcinoma variants compared to hepatocellular carcinoma.
Authors: Zakka Katerina Mary , Jiang Renjian , Alese Olatunji B. , Shaib Walid Labib , Wu Christina , Wedd Joel , Sellers Marty T. , Behera Madhusmita , El-Rayes Bassel F. , Akce Mehmet
Published: January 2019

435

Background: There is no consensus regarding treatment for HCC variants. Clinical outcomes of HCC variants differ from pure HCC. The aim of this study is to compare clinicopathological characteristics, treatment, and outcomes of HCC variants with pure HCC. Methods: Patients with HCC and variants with 8170/3-8175/3 and 8180/3 ICD-O-3 codes were identified from National Cancer Database between 2004 and 2013. Univariate and multivariate survival analyses were conducted to analyze the association between histology and overall survival (OS). Results: 80,280 patients were identified; pure HCC 78,461 (97.7%), fibrolamellar (FLHCC) 310 (0.4%), scirrhous 161 (0.2%), spindle cell 72 (0.1%), clear cell 487 (0.6%), pleomorphic 23 (0.0%), and combined HCC and cholangiocarcinoma (mixed HCC) 766 (1.0%). 76.7% were male and 72% Caucasian. The mean age was similar in all except FLHCC (37.9 vs. 60.9-64.1 years, p < 0.001). Liver transplant was performed in 10.1% of pure HCC, 14.5% of mixed HCC, 16.2% of scirrhous, 6.9% of spindle cell, 8.8% of clear cell, 8.7% of pleomorphic, and 3.2% of FLHCC (p < 0.001). Pure HCC (10.57%) underwent surgical resection less often than variants; FLHCC (54.8%), clear cell (34.5%), mixed HCC (29.8%), spindle cell (33.3%), pleomorphic (34.8%), and scirrhous (9.9%) (p < 0.001). Ablation was performed in 9.8% of pure HCC, and in up to 8.7% of HCC variants. More than a third of all patients received chemotherapy; pure HCC (42.3%), mixed HCC (38.5%), scirrhous (31.1%), spindle cell (36.1%), clear cell (35.5%), pleomorphic (34.8%), and FLHCC (41.3%). FLHCC had the best 5-year OS (38.7%), spindle cell and pleomorphic had the worst (9.6% and 13.0%). In univariate and multivariate analyses, fibrolamellar histology, female sex, diagnosis between 2009 and 2013, treatment at academic center, well/moderately differentiated histology, early stage, and chemotherapy was associated with better OS compared to pure HCC, male sex, diagnosis between 2004 and 2008, treatment at community cancer program, poorly differentiated, late stage, and no chemotherapy (p < 0.001). Conclusions: HCC variants underwent surgical resection more often than HCC. FLHCC had the best 5-year OS. Liver transplant is commonly performed in HCC variants.
Neoadjuvant therapy duration and outcome of patients with resectable and borderline resectable pancreatic ductal adenocarcinoma (PDAC).
Authors: Shahda Safi , Perkins Susan , Cramer Harvey M , House Michael Garrett , Nakeeb Attila , Zyromski Nicholas J , Ceppa Eugene P , Sehdev Amikar , Akisik Fatih , Lin Jingmei , Schmidt Christian , Ellsworth Susannah G. , O'Neil Nina , Link Kristen , O'Neil Bert
Published: January 2019

