bluuebunny/crossref_metadata_2025 huggingface dataset:
Thermal safety and effectiveness of tumor treating fields’ delivery to the abdomen as determined by computational simulations.
Authors: Weinberg Uri , Bomzon Zeev , Naveh Ariel , Yesharim Ofir , Farber Ori , Kirson Eilon
Published: January 2019

272

Background: Tumor Treating Fields (TTFields), an antimitotic cancer treatment, utilizes low intensity (1-3 V/cm), intermediate frequency (100-300 kHz), alternating electric fields delivered non-invasively by transducer arrays placed on skin over tumor region. Safety of TTFields has been established in pancreatic cancer (Phase II study; PANOVA; NCT01971281). A Phase 3 study in locally-advanced pancreatic cancer (PANOVA-3) and a phase 2 study in hepatocellular cancer are ongoing. Preclinical studies suggest that TTFields’ intensity correlates with treatment efficacy. Simulations can determine the thermal safety of TTFields by evaluating tissue heating due to field absorption and resultant risk of thermal damage. We used computational simulations to study the effectiveness of field distribution and associated heating in realistic phantoms during TTFields delivery to the abdomen. Methods: Delivery of TTFields to computational phantoms of a male (DUKE 3.0), a female (ELLA 3.0) and an obese male (FATS 3.0) was simulated. For each phantom, 6-8 different transducer array layouts to the abdomen were tested. Specific Absorption Rate (SAR) levels were calculated to assess the risk of thermal damage to tissues, and compared to the SAR control level of 10 W/kg per International Commission on Non-Ionizing Radiation Protection (ICNIRP) guidelines for occupational exposure (Health Physics 74 (4) 494; 1998). The field intensities were measured to determine the effectiveness of treatment delivery. Results: Altering the size and position of the arrays facilitates field intensities above the therapeutic threshold of 1 V/cm. Within the abdominal internal organs, the SAR values were generally below the ICNIRP recommended level of 10 W/kg. The maximum SAR levels did not exceed 20 W/kg. Conclusions: TTFields could be delivered at intensities above therapeutic threshold of 1 V/cm by strategizing the array size and placement. TTFields to the abdomen can be delivered to target gastrointestinal cancers without causing thermal damage to abdominal tissues. These results also indicate that TTFields delivery can be optimized in gastrointestinal cancers.
Patient reported abdominal pain as a surrogate of the clinical benefit of tipifarnib in pancreatic cancer patients.
Authors: Gualberto Antonio , Scholz Catherine Rose , Van Cutsem Eric
Published: January 2019

275

Background: Tumor CXCL12 expression identifies patients who may benefit from tipifarnib therapy. In pancreatic cancer, CXCL12 is known to decrease abdominal pain by inducing the migration of pain suppressing Schwann cells to tumor lesions. Given the association between CXCL12 and pain suppression, we investigated whether the absence of patient reported abdominal pain could be a surrogate of clinical benefit from tipifarnib in pancreatic cancer patients. Methods: We conducted a retrospective analysis of a randomized placebo-controlled trial comparing gemcitabine plus tipifarnib (GT) versus gemcitabine plus placebo (GP) in pancreatic adenocarcinoma patients. Tipifarnib was given at 200 mg bid orally continuously; gemcitabine at standard dosing. Primary study end point was overall survival. Results: 688 patients were enrolled of whom 155 (22.5%) reported no abdominal pain at study entry, 81 received GT and 74 GP. Baseline characteristics were balanced in the subset of patients with no reported abdominal pain (GT,GP): median age (63,59), female gender (35%,43%), ECOG 0-1 (89%,90%), metastatic disease (64%,70%), 6-month weight loss >10% (48%,39%), 6-month jaundice history (51%,45%), and prior Whipple surgery (16%,13%). Subjects receiving GT who did not report abdominal pain at study entry had higher frequency of locally advanced disease (36% vs 24%) and 6-month jaundice (51% vs 38%), and lower frequency of lung (6% vs 14%) and peritoneum (4% vs 13%) metastases than those reporting pain. No differences in survival were observed in the overall study. Median overall survival for GT was 193 vs 182 days for GP. Notably, absence of abdominal pain at study entry was associated with higher median survival in the GT arm (no pain, pain): 305 vs 176 days, HR=0.52, p<0.0001, whereas no significant effect was observed in the control arm: 184 vs 182 days. A trend for better survival with GT was observed in subset of patients with no abdominal pain at study entry (GT,GP): 305 vs 184 days, p=0.058. Conclusions: Absence of abdominal pain may serve as a surrogate of clinical benefit from tipifarnib in pancreatic cancer. (Van Cutsem et al. JCO 2004;22:1430-8; NCT00005648; Trial Sponsor: J&J PRD). Clinical trial information: NCT00005648.
The impact of CDKN2A mutations on overall survival in pancreatic adenocarcinoma.
Authors: Doyle Allison , Kubler Manfred M , Harris Ashton C , López Alfredo , Govindaraj Prateek , Prins Petra , Weinberg Benjamin Adam
Published: January 2019

278

Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a five-year survival rate of only 9%. Analyses based on tumor DNA mutations indicate the presence of specific molecular subtypes of PDAC. Tumor genomic profiling could result in better treatment selection and improved overall survival. We performed a single institution analysis of PDAC mutations and correlated them with clinical outcomes. Methods: PDAC samples from patients (pts) seen at the Lombardi Comprehensive Cancer Center between 2014 and 2018 were profiled using next generation sequencing including 592 whole-gene targets (Caris Life Sciences). Relevant clinical data was mined retrospectively and correlated with genomic data. Pt outcomes were correlated with the presence of mutations in KRAS, MSH2, MSH6, MLH1, PMS2, TP53, SMAD4, CDKN2A, BRCA1, and BRCA2. Results: Our cohort (N = 100) included 50% men and 50% women, 59% were Caucasian and 21% African-American. Thirty-two percent had stage II, 14% had stage III, and 38% had stage IV disease. Seventy-seven percent developed metastatic disease. Genetic mutations were found in KRAS 87% (N = 82), TP53 76% (N = 82), SMAD4 37% (N = 49), CDKN2A 29% (N = 66), and BRCA2 21% (N = 81). Sixty percent of pts with KRAS mutations also had TP53 mutations. Almost all pts with mutated SMAD4, CDKN2A, or BRCA2 also had mutated KRAS (89%, 84%, and 80%). Median overall survival (OS) for all pts from time of diagnosis was 31 months (m). Stratification of OS based on single gene mutations did not significantly impact OS except for CDKN2A. Patients with CDKN2A mutations had significantly reduced OS compared to wild type (22 m vs. 35 m; P = 0.018). OS based on presence of co-occurring mutations only showed a negative OS impact when CDKN2A mutations were present (14 m vs. 35 m; P = 0.021). Conclusions: Our data demonstrate that the presence of CDKN2A mutations is an independent negative prognostic OS indicator for patients with PDAC. This finding highlights the need to select PDAC pts for potential targeted therapies, including those that target the cell cycle pathway (e.g. cyclin-dependent kinase inhibitors).
A multi-institutional study assessing prevalence of deleterious germline mutations in pancreatic cancer.
Authors: Sadaps Meena , Funchain Pauline , Heald Brandie , Huether Robert , Pitt Jason , White Kevin , Khorana Alok A. , Sohal Davendra
Published: January 2019

