bluuebunny/crossref_metadata_2025 huggingface dataset:
Anti-Her2neu directed therapy in advanced gall bladder cancer: A prospective, multicenter experience from India.
Authors: Das Chandan Krushna , Patel Amol , Raj Abhishek , Gupta Vineet Govinda , Mehta Prashant , Bhethanabhotla Sainath , Reddy Rakesh , Yadav Ajay
Published: May 2020

e16682

Background: Prognosis of Gallbladder cancer (GBC) remains unchanged over the last 20 years. Her2neu amplification is present in 17% of cases of advanced GBC. We present our experience of anti Her2 targeted therapy. Methods: This is a multicenter, prospective, observational study conducted in northern India from Sept2017-Sept2019. All consecutive patients were tested for Her2neu by standard techniques or next-generation sequencing (NGS). Trastuzumab or Lapatinib was used as the anti Her2 therapy along with chemotherapy. Outcome measures were overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) and compared to historical controls. Data were censored on 31Dec2019. Results: A total of 181 patients were screened; 38 (20.9%) patients were positive for Her2neu or Her3neu. Demographic details are depicted in the table. Her2 was detected by IHC 18 (47%), FISH 6(15.7%) or NGS 14(36.8%). Five patients were positive for Her3 mutation and/or amplification. Twenty-one patients received anti Her2 therapy upfront with chemotherapy. At a median follow-up of 6.8 months, median PFS was 4.1 months for chemotherapy only (n = 85) and 9.7 months for trastuzumab with chemotherapy (n = 21) (HR 0.22; P < 0.05). The median OS was 14 and 6 months in patients with or without trastuzumab-based therapy (HR 0.08 P = 0.001), respectively. Trastuzumab with chemotherapy was well tolerated. Conclusions: Her2neu directed therapy significantly improve ORR, PFS, and OS in GBC with no added toxicities in the first line. It must be evaluated in a randomized phase 3 clinical trials. [Table: see text]
A phase II study of apatinib treatment for advanced biliary tract carcinoma after failure of the standard chemotherapy.
Authors: Wang Chenchen , Guo Weijian , Huang Mingzhu
Published: May 2020

e16684

Background: There is no standard second-line therapy for advanced biliary tract carcinoma (BTC). Apatinib, a VEGFR2 tyrosine kynase inhibitor, showed an inhibitary effect on tumor formation in BTC tumorgraft mouse model in previous study, with tolerable toxicity in clinical trials for other types of advanced cancer such as gastric cancer. We conducted an exploratory study to evaluate the efficacy and safety of apatinib in patients with advanced BTC. Methods: This is a single-center, single-arm phase II study (NCT03427242). The key inclusion criteria were:(1) histologically confirmed advanced or metastatic BTC; (2) Prior lack of response or intolerance to at least one chemotherapeutic regimens; (3) At least one measurable lesion as defined by RECIST 1.1; (4) No prior use of anti-angiogenic targeted drugs. Eligible patients received oral apatinib 500mg each day continuously until unacceptable toxicity or tumor progression. The primary endpoint was progression free survival (PFS). The secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR) and treatment safety. Results: From Dec 1, 2017 to Jan 31, 2020, a total of 18 patients (12 males and 6 females) had been recruited, and 16 patients who had received the medication of apatinib were included in this analysis. Among these patients, 10 were previously treated with only first-line chemotherapy and 6 were treated with two or more lines of therapy. The median age was 65 (range 45-76) years old. Fourteen patients had received the efficacy evaluation after treatment. Two patients achieved partial response (PR, 14.3%), 6 patients with stable disease (SD, 42.9%),and 6 patients with progressive disease(PD). The ORR and DCR were 14.3% and 57.1%, respectively. At the last follow-up date on Jan 30, 2020, 4 patients are still on apatinib medication. The median PFS was 2.70 months (95% CI, 1.94 - 3.46), and the median OS was 7.03 months (95% CI, 3.16 - 10.9). Grade 3 or 4 adverse events were reported in 7 patients (43.8%). The detailed grade 3 or 4 adverse events were proteinuria in 5 patients, hand-foot syndrome in 2 patients, platelet count decrease in 1 patients, diarrhea in 1 patients and urine bilirubin in 1 patients (Table). Conclusions: For the patients with advanced biliary tract carcinoma, apatinib showed an anti-tumor activity with acceptable safety. Clinical trial information: NCT03427242 . [Table: see text]
Parameters of oxidative metabolism in the blood of patients with pancreatic tumors of different histotypes.
Authors: Goroshinskaya Irina A. , Frantsiyants Elena M. , Aleynov Viacheslav A. , Nemashkalova Ludmila A. , Cheryarina Natalia D. , Trifanov Vladimir S. , Mezentsev Stanislav S. , Grechkin Fedor N. , Duritskiy Maksim N. , Kit Oleg I. , Zhukova Galina V. , Fomenko Yuriy A. , Petrov Dmitry S.
Published: May 2020