436

Background: Neoadjuvant chemotherapy (NA CT) may improve surgical selection for resectable (R) PDAC, and margin negative resection in borderline resectable (BR) PDAC. Optimal duration of NA CT is unknown, as is the role of XRT with modern chemotherapy. We compared survival outcomes by duration of NA CT and NA CT + XRT. Methods: Patients with R or BR PDAC who underwent NA CT with or without XRT and followed by curative resection were included in this analysis. Data was extracted from an IRB approved pancreatic cancer database at Indiana University. Disease Free (DFS) and Overall (OS) survival were calculated from the surgery date and compared between: 1) < 3 v ≥ 3 months NA CT and 2) NA CT with/without XRT. Results: Between Summer 2008 and Summer 2018, 116 patients received NA CT with or without XRT and completed surgical resection. Median (range) age was 63 years (36, 84), stages were R=47%, BR=53%. Most patients received modified FOLFIRINOX or FOLFIRINOX (59 %), or gemcitabine/nab-paclitaxel (13%) and 24% received XRT. There were four (3 %) pathologic complete responders, all in the ≥ 3 mo NA CT + XRT group. Percent node positive was lower in NA CT + XRT versus NA CT only (median 0% vs 7.4%, p < 001), but did not differ by duration of NA CT. With a median (range) follow-up time of 13.7 mo (0.7, 83.0), median OS was 22.5 mo (19.5, 29.8) with < 3 mo NA CT versus 16.3 (12.2, 18.9) with ≥ 3 mo NA CT (p = 0.02) and was 22.6 mo (17.0, 82.9) with NA CT + XRT versus 19.5 (13.1, 22.5) in NA CT only (p = 0.03). There was no difference in DFS by duration of NA CT or XRT. Conclusions: In this study, patients who received a shorter course of chemotherapy and radiation had improved mOS when calculated from the surgery date. While this unexpected results could reflect selection bias of therapy, further analysis will account for tumor stage at diagnosis, perioperative complications and use propensity score adjustment to examine/adjust for possible treatment selection bias.
MSI-low is an intermediate type between MSI-high and MSS in esophagogastric junction adenocarcinoma.
Authors: Imamura Yu , Toihata Tasuku , Takamatsu Manabu , Tanaka Norio , Mine Shinji , Mori Seiichi , Oki Eiji , Morita Masaru , Baba Hideo , Sano Takeshi , Watanabe Masayuki
Published: January 2019

44

Background: High level of microsatellite instability (MSI-high) is an actionable molecular status in oncology, informing tumor response to immune checkpoint inhibitor. However, little is known about MSI-low. The aim of this study is to unveil the characteristics of MSI-low tumor in esophagogastric junction (EGJ) adenocarcinoma. Methods: Using 372 cases with chemo-naive EGJ adenocarcinoma tissue, MSI testing and Epstein Barr Virus (EBV)-DNA detection were performed by DNA fragment analysis (BAT25, BAT26, BAT40, D2S123, D5S346, and D17S250) and real-time PCR, respectively. MSI-high was defined as having two or more unstable markers, MSI-low as one, and microsatellite stable (MSS) as none. MSI status was compared with clinicopathological and molecular status including epigenetic alteration in MLH-1, LINE-1, and CpG methylator phenotype (CIMP), TP53 status (sequencing and immunohistological expression), Ki-67 index, intra-/peri-tumoral lymphocyte counts (CD8+ or FOXP3+), combined positive score (CPS) of PD-L1 expression. Results: MSI-low was detected in 29, MSI-high in 28, and EBV (+) in 9 cases. Three cases with MSI-low showed EBV (+), but MSI-high and EBV (+) were mutually exclusive. In 363 EBV (-) cases, MSI-low was associated with younger age (MSI-high 71.7 ± 11.3, MSI-low 61.3 ± 12.5, and MSS, 65.0 ± 12.3 years old, P = 0.003). Notably, MSI-low exhibited an intermediate type between MSI-high and MSS, in terms of no. of lymph node metastasis, and tumor immune microenvironment [no. of intra-/peri-tumoral CD8+ cells, no. of intra-/peri-tumoral FOXP3+ cells, and CPS of PD-L1 (all P among the 3 groups < 0.05)]. In contrast to MSI-high tumors, MSI-low tumor was not associated with epigenetic alteration in any of MLH-1, LINE-1, or CIMP status. In survival analysis, 3-year disease-specific survival rate of MSI-low was better than that of MSS tumors, and similar to MSI-high (92.2% for MSI-low, 92.2% for MSI-high, and 69.6% for MSI-low). This trend was also observed in time to recurrence (P = 0.01). Conclusions: MSI-low cases exhibited an intermediate immune microenvironment between MSI-high and MSS, and favorable outcome. Our results may implicate MSI-low as a predictive biomarker for immune checkpoint inhibitor.
Comparison of radiation treatment volumes for borderline resectable pancreatic cancer.
Authors: Bluemel Trevor Scott , Kharofa Jordan
Published: January 2019