280

Background: Pancreatic cancer is being increasingly associated with germline implications. Some large single-center studies have reported results ranging from 3.9% to 19.8% of patients found to have germline variants [Shindo, JCO 2017; Lowery, JNCI 2018]. Due to this wide range, we aim to further delineate prevalence of deleterious germline mutations in pancreatic cancer using a multi-institutional data set. We also aim to analyze predictive factors such as mutant allele frequency (MAF, in %) in germline versus somatic calls. Methods: We sequenced 23 genes in DNA prepared from clinical tissue and blood specimens submitted to Tempus Labs. Germline variants and somatic variants were processed separately. Germline variants were determined to be deleterious through the sum effect of a combination of in silico predictors, population databases, and internal evaluations. Tumor-normal comparisons were used to define somatic versus germline, and MAFs were calculated for each. Results: A total of 234 patient samples from 17 institutions were analyzed. Of these, 12 (5.1%) had predicted deleterious germline variants involving 8 different genes: BRCA1 (n = 3), CHEK2 (n = 3), ATM (n = 1), MLH1 (n = 1), MUTYH (n = 1), PALB2 (n = 1), SMAD4 (n = 1), TP53 (n = 1). For most somatic alterations, the MAFs were found to be greater than the germline deleterious alterations, with the latter approaching ~50% in most cases (Table). Conclusions: This multi-institutional study identifies 5% of patients with pancreatic cancer to have deleterious germline alterations. Somatic variant testing, particularly when paired with germline, can be used as a screening method for genetic counseling referrals, especially with MAF analyses of paired tumor-normal samples. [Table: see text]
Pilot study of plasma KRAS as a prognostic biomarker in localized pancreas ductal adenocarcinoma (PDAC).
Authors: Krantz Benjamin A. , Gedvilaite Erika , Chou Joanne F. , Capanu Marinela , You Daoqi , Yu Kenneth H. , Varghese Anna M. , Iacobuzio-Donahue Christine A , Kelsen David Paul , Tsui Dana , O'Reilly Eileen Mary
Published: January 2019

294

Background: Validated predictive and prognostic biomarkers are needed in PDAC. Such biomarkers could predict response and resistance early in treatment. As 95% of PDAC harbor KRAS mutations (mKRAS), plasma mKRAS has utility as a biomarker. We explored the prognostic value of mKRAS in a PDAC cohort at Memorial Sloan Kettering. Methods: 10 mL of whole blood was collected at diagnosis of localized PDAC and early interval CT scan (approx. 8 weeks). DNA was extracted with QIAamp DNA kits (Qiagen, Valencia, CA). Single locus, if tissue KRAS known, or multiplex (G12A, G12C, G12D, G12R, G12S, G12V, G13D) digital droplet PCR (ddPCR) was performed with QX200 (BioRad, Hercules, CA) ddPCR system. Disease status was determined by radiographic, CA19-9 and clinical evaluation. Results: N = 18 enrolled (median age: 65 [range 34-85]). Median time between baseline (B) and interval (I) blood was 2.53 months (range 0.9-6). One had locally recurrent disease, 2 AJCC stage IIa, 1 IIb and 14 III. Three had tissue KRAS G12D mutation, 6 G12V and 9 unknown. Eight had gemcitabine-based treatment, 10 5-FU-based and 5 radiation. See table. mKRAS and CA19-9 at B were not associated with progression free survival (PFS) or overall survival (OS). mKRAS detection at I was associated with shorter PFS/OS (P < 0.01), but CA19-9 was not. mKRAS change from B to I was also associated with PFS/OS. For every 1 copy/mL increase in the change of mKRAS from B to I, the risk of death or progression/death increased by nearly 2 fold after controlling for baseline value (p = 0.01 for OS, p = 0.03 for PFS). Four patients, all undetectable mKRAS at I, went to surgery; 2/4 resected. Conclusions: In this pilot, 59% of localized PDAC patients had detectable mKRAS at B. mKRAS detection at I and change from B to I were associated with PFS/OS supporting that mKRAS early in treatment may be a useful prognostic and predictive marker in localized PDAC. We have initiated a large prospective trial to evaluate the predictive and prognostic potential of plasma mKRAS in advanced PDAC. [Table: see text]
Phase I study of nivolumab (Nivo) + nab-paclitaxel (nab-P) + gemcitabine (Gem) in advanced pancreatic cancer (APC).
Authors: Wainberg Zev A. , Hochster Howard S. , Kim Edward Jae-Hoon , George Ben , Kalyan Aparna , Chiorean E. Gabriela , Waterhouse David Michael , Gutierrez Martin , Parikh Aparna Raj , Jain Rishi , Carrizosa Daniel R. , Soliman Hatem Hussein , Bhore Rafia , Banerjee Sibabrata , Lyons Larry , Louis Chrystal Ursula , Ong Teng Jin , O'Dwyer Peter J.
Published: January 2019

298

Background: Chemotherapy may work synergistically with immune checkpoint inhibitors by increasing tumor antigen exposure. This 2-part phase I study assessed safety and efficacy of Nivo + nab-P + Gem in APC. Methods: Treatment-naive patients (pts) with APC (locally advanced or metastatic) received nab-P 125 mg/m2 + Gem 1000 mg/m2 on d 1, 8, and 15 + Nivo 3 mg/kg on d 1 and 15 of each 28-d cycle until disease progression (PD), unacceptable toxicity, or withdrawal. Pts could continue Nivo alone beyond initial PD. Part 1 assessed dose-limiting toxicities (DLTs) and determined the recommended Part 2 dose; Part 2 (expansion phase) further assessed safety. The primary endpoints were DLTs (Part 1) and safety and tolerability (Parts 1 and 2). Key secondary endpoints were response rates, progression-free survival (PFS), and overall survival (OS). Results: As of July 13, 2018, 50 pts with APC were treated: 6 in Part 1; 44 in Part 2. The median age was 67.5 years; 56% were male; 62% had an ECOG PS 1. Of 40 pts with available data, 12 (24%) had ≥ 1% and 6 (12%) had ≥ 5% PD-L1 expression at baseline (data missing for 10 pts). The median follow-up was 11.3 mo. In Part 1, 1 DLT (hepatitis, as evidenced by grade 3 elevated liver function tests; suspected to be related to nab-P + Gem) was reported. In Parts 1 and 2, 48 pts (96%) had ≥ 1 grade 3/4 TEAE; 7 (14%) discontinued treatment due to a TEAE. Most common (> 10%) grade 3/4 TEAEs of special interest were anemia (36%), neutropenia (36%), gastrointestinal events (24%), hepatic toxicity (22%), peripheral neuropathy (16%), thrombocytopenia (12%), and colitis (12%). One grade 5 TEAE, respiratory failure (most likely pneumonitis), was reported. The table shows treatment responses. Of 7 pts (14%) who continued Nivo beyond initial PD, 4 achieved disease control. The median PFS was 5.5 mo (6-mo PFS rate, 47%). The median OS was 9.9 mo (6-mo OS rate, 73%). Conclusions: Combining Nivo with nab-P + Gem is feasible in pts with APC: 1 DLT was reported, and no unexpected safety signals were detected. Clinical trial information: NCT02309177. [Table: see text]
Biliary tract cancers and the associated risk of venous thromboembolism.
Authors: Khanuja Jasleen , Bahrami Tabar Samira , Tsao-Wei Denice , Piatek Caroline Irene , Barzi Afsaneh
Published: January 2019

304

Background: Venous thromboembolism (VTE) is a common cause of morbidity and mortality in cancer patients. Because biliary tract cancers (BTC) cholangiocarcinoma and gallbladder (GB) cancer are uncommon, the incidence of VTE in this population are not well-described. Methods: We conducted a retrospective study of patients with BTC identified by the cancer registry at the Los Angeles County-University of Southern California (USC) Medical Center, USC Norris Cancer Center, and USC Keck Hospital between January 2011 to December 2016 to describe the incidence of VTE. 330 BTC patients’ medical records were reviewed for demographics, tumor characteristics, treatment history, and VTE events. 41 patients were excluded due to incomplete records/follow-up. Overall survival (OS) was calculated from date of diagnosis to date of death or last follow-up. Logrank test was used to evaluate the association of VTE with OS. Results: 289 patients with BTC were identified (177 cholangiocarcinoma, 112 GB) with a median follow-up period of 16.7 (0.3-89.0) months (mo). 169 (58%) were women. The median age at diagnosis of 66 years (range 22-89). 144 (59%) underwent cancer surgery and 274 (95%) received chemotherapy. 65 (22%) patients had VTE events: 22 pulmonary embolism [PE] with or without lower extremity (LE) deep vein thrombosis [DVT], 15 with LE DVT alone, three with upper extremity DVT, and 30 with visceral thrombosis (27 portal vein thrombosis [PVT] with or without inferior vena cava thrombosis [IVC], 2 IVC thrombosis, two hepatic vein thrombosis). Five patients had both DVT/PE and visceral thrombosis. The median time from cancer diagnosis to VTE event was not met. Patients with a PVT or any visceral thrombosis had an inferior OS compared to those without (PVT: median OS 16.2 mo [95% CI 12.2-25.8] versus 7.5 [3.4-14.2], p = 0.10, visceral thrombosis: 17.0 mo [95% CI 11.8-25.9] versus 8.4 [95% CI 3.7-14.3], p = 0.30). There was a non-significant trend towards inferior OS in patients with any VTE event type (median OS 17.0 mo [95% CI 11.8-39.0] versus 11.4 [95% CI 7.2-18.4], p = 0.10). There was no difference in OS for patients with PE/DVT compared to those without. Conclusions: VTE is commonly observed in patients with BTC. Visceral thrombosis is associated with inferior survival in patients with BTC.
A phase I study of mesothelin-targeted immunotoxin LMB-100 in combination with nab-paclitaxel for patients with previously treated advanced pancreatic cancer.
Authors: Alewine Christine Campo , Hassan Raffit , Ahmad M. Iqra , Trepel Jane B , Peer Cody , Figg William Douglas , Pastan Ira
Published: January 2019