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Background: Optimal radiation target volumes for downstaging and local control in patients with borderline resectable pancreatic cancer (BRPCa) are undefined. Most local recurrences are near the celiac axis (CA) and superior mesenteric artery (SMA), as demonstrated by pattern of failure mapping (Dholakia et al IJROBP 2013). Methods for generating target volumes include symmetric margins around the tumor or a customized approach. We investigated three current prospective trials’ coverage of vascular regions at risk of recurrence. Methods: CT simulation scans of 14 patients with BRPCa from an institutional prospective trial were used to create treatment volumes for comparison. Treatment volumes from three current prospective trials (PREOPANC, Alliance A021101, and Alliance A021501) were generated for each patient based upon their respective protocols. The trials’ volumes were compared to two reference volumes created for coverage evaluation. A customized vasculature (CustVasc) CTV was based on the CA, SMA, and vessels abutting the tumor. The Hopkins PTV reference volume was based upon the proximal 1 cm of the CA and 3 cm of the SMA, and expanded according to the study’s protocol. Boolean operators located regions the three prospective trials would not provide treatment when compared to reference volumes. Results: Table outlines the target volumes and the proportion of the CustVascPTV and Hopkins PTV covered by each trial definition. Conclusions: Symmetric expansion from the primary tumor to generate target volumes may not adequately cover the mesenteric vasculature which is at high risk of local recurrence and varies based on patient/tumor anatomy. An approach utilizing a customized target volume that specifically includes the SMA and CA will improve coverage to this region at high risk of local recurrence.[Table: see text]
Neutrophil-to-lymphocyte ratio as a prognostic marker in patients with metastatic gallbladder cancer.
Authors: Mady Mohamed , Prasai Kritika , Yadav Siddhartha , Hassan Mohamed Abdelrahim Muddathir , Roberts Lewis R. , Borad Mitesh J. , Mahipal Amit
Published: January 2019

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Background: Neutrophil to lymphocyte ratio (NLR) has been used as an inflammation-based prognostic marker for various malignancies. The aim of our study was to determine whether NLR can independently predict the overall survival in patients with metastatic gallbladder cancer (GBC). Methods: We identified patients diagnosed with GBC who were treated at Mayo Clinic between the years 2000 and 2016. Patients who had nonmetastatic GBC were excluded along with the patients who did not have data for neutrophils and lymphocytes. Optimal cutoff point for NLR was identified by plotting martingale residuals against NLR and patients were divided into two groups, ≥ 5 or < 5. Demographic, follow-up data and outcomes were collected by retrospective review of electronic medical records. Fisher’s exact test was used to compare categorical variables, while The Mann- Whitney U test was used to compare continuous variables. Kaplan-Meier curves were plotted for NLR ≥ 5 and NLR < 5 and overall survival (OS) between the two groups were compared using log rank test. Multivariate survival analysis was performed using Cox-proportional hazard regression. Results: A total of 231 patients met our inclusion criteria, of which, 138 (60%) had NLR < 5 and 93 (40%) had NLR ≥ 5. Patients with NLR ≥ 5 were more likely to be older and have poor performance score, lower albumin level, higher alkaline phosphatase level, and higher platelet count. There were no significant differences noted in gender, race and administration of chemotherapy between the two groups. In univariate analysis, patients with NLR ≥ 5 at presentation had a significantly worse OS compared to those with NLR < 5 (Median survival: 3.6 vs. 8.8 months, p < 0.001). In multivariate analysis, adjusting for age, ECOG status, albumin, ALP, AST, ALT, bilirubin, platelet count and administration of chemotherapy, NLR of ≥ 5 was associated with a worse OS compared to NLR < 5 (HR: 1.70, 95% CI:1.20 – 2.39. p < 0.05). Conclusions: Our study demonstrates that NLR ≥ 5 is an independent predictor of poor prognosis in patients with metastatic gallbladder cancer.
Combination therapy with TACE + ablation versus TACE + SBRT for hepatocellular carcinoma (HCC): Comparative analysis with propensity score-weighted cohorts.
Authors: Nabavizadeh Nima , Jahangiri Younes , Rahmani Ramtin , Degnin Catherine , Chen Yiyi , Geeratikun Yindee , Hung Arthur , Thomas Charles R. , Kolbeck Kenneth , Schenning Ryan , Kaufman John , Farsad Khashayar
Published: January 2019