307

Background: LMB-100 is a Pseudomonas exotoxin A-based immunotoxin that targets mesothelin (MSLN). MSLN is expressed by >75% of pancreatic adenocarcinomas (PDAC). LMB-100 kills MSLN-expressing cells by irreversibly modifying elongation factor-2 to halt protein synthesis. Phase I studies of LMB-100 defined the maximum tolerated dose (MTD) of 140 mcg/kg IV given on D1, 3 and 5 of a 21-day cycle. Development of anti-drug antibodies (ADAs) limited patient drug exposure beyond cycle 2. Our pre-clinical data showed that combination of LMB-100 with a taxane resulted in synergistic anti-tumor activity. Methods: We conducted a phase I single center study (standard 3+3 design) to determine the MTD of LMB-100 given with nab-paclitaxel in patients with previously treated advanced PDAC. LMB-100 was given on D1, 3 and 5 of a 21-day cycle, and nab-paclitaxel (125 mg/m2) on D1 and D8. Initial patients could receive a maximum of 4 cycles, but subsequently a 2-cycle maximum was employed. Results: Fourteen patients (median age 58) were enrolled. Two of 6 patients experienced DLTs at the 100 mcg/kg dose of LMB-100 (myalgia- 2 pts, fatigue- 1 pt, hypotension- 1 pt; all grade 3). One of 8 patients had DLT at the 65 mcg/kg dose (edema, urine output decrease- both grade 3). Other toxicities related to LMB-100 included hypoalbuminemia, edema-associated weight gain, hyponatremia, fatigue, drug fever, infusion-related reaction, hypophosphatemia, nausea and anorexia. One patient died on treatment from complications of bowel perforation attributed to cancer. All patients achieved detectable serum levels of LMB-100 during the first cycle, even those with pre-existing ADAs, and 5 of 8 did so during cycle 2. One patient receiving the 65 mcg/kg dose had a confirmed partial response, and CA 19-9 dropped by > 50% in 5 of 8 evaluable patients. Conclusions: MTD of LMB-100 is 65 mcg/kg given with nab-paclitaxel on this schedule. Anti-tumor activity was observed. A phase II cohort is currently being accrued. Clinical trial information: NCT02810418.
Adjuvant gemcitabine versus 5-fluorouracil/folinic acid based on hENT1 immunostaining in curative resected pancreatic adenocarcinoma: A biomaker stratified trial.
Authors: Shin Dong Woo , Kim Min Jae , Yang Se Yeol , Lee Jong-chan , Hwang Jin-Hyeok
Published: January 2019

308

Background: The human equilibrating nucleoside transporter (hENT1) protein transports gemcitabine into the cell. However, role of hENT1 as a predictive biomarker for gemcitabine responsiveness in pancreatic adenocarcinoma (PDA) is still needed to be elucidated, although several studies had been conducted. We investigated whether hENT1 has a predictable role on adjuvant chemotherapy responsiveness in PDA according to stratification of hENT1 immunostaining. Methods: The 44 patients who underwent curative surgery (R0 or R1) due to PDA at Seoul National University Bundang Hospital from May 2015 to June 2017 were enrolled prospectively. The hENT1 expressions were measured by immunochemical staining (SP120-rabbit monoclonal antibody, Ventana). According to hENT1 immunostaing (≥ 50% vs. < 50%), higher hENT1 group received gemcitabine [1,000mg/m2 (day 1, 8, 15) q 4 weeks x 6 cycles] and lower hENT1 group received [5-FU 425mg/m2 (day 1-5) plus folinic acid 20 mg/m2 (day 1) q 4 weeks x 6 cycles]. Primary outcome was overall survival (OS) and secondary outcomes were toxicity and recurrence free survival (RFS). Results: Among 44 patients, 5 patients were excluded due to withdrew consent (3 patients) and toxicities (2 patients in 5FU/LV group). Eighteen patients in the higher hENT1 group and twenty-six patients in the lower hENT1 group were followed up for 24.1 months. Our data showed OS was 97.4% at 12 months and 86.4% at 24 months. Moreover, RFS was 76.8% at 12 months and 64.2% at 24 months. Although it is preliminary data, it showed better OS and RFS compared to previous study (Neoptolemos JP et al., JAMA 2010) (OS, 61.3% at 12 months, 30.7% at 24 months; RFS, 58.7% at 12 months and 30.1% at 24 months). Conclusions: Adjuvant chemotherapy based on hENT1 immunostaining stratification provides excellent survival in resected PDA. Therefore, hENT1 immunostaining should be used for making a decision for adjuvant chemotherapy remimen in PDA. Clinical trial information: NCT02486497.
Neoadjuvant chemotherapy versus upfront resection in ampullary adenocarcinoma stratified by stage: A retrospective analysis using the National Cancer Database.
Authors: Leonard-Murali Shravan , Shah Rupen A. , Ivanics Tommy , Han Xiaoxia , Steffes Christopher P. , Kwon David S.
Published: January 2019

318

Background: Outcomes of a neoadjuvant therapy (NAT) strategy to treat ampullary adenocarcinoma (AAC) are unclear. Upfront resection (UR) (typically pancreaticoduodenectomy) with or without adjuvant therapy (AT) is currently the standard of care. We looked to assess outcomes of NAT followed by radical surgery for AAC. Methods: The NCDB was queried for ampullary carcinoma patients from 2004-2015. Patients with Stage I to III AAC who underwent radical surgery were included, and separated into NAT with surgery and UR groups. Demographic/clinical/pathologic data and their associations to survival were analyzed with univariate and multivariate cox proportional hazard models. Overall survival was estimated from time of diagnosis using Kaplan-Meier curves and compared using log-rank tests (LRT) (see table). Statistical analyses were performed using R version 3.5.1 with significance established at p < 0.05. Results: There was no difference in overall survival between the NAT (n = 47) and UR (n = 1521) groups, either as total groups (LRT p = 0.2), or when stratified by stage (stratified LRT p = 0.5). Rates of AT were higher in the UR group (p = 0.038). Receiving AT was significantly associated with improved survival (hazard ratio (HR) = 0.648), while positive nodal status (HR = 2.06), stage 3 disease (HR = 1.542), age > 65 (HR = 1.494), and male gender (HR = 1.241) were significantly associated with decreased overall survival by multivariate analysis. Conclusions: NAT does not offer a survival advantage over UR either overall or for stage-specific disease. This finding extended even to stage III disease, where NAT would theoretically offer greatest benefit. This study suggests that a NAT strategy is not preferable to UR for treatment of resectable AAC, regardless of stage. Higher powered study of NAT for AAC with controls for AT is warranted before discarding a NAT strategy. [Table: see text]
Multicenter retrospective analysis for efficacy and safety of liposomal irinotecan (nal-IRI) plus 5-FU/leucovorin (5-FU/LV) after progression on gemcitabine-based therapy in Korean patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDAC): A study by Korean Cancer Study Group (KCSG).
Authors: Yoo Changhoon , Im Hyeon-Su , Kim Kyu-Pyo , Oh Do-Youn , Lee Kyung-Hun , Chon Hong Jae , Kim Joo Hoon , Kang Myoung Joo , Kim Il-Hwan , Lee Guk Jin , Oh Sung Yong , Choi Younak , Choi Hye Jin , Kim Seung Tae , Park Joon Oh , Ryoo Baek-Yeol
Published: January 2019

344

Background: Nal-IRI plus 5-FU/LV has demonstrated efficacy in mPDAC pts who previously received gemcitabine-based therapy in the pivotal NAPOLI-1 trial. Real-world data are helpful to measure the clinical outcomes and safety profile of this regimen in daily practice setting. Methods: Between January 2017 and April 2018, a Named Patient Program (NPP) was activated to provide controlled, pre-approval access of nal-IRI in Korea. This analysis is multicenter retrospective study for patients who received nal-IRI plus 5-FU/LV under the NPP. Results: A total of 86 patients entered into this NPP among 10 Korean institutions. Median age was 61 years (range, 37-79) and 52 pts (60%) were male. Liver (n=49, 57%), peritoneum (30, 35%), and lung (27, n=31%) were the most common metastatic sites. All patients had ECOG performance status 0-1 and previously received gemcitabine-based therapy. Prior to nal-IRI plus 5-FU/LV, 35 (41%) and 51 (59%) patients received <2 and ≥ 2 lines of chemotherapy for unresectable/metastatic disease, respectively. Best response was complete response (n=2, 2%), partial response (7, 8%), stable disease (38, 44%), and progressive disease (32, 37%), indicating overall response rates of 10% and disease control rate of 55%. With median follow-up duration of 6.4 months, median progression-free survival (PFS) was 3.5 months (95% CI, 1.3-5.7) and median overall survival (OS) was not yet reached. The 6-month PFS and OS rates were 37.5% and 65.1%, respectively. Most common grade 3-4 toxicities were neutropenia (n=32, 37%), nausea (9, 10%), vomiting (8, 9%), anemia (7, 8%), and diarrhea (4, 5%). Febrile neutropenia occurred in 7 patients (8%). Conclusions: Nal-IRI plus 5-FU/LV was well tolerated and effective for mPDAC patients who progressed on gemcitabine-based therapy. Despite heavily pretreated patients were included, efficacy and safety outcomes in our cohort were consistent with the results of previous NAPOLI-1 trial.
Adjuvant therapy is associated with improved survival in pT1N1 gastric cancer in a heterogeneous western patient population.
Authors: Porembka Matthew R. , Hester Caitlin , Augustine Mathew M , Mansour John C. , Polanco Patricio , Yopp Adam Charles , Zeh Herbert , Wang Sam C.
Published: January 2019

36

Background: Two recent South Korean studies showed adjuvant therapy (AT) was not associated with improved survival in pT1N1 gastric adenocarcinoma (GAC). We aimed to establish the prognostic utility of lymph node status, determine the pattern of use of AT, and compare survival stratified by type of AT in pT1N1 GAC in a Western patient population. Methods: We identified patients with pT1N0 and pT1N1 GAC using the National Cancer Database from 2004 to 2012. Clinicopathologic variables, treatment regimens, and overall survival (OS) were compared. Results: We compared 4,516 (86.6%) pT1N0 to 696 (13.4%) pT1N1 patients. pT1N1 tumors were larger (median size 2.5 vs. 1.8 cm, p < 0.001), more often poorly differentiated (56.2% vs. 39.6%, p < 0.001), and had higher median retrieved lymph nodes (RLN) (14 vs. 12, p < 0.001) compared to pT1N0. pT1N1 was associated with worse median OS (6.9 years vs. 9.9 years for pT1N0, p < 0.001). pN1 was independently associated with worse OS (HR 2.17 95% CI 1.84-2.56). Increased RLN was associated with improved OS (HR 0.73, 95% CI 0.65-0.83). Among pT1N1 patients, 330 (47.4%) had observation (OBS), 77 (11.1%) received adjuvant chemotherapy (ACT), 68 (9.8%) received adjuvant radiation therapy (ART), and 221 (31.8%) received adjuvant chemoradiation therapy (ACRT). ACT and ACRT were independently associated with improved OS (HR 0.37, 95% CI 0.22-0.65 and HR 0.40, 95% CI 0.28-0.57). Conclusions: pN1 was associated with worse survival and RLN ≥ 15 was associated with improved survival in pT1 GAC. ACT and ACRT were independently associated with improved survival in pT1N1 gastric cancer suggesting a valuable role in Western patients.
The effect of lymphocyte-to-monocyte ratio on efficacy of sorafenib for recurrent hepatocellular carcinoma after curative resection.
Authors: Yokoo Hideki , Kamiyama Toshiya , Sugiyama Ko , Orimo Tatsuya , Shimada Shingo , Nagatsu Akihisa , Kamachi Hirofumi , Taketomi Akinobu
Published: January 2019

367

Background: Sorafenib, an oral multikinase inhibitor, is approved for advanced hepatocellular carcinoma (HCC) treatment. Predictive biomarkers of sorafenib are needed due to its frequent adverse effect. Lymphocyte to monocyte ratio (LMR) has been reported as a prognostic or predictive biomarker of chemotherapy in cancer. However, clinical significance of LMR are unclear as predictive biomarker of sorafenib. To investigate the efficacy prediction value of LMR in patients who received sorafenib for recurrent HCC after curative resection. Methods: Clinicopathological data of 59 patients who received sorafenib for recurrent HCC after surgical treatment between 2009 and 2017 were retrospectively analyzed. Sorafenib was administered at a dose of 400mg or 800mg. Survival outcomes were estimated using the Kaplan-Meier method and compared by the log-rank test. Univariate and multivariate analyses were performed to evaluate the predictive impact of LMR and other clinicopathological factors for efficacy of sorafenib on overall survival (OS) and progression free survival (PFS). Results: The optimal cutoff value of LMR for response evaluation was 3.1, which resulted in the most appropriate sensitivity of 60.5% and specificity of 71.4%, with the area under the curve (AUC) of 0.641 (95% C.I.: 0.515-0.806). All patients were divided into either a low ( < 3.1) LMR (LLMR) group (n = 27), or a high ( > 3.1) LMR (HLMR) group (n = 32). Patients with HLMR group had significantly increased OS (MST: 20.0M vs 8.0M, P = 0.001) and PFS (MST: 10.2M vs 5.1M, P < 0.001) compared to those with a LLMR group. Multivariate analyses indicated that a HLMR was a significantly independent predictor of superior OS (P = 0.006) and PFS (P < 0.001). Conclusions: LMR in pre-administration of sorafenib was demonstrated to serve as an independent efficacy prediction factor of sorafenib in recurrent HCC patients after curative resection.
Phase Ib study of WNT inhibitor ipafricept (IPA) with nab-paclitaxel (Nab-P) and gemcitabine (G) in patients (pts) with previously untreated stage IV pancreatic cancer (mPC).
Authors: Dotan Efrat , Cardin Dana Backlund , Lenz Heinz-Josef , Messersmith Wells A. , O'Neil Bert , Cohen Steven J. , Denlinger Crystal S. , Shahda Safi , Kapoun Ann M. , Brachmann Rainer Karl , Uttamsingh Shailaja , Weekes Colin D.
Published: January 2019