443

Background: To assess the relative efficacy and toxicity associated with TACE+Ablation (Ablation) or TACE+SBRT (SBRT) in a large cohort of patients with unresectable HCC. Methods: Patients with HCC undergoing Ablation or SBRT from 2006-2016 with available follow up were included. Treatment groups were different at baseline regarding tumor stage (BCLC A, B and C: 96%, 4%, 0% (Ablation) vs. 73%, 14% and 13% (SBRT), P < 0.001) and severity of liver disease (CTP A, B, and C: 55%, 45% and 0% (Ablation) vs. 50%, 41%, and 9% (SBRT), P = 0.007). Propensity scores were calculated with age, sex, BCLC stage, CTP class, etiology of liver disease, tumor number, and diameter to balance the cohorts. Average treatment effects on survival with multivariable propensity score-weighted competing risk Cox regression models were evaluated, with BCLC stage, number of treated tumors and liver transplant as additionally controlled variables. Primary outcome was overall survival (OS). Secondary outcomes were progression-free survival (PFS), local tumor control and hepatotoxicity. Treatment-related hepatotoxicity was defined as a two point change in CTP within six months after treatment. Results: 192 subjects were included (101 Ablation, 91 SBRT; median age=60 years, 75% men). Liver disease included HCV (78%), alcohol (35%) and NASH (8%). Liver transplant-adjusted 1- and 2-year OS rates were significantly greater for Ablation vs SBRT (88% vs. 75% and 77% vs. 50%, P<0.001). 1-and 2-year PFS rates were significantly greater for Ablation vs. SBRT (84% vs. 65% and 75% vs. 51%, P < 0.001). 1- and 2- year local tumor control rates were similar with both strategies (99% vs. 91% and 94% vs. 87%, P=0.298). Propensity score-weighted multivariable analysis showed significantly higher OS (sHR: 2.31, P = 0.006) and PFS rates (sHR:1.75, P = 0.008) with Ablation compared to SBRT. Ablation was also associated with lower post-treatment hepatotoxicity compared with SBRT (5% vs. 12%, P = 0.001). Conclusions: TACE+Ablation demonstrated higher OS/PFS and lower post-treatment hepatotoxicity compared with TACE+SBRT. Local disease control up to two years was equivocal, potentially suggesting equipoise for bridge to transplant.
Impact of an inter-professional clinic on pancreatic cancer outcomes: The Princess Margaret Cancer Centre (PM) experience.
Authors: Albaba Hamzeh , Dodd Anna , Prince Rebecca M. , Aung Kyaw Lwin , Hedley David W. , Gallinger Steven , Kim John , Brierley James D. , Moura Shari , Moignard Stephanie , Fraser Adriana , Hutchinson Shawn , Espin-Garcia Osvaldo , Moulton Carolanne , Wei Alice Chia-chi , Greig Paul David , McGilvray Ian M , Dhani Neesha C. , Elimova Elena , Knox Jennifer J.
Published: January 2019