369

Background: The first-in-class recombinant fusion protein IPA blocks WNT signaling by binding WNT ligands, and in combination with Nab-P/G caused tumor regression in pt-derived PC xenografts. This open-label Phase 1b dose escalation study evaluated the combination of IPA with Nab-P/G in untreated mPC pts using a standard 3+3 design. Methods: Dose escalation in cohort 1 started with Nab-P 125 mg/m2 and G 1000 mg/m2 given on days 1, 8 ,15, with IV IPA (3.5 mg/kg) on days 1 and 15, in 28-day cycles. Due to fragility fractures seen in other studies with similar targeted agents, cohorts 2-4 were 6-pt cohorts treated with weekly Nab-P/G + IPA 3 mg/kg (cohort 2) or 5 mg/kg (cohorts 3 and 4) on day 1. These cohorts included strict bone marker monitoring and use of bisphosphonates as indicated. Based on pre-clinical data suggesting improved efficacy with sequential dosing, pts in Cohort 4 received IPA on day 1 followed by weekly chemotherapy starting on day 3 of 28-day cycles. Objectives included safety, maximum tolerated dose, recommended phase 2 dose, pharmacokinetics, immunogenicity, pharmacodynamics, and preliminary efficacy. Results: Twenty-six pts in four dose escalation cohorts were enrolled, five in the cohort one and seven each in cohorts 2-4. Median age was 61.7 years and a majority were male (73%). Reported IPA-related AEs of any grade occurring in ≥ 20% of pts included fatigue, nausea, vomiting, anorexia and pyrexia. IPA-related AEs grade ≥ 3 included 2 events of AST elevation, and 1 each of nausea, maculopapular rash, vomiting and WBC decrease. No dose limiting toxicities or fragility fractures were observed. Of 26 evaluable pts, 9 (34.6%) had a partial response and 12 (46.2%) stable disease, with clinical benefit rate of 80.8%. The study was closed due to termination of the program by the sponsor. At time of data cut off, median progression free survival was 5.9 months (95% CI 3.4-18.4), median overall survival was 9.7 months (95% CI: 7.0-14). One pt remains on therapy under compassionate use with ongoing response. Conclusions: IPA can be safely administered with Nab-P and G in pts with mPC. Additional studies targeting the WNT pathway in pancreatic cancer are warranted. Clinical trial information: NCT02050178.
Prospective trial of functional liver image-guided hepatic therapy (FLIGHT) with hepatobiliary iminodiacetic acid (HIDA) scans and update of institutional experience.
Authors: Long David Emmert , Huang Colin , Tann Mark , Dawson Benjamin , Bartlett Gregory , Maluccio Mary A. , Rhome Ryan , Kong Feng-Ming Spring , Ellsworth Susannah G.
Published: January 2019

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Background: Functional liver image-guided hepatic therapy (FLIGHT) is a novel stereotactic body radiation therapy (SBRT) planning technique. A functional map, generated from hepatobiliary iminodiacetic acid (HIDA) scans, is used to maximize the functional residual capacity of liver receiving < 15 Gy (FRC15HIDA). We present initial results of a prospective trial evaluating FLIGHT vs standard planning and update our institutional experience. Methods: Eligible patients were ≥ 18 yo with 1o or 2o liver malignancy and Child-Pugh ≤ B7. Liver function was assessed with HIDA and blood chemistry at baseline, mid-treatment, and 3, 6, and 12 months post SBRT. Both standard and FLIGHT (optimized to avoid high functioning liver) plans were generated for each patient. Treating MDs were blinded to planning technique before selecting the treatment plan. The primary endpoint was to show > 5% increase in FRC15HIDA in 3/15 pts. Secondary endpoints included the rate FLIGHT plans were selected and changes in HIDA and other liver function tests. Prior institutional experience included 27 pts with FLIGHT planned retrospectively. Paired t-test was used to compare dosimetric endpoints for FLIGHT vs. standard plans, including: FRC15HIDA, mean liver dose, effective uniform dose (EUD), and functional EUD (FEUD). Results: Fifteen pts were enrolled. The primary endpoint was met, as 4/15 pts had > 5% improvement in FRC15HIDA (mean 5.2%, range -2.3-19.8%). Notably, the FLIGHT plan was selected in 11/15. The mean improvements in FRC15HIDA (5.2 vs 5.0%), mean liver dose (11.9 vs. 13.0%), EUD (5.1 vs 5.2%), and FEUD (6.9 vs 7.1%) were similar between prospective and retrospective cohorts (p > 0.5). In the entire cohort (n = 42), FLIGHT improved FRC15HIDA, mean liver dose, EUD, and FEUD ( p ≤ 0.001). There were > 5% improvements in FRC15HIDA in 15, mean liver dose in 31, EUD in 19, and FEUD in 27. Conclusions: FLIGHT with HIDA led to improvements in all analyzed dosimetric parameters. The extent of benefit was similar in both cohorts, and there was individual variation in the extent of benefit. Longer follow-up is required to determine the effect of FLIGHT on post-SBRT liver function. Clinical trial information: NCT03338062.
An analysis of the safety and efficacy of rivaroxaban (Riv) and low molecular weight heparin (LMWH) in gastrointestinal cancer-associated venous thromboembolism (GICA-VTE).
Authors: Recio Boiles Alejandro , Veeravelli Sumana , Vondrak Jessi , Babiker Hani M. , Scott Aaron James , McBride Ali , Elquza Emad
Published: January 2019

374

Background: CAVTE has a significant morbidity and mortality burden, with higher incidence and bleeding complications of anticoagulation (AC) in GICA. Current guidelines prefer LMWH, and recently added Riv, as an alternative standard after the SELECT-D trial (S-D). There is a paucity of data comparing the safety and efficacy of other DOACs in pts with GICA. We indirectly compared the safety and efficacy of Riv vs LMWH of our pts with active GICA-VTE at the University of Arizona Cancer Center (UACC) to the S-D GI-population. Methods: Pts with biopsy proven GICA, symptomatic or incidental VTE, and 6 months or more treatment with Riv or LMWH at UACC from 11/2013 - 12/2017 were retrospectively reviewed. S-D GICA data was extracted. Primary efficacy outcome was recurrent deep vein thrombosis (DVT), nonfatal pulmonary embolism (PE), or fatal PE. Safety outcomes for major bleeding (MB) include Hg drop ≥ 2 g/dL, transfusion of ≥ 2 units PRBC, bleeding in critical site, or bleeding contributing to death. Fisher exact test was used for p-value < 0.05. Results: Our review included pts on LMWH (n = 40), and Riv (n = 37) balanced population to the S-D trial. Recurrent VTE at 6mo was noted in 7.5% and 2.7% of pts, compared to S-D trial 11% and 4%, for LMWH and Riv respectively. MB at 6mo was 5% and 21.6% [p < 0.04] of pts, compared to S-D trial 5.8% and 8.7%, for LMWH and Riv, respectively. There was a non-significant difference [p > 0.07] between Riv and LMWH efficacy and safety beyond 6mo of AC. Conclusions: VTE secondary prophylaxis in GICA pts is complicated by high rates of recurrence and bleeding risk, DOACs provide another AC option. The most recent systemic review that included the two published DOACs RCTs for CAVTE [Hokusai and SELECT-D 2018], showed a higher incidence at 6-month of MB compared to LMWH RR: 1.74 (95% CI: 1.05–2.88) [Ang Li 2018], mainly driven by GICA. Our retrospective study showed a non-significant improved efficacy outcome although worse safety profile with Riv versus LMWH in GICA pts, by indirect comparison. Future RCTs with multi-center participation, particularly focused on GICA, can further provide information to guide safe and effective AC selection.
Outcome analysis of chemotherapy duration for resected stage I-II and unresected stage III pancreatic cancer.
Authors: Ma Sung Jun , Iovoli Austin J , Prezzano Kavitha M , Hermann Gregory , Serra Lucas M , Singh Anurag K
Published: January 2019

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Background: For resected early-stage pancreatic cancer, RTOG 9704 has evaluated the outcome of 3 weeks of adjuvant chemotherapy (C) followed by chemoradiation (CRT) and post-CRT C. For locally advanced pancreatic cancer, a recent literature review showed that the typical duration for induction C is between 1 and 6 months prior to CRT. The ideal duration of C prior to CRT remains unclear. This National Cancer Database (NCDB) study was performed to identify the optimal duration of C prior to CRT in patients with pancreatic cancer. Methods: The NCDB was queried for primary stage I-II, cT1-3N0-1M0, resected and stage III, cT4N0-1M0, unresected pancreatic adenocarcinoma treated with C+CRT (2004-2015). Cohorts I-II and III included stage I-II and stage III cases, respectively. In each cohort, the patients were stratified by the short (short C) and long duration (long C) of chemotherapy based on their median durations (70 and 90 days between the onset of chemotherapy and radiation for cohorts I-II and III, respectively). Baseline patient, tumor, and treatment characteristics were examined. The primary endpoint was overall survival (OS). Kaplan-Meier analysis, multivariable Cox proportional hazards method, and propensity score matching were used. Results: Among 1,577 patients, cohort I-II had 839 patients (n = 409 with short C, n = 430 with long C) and cohort III had 738 patients (n = 360 with short C, n = 378 with long C). Median follow-up was 39.5 months and 24.3 months for cohorts I-II and III, respectively. The long C group showed improved OS in the multivariable analysis in both cohort I-II (HR 0.72, p < 0.001) and cohort III (HR 0.83, p = 0.025). Using 1:1 propensity score matching, a total of 610 patients for cohort I-II and 542 patients for cohort III were matched. After matching, long C remained statistically significant for improved OS compared with short C in both cohort I-II (median OS 26.1 vs 21.9 months, p = 0.003) and cohort III (median OS 16.7 vs 14.2 months, p = 0.021). Conclusions: Our NCDB study using propensity score matched analysis showed a survival benefit in the use of longer duration chemotherapy compared to shorter duration chemotherapy for both resected stage I-II and unresected stage III pancreatic cancer.
Clinical characteristics and predictors of outcomes in patients with fibrolamellar carcinoma: An eleven-year analysis of the National Cancer Database (NCDB).
Authors: Assi Hussein , Hatoum Hassan , Mukherjee Sarbajit , Machiorlatti Michael , Vesely Sara , Pareek Vipul
Published: January 2019

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Background: Fibrolamellar carcinoma (FLC) is a very rare liver tumor, comprising only 1% of all primary liver tumors in the United Sates. There is no standard of care for unresectable disease. Current practices are based on small retrospective studies and case series. We aim to analyze the clinicopathologic factors and treatment modalities affecting overall survival (OS) in FLC. Methods: Using the National Cancer Data Base (NCDB), we identified 496 patients diagnosed with FLC between 2004 and 2015. Simple descriptive statistics were created for all covariates. Survival data was available on 461 patients. Kaplan Meier Survival analysis was used for unadjusted results, and Cox proportional hazards model was used for multivariable analysis. The objective of the study is to identify predictors of survival in FLC. Results: The median age at diagnosis was 32 (range 18-90) years. Fifty-six percent were males. Stage distribution included 114 (31.2%), 43 (11.8%), 89 (24.3%) and 120 (32.8%) patients for stages I, II, III and IV, respectively. Median follow-up was 24 months. Surgery of the primary site was performed on 282 (56.9%) of patients, 146 (51.2%) of which had regional lymph node dissection. Seventy (47.9%) patients had pN+ disease. Among patients with available serum alpha fetoprotein (AFP) data, 146 (42.5%) had abnormal AFP levels (> 20 ng/mL). Median OS by stage were 78.5, 87.2, 18.6, and 10.6 months for stages I, II, III, and IV, respectively. Multivariate analysis showed that age (HR 1.01, p < 0.0001), pN+ (HR 2.31, p = 0.0003), and abnormal AFP (HR 1.69, p = 0.0003) were negative predictors of survival. Among metastatic patients, 57 (11.4%) had metastatectomy. Metastatectomy improved overall survival in stage IV FLC, HR 0.51 (95% CI 0.29-0.89). Conclusions: Independent predictors of decreased OS in patients with FLC include age, pN+ and abnormal AFP. Metastatectomy improved OS. FLC is a rare disease entity that warrants further investigations to better delineate optimal treatment approaches.
SWOG S1505: Initial findings on eligibility and neoadjuvant chemotherapy experience with mfolfirinox versus gemcitabine/nab-paclitaxel for resectable pancreatic adenocarcinoma.
Authors: Sohal Davendra , McDonough Shannon , Ahmad Syed A. , Gandhi Namita , Beg Muhammad Shaalan , Wang-Gillam Andrea , Wade James Lloyd , Guthrie Katherine A , Lowy Andrew M. , Philip Philip Agop , Hochster Howard S.
Published: January 2019