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Background: Patients with pancreatic ductal adenocarcinoma (PDAC) have limited treatment options. Management of complex symptoms and psychosocial implications requires an interprofessional approach as prognosis is often measured in months. A multidisciplinary approach has been associated with improvement in clinical outcomes including survival. We aimed to evaluate the impact of an inter-professional approach for PDAC patients at the Wallace McCain Centre for Pancreatic Cancer (WMCPC) at PM on their management and clinical outcomes. Methods: We undertook retrospective review of all patients with PDAC seen at PM two years before (July ‘12 – June ‘14) and two years after (July ‘14 – June ‘16) establishment of the WMCPC. Standard therapies (surgical approach, chemotherapy, radiation therapy) were the same during both time periods. Comparison of overall survival (OS), stage at diagnosis, surgical outcomes, waiting times, and proportion seen by social worker, dietician and clinical nurse specialist (CNS) was explored with descriptive statistic and survival analysis. Results: A total of 993 patients were reviewed; 482 patients pre- and 511 patients post-WMCPC. Age (median 67 yrs), sex (54% men) and stage III/IV (52%) were similar in both groups. There was a trend to improved OS in the post-WMCPC group (9.6 vs. 10.9 m; p = 0.055); multivariable analysis found a significant improvement in OS after adjustment for performance status and stage (p = 0.023; HR 0.84, 95% CI 0.72-0.98). Rate of R0 versus R1/R2 resection for curative surgery (n = 264, 28%) was similar in both groups. Time from referral to first clinic visit significantly decreased from 13.4 to 8.8 days in the post-WMCPC group (p < 0.001) as did time from first clinic appointment to diagnostic biopsy (25.9 vs. 16.9 days, p = 0.022). Patients in the post-WMCPC were more frequently seen by a social worker, dietician or CNS (8% vs. 38%, 9% vs. 35% and 31% vs. 50% respectively, p < 0.001). Conclusions: Establishment of an interprofessional clinic for the treatment of PDAC patients at PM has streamlined diagnosis, aided symptom management and improved overall survival. This has implications for planning care delivery models and proves the value of this intervention.
Rare subtypes of pancreatic cancer: Clinical outcomes and implications for clinical trial enrollment.
Authors: David John , Tuli Richard , Nissen Nicholas , Gong Jun , Gangi Alexandra , Placencio-Hickok Veronica , Gresham Gillian , Hendifar Andrew Eugene
Published: January 2019

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Background: Pancreatic cancer subtypes such as adenosquamous (AS) and squamous cell carcinoma (SCC) are rare and poorly understood. Treatment recommendations are extrapolated from pancreatic adenocarcinoma (AC) and these patients are often included in AC clinical trials. Herein, we describe clinical outcomes and inclusion of these subtypes in AC clinical trials. Methods: The National Cancer Database (NCDB) was queried to identify patients with AC, AS, and SCC between 2004 and 2014. Overall survival was evaluated using Kaplan-Meier methodology and multivariable (MVA) cox regression models were fit to identify differences in survival outcomes between subtypes adjusted by baseline demographic and clinical variables. ClinicalTrials.gov was interrogated to identify inclusion of AS and/or SCC in contemporary PA clinical trials. Results: We identified 115,061 patients with pancreatic cancer. Median age was 69 (range 18 – 90) and median follow up was 54 months (95% CI 53 – 55). Age, sex, median income, education, comorbidities, race, and stage were significantly associated with overall survival (OS). OS by subtype compared to AC: AS HR of 0.98 (p = 0.59) and SCC HR 1.29 (p < 0.001). OS by subtype and stage compared to AC: stage I/II, AS HR of 0.98 (p = 0.59), SCC HR 1.44 (p = 0.001); stage III, AS HR of 1.32 (p = 0.02) and SCC HR 1.48 (p = 0.01); stage IV, AS HR of 1.1 (p = 0.06), SCC HR 1.2 (p = 0.06). Data from 283 phase II or III interventional trials completed between 2008-2018 were exported from clinicaltrials.gov. The majority of trials listed did not specify inclusion or exclusion of AS or SCC subtypes. Conclusions: This is the largest report of clinical outcomes in rare subtypes of pancreatic cancer. SCC and to a lesser extent, AS, have worse OS compared to AC. It is unclear how rare pancreatic cancer subtypes are handled in the inclusion and analysis of clinical trial data and how this may impact enrollment and survival outcomes.[Table: see text]
Small bowel adenocarcinoma: A single center experience.
Authors: Hannan Lindsay Marie , Harris William Proctor , Shankaran Veena , Coveler Andrew L. , Pritchard Colin , Zhen David Bing , Cohen Stacey , Konnick Eric Quentin , Chiorean E. Gabriela , Wong Kit Man
Published: January 2019

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Background: Small bowel adenocarcinoma (SBA) represents only 2% of GI malignancies. There is limited data to guide clinical decisions, largely extrapolated from colorectal cancers (CRC). We evaluated treatment strategies and outcomes in patients (pts) with early and advanced SBA. Methods: We identified 56 pts with SBA diagnosed between 1/2005 - 1/2018 and treated at our institution. Demographics, pathological features, treatments, and molecular data were abstracted via medical record review. Data was analyzed with SAS statistical software. Results: Median age was 61, 54% male, site: duodenum (D 37.5%), duodenal ampula (A 17.9%), jejunum (J 19.6%), ileum (I 12.5 %), unknown (12.5%). Predisposing conditions were: IBD (6), Lynch (2), and Peutz-Jeghers syndromes (1). Stage (stg) at diagnosis was I (5%), II (20%), III (34%) and IV (41%). Primary tumor resection occurred in 33 pts: 21 received adjuvant chemotherapy, mostly FOLFOX; 17 developed metastatic disease. Treatment for metastatic SBA (n = 40) included 5FU-based chemotherapy without or with anti-VEGF (n = 18), or anti-EGFR therapies (n = 9). Median lines of therapy was 2 (range 1-7). For pts with stg I-III SBA, median DFS/OS was 21/38 mos. For stg IV pts, OS was 19.8 mos; 18/35/8/14 mos for D, A, J and I, respectively. Molecular biomarkers with targeted (28) or next generation sequencing (10) were available for 28 metastatic SBA pts: KRAS MUT (8), TP53 MUT (5), ERBB2 MUT (2), MSI-H (2), ERBB2, CCNE1 amplification (1 each), and NRAS, BRAF, CDKN2A, ERBB3, ATM, PIK3CA MUT (1 each). OS was 20 vs 19 mos for pts with KRAS WT vs MUT stg IV SBA, respectively. Among 16 pts with KRAS WT SBA, OS for those treated (9) or not (7) with anti-EGFR antibodies was 25 mos vs 21 mos. One pt with KRAS WT, ERBB2 amplification/ERBB2 V777L activating mutation is alive 5yrs+ from stg IV diagnosis on anti-EGFR plus chemotherapy (best response was 4 mos SD with trastuzumab/pertuzumab). Conclusions: This retrospective study demonstrates heterogeneity among SBA, overall inferior outcomes compared to CRC pts, and emphasizes genomic alterations which could be exploited therapeutically. Randomized studies for KRAS WT SBA pts should test the benefit from anti-EGFR targeted therapies in this rare tumor type.
Genomic profile of gastric cancer in the United States versus East Asia.
Authors: Gilmore Gregory A. , Barakat Mohamad , Chaudhary Uzair Bashir , Gregg Jeffrey P. , Fathi Amir
Published: January 2019

45

Background: Gastric cancer is the fourth most common cancer type and is the third leading cause of cancer deaths worldwide. Much heterogenicity exists in gastric cancer including geographic variation, with significantly higher incidence in Eastern Asia and a well-known but poorly understood relationship with Asian ethnicity. It has thus been hypothesized that differences in incidence and survival between United States and Asia may be related to a difference in the underlying tumor biology. Methods: We sought to compare the mutational frequencies by comparison of proportions of the 25 most frequent mutations between a US and Chinese population. The US population was derived from The Cancer Genome Atlas (TCGA) PanCancer Atlas comprising 440 patients and the Chinese from a University of Hong Kong Study comprising 100 patients. Results: We found there was a statistically significant difference (P ≤ 0.05) in the frequency of recurrent mutations between US and China population in 14 of the 25 most common genes mutations (table). Conclusions: This data suggests an underlying difference in the mutational profile of gastric cancers in the US as compared with Asia. These findings thus may help to describe the differences in incidence, histology, and outcomes that has been well described in the literature between these two regions of the world. [Table: see text]