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Background: Clinical outcomes after curative therapy of resectable pancreatic ductal adenocarcinoma (PDA) remain suboptimal. For early control of systemic disease with aggressive perioperative chemotherapy (CTx), we conducted a prospective trial in the National Clinical Trials Network (NCTN) setting. Methods: S1505 was a randomized phase II trial of periop (12 weeks pre-, 12 weeks post-op) CTx with either mFOLFIRINOX (5-fluorouracil, irinotecan, oxaliplatin – without bolus 5-FU and leucovorin; Arm 1), or gemcitabine/nab-paclitaxel (Arm 2). Eligibility required adult patients with ECOG PS 0 or 1, confirmed tissue diagnosis of PDA, and resectable disease: no involvement of the celiac, common hepatic, or superior mesenteric arteries (and, if present, variants); < 180° interface between tumor and vessel wall, of the portal or superior mesenteric veins; patent portal vein/splenic vein confluence; no metastases. Primary outcome is 2-year overall survival (OS), using a “pick the winner” design; for 100 eligible patients, accrual up to 150 patients was planned, to account for cases deemed ineligible at central radiology review. Results: From 2015 to 2018, 147 patients were enrolled; 74 to Arm 1; 73 to Arm 2. At central radiology review, 42/147 (29%) were ineligible; of these, 15 (36%) had venous involvement ≥ 180°, 22 (52%) had arterial involvement, 28 (67%) had distant disease. One patient had distal cholangiocarcinoma (ineligible); one withdrew consent after randomization. Eligible patients (n = 103) had median age 64 years; males 58%; whites 89%; PS 0 64%. Of 103, 99 (96%) started and 86 (83%) completed preop CTx. There was one death due to sepsis and 61 additional patients experienced grade 3/4 toxicities. To date, 76 of 99 (77%) patients went to surgery and 72 (73%) underwent resection. Conclusions: This is the first-ever NCTN study of periop CTx for resectable PDA. Accrual was brisk, establishing feasibility. Ineligible cases after central radiology review highlight quality control and physician education imperatives for neoadjuvant PDA trials. Preop CTx safety and resection rates are encouraging. Follow up for OS is ongoing. Clinical trial information: NCT02562716.
Outcomes following liver SBRT for metastatic pancreatic cancer.
Authors: Oladeru Oluwadamilola Temilade , Vaios Eugene J , Eyler Christine , Noe Bridget N. , Fernandez Del-Castillo Carlos , Weekes Colin D. , Ferrone Cristina , Lillemoe Keith D , Qadan Motaz , Parikh Aparna , Clark Jeffrey W. , Ryan David P. , Allen Jill N , Hong Theodore Sunki , Wo Jennifer Y
Published: January 2019

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Background: Traditionally, the role of localized therapy for metastatic pancreatic cancer (MPC) has been limited. However, with more effective systemic therapies, recent studies have explored a potential role for local therapies. We aimed to report outcomes following SBRT (stereotactic body radiation therapy) for liver metastases (LM) in setting of MPC and to identify predictors of response. Methods: 41 patients who underwent ablative RT to LM for MPC (2005-17) were retrospectively identified. Median RT dose was 50 Gy (range: 8-60 Gy), delivered in 5-6 fractions. Kaplan Meier method was used to calculate local control (LC), progression-free survival (PFS) and overall survival (OS). Univariate (UVA) and multivariate (MVA) Cox proportional hazards models were used to identify predictors of clinical outcomes. Results: Median follow up was 14.6 months. This cohort included 19 men and 22 women. 61% of pts had metachronous LM, 39% had synchronous LM. At time of RT, the treated lesion was stable /responding to chemotherapy (CTX) in 36.6% of pts; 46.3% were progressing with mixed response; 17% were off/refused CTX. Median number of prior CTX regimens was 2 (range: 0-5). Median number of LM was 1 (range: 1-4). Median pre-RT CEA was 7 ng/mL, median pre-RT CA19-9 was 354 U/ml. The 12-month outcomes were 75.8% LC, 16.5% PFS, and 36.3% OS. 8/41 (20%) patients were off CTX for ≥ 4 months. On UVA for LC, pre-RT CA19-9 (log10 scale) was associated with LC (HR 2.28, p = 0.03). Timing of LM, CTX response of LM, number of lesions, RT dose and CEA did not predict LC. On UVA for PFS, extrahepatic disease at time of RT was associated with worse PFS (HR: 2.47, p = 0.04), and response to CTX (progressive vs. stable/responding) approached significance (HR 1.83, p = 0.10). On UVA for OS, lower pre-RT CEA (HR 1.009, p = 0.03), lower pre-RT CA19-9 (HR 1.67, p = 0.01), and response to CTX (HR 6.42, p < 0.001) were associated with improved OS. On MVA for OS, response to CTX at time of liver RT remained significant for OS. Conclusions: SBRT of LM for MPC offers high rate of LC. In a small subset of patients, SBRT to LM may offer prolonged duration off systemic therapy. Lower pre-RT CA 19-9 and CEA, absence of extrahepatic disease, and stability/response of CTX at time of liver RT may select for patients most likely to benefit.