e16697

Background: High mortality rates in patients with pancreatic tumors and especially with neuroendocrine tumors necessitate the study of their molecular features. Our purpose was the comparative analysis of the intensity of lipid peroxidation and functioning of the enzymatic unit of the antioxidant system in the blood of patients with pancreatic tumors depending on the presence of a neuroendocrine component in them. Methods: The study included 42 patients with pancreatic cancer before the treatment and 22 donors. Parameters of lipid peroxidation (LPO) - the content of malondialdehyde (MDA) and diene conjugates, the activity of superoxide dismutase (SOD) and catalase were measured in the plasma and red blood cells, and the content of SOD1, SOD3 and catalase were measured in the blood plasma by ELISA. The results were analyzed depending on the histotype of removed tumors: pancreatic neuroendocrine tumors (n = 12), pancreatic adenocarcinoma (n = 9), pancreatic adenocarcinoma with a neuroendocrine component from 1% to 10-30% (n = 21). Results: The most pronounced changes in the blood oxidative status relative to the group of donors were observed in neuroendocrine cancer: an increase in plasma MDA levels by 30% (p = 0.006), diene conjugates in plasma and red blood cells by 2.6 and 2.9 times (p≤0.0003), a decrease in SOD and catalase activity in red blood cells by 39.7%, and 46.5% (p = 0.000000), reduced (by 20%, p = 0.047) plasma catalase activity and the minimal ratio of activity to content of both antioxidant enzymes (37.2% and 54.8% of donor levels, p < 0.0002). Conclusions: The LPO intensification most typical of neuroendocrine cancer is promoted by more significant inhibition of enzymes of the first-line antioxidant defense in red blood cells and decreased plasma catalase activity, compared to the values in adenocarcinoma.
Real-world analysis of peptide receptor radionuclide therapy (PRRT) in the treatment of neuroendocrine tumors.
Authors: Chau Justin , Yu Nanmeng , Bakeri Hirva , Menda Yusuf , Dillon Joseph S. , Chandrasekharan Chandrikha
Published: May 2020

e16701

Background: PRRT received FDA approval in 2018 for treatment of somatostatin receptor positive gastroenteropancreatic neuroendocrine tumors (GEPNETs) based on NETTER-1 trial data that included only small bowel grade 1 and 2 neuroendocrine tumors. We present real-world data of PRRT outcomes and implementation from a large tertiary treatment center following approval. Methods: Patients treated with PRRT at University of Iowa between Jan 2018 - July 2019 were included in this retrospective study. Patient and tumor characteristics, cumulative dose and cycles of Lu 177 PRRT administered, treatment course, treatment-related toxicity and responses were reviewed, and 1-year progression-free and overall survival rates were calculated. Results: 67 patients received PRRT, of which 61 completed at least 2 doses. Primary tumor sites included small bowel (64.1%), pancreas (20.3%), and lung (9.4%). 43 (64%) had grade 2 NET; 5 had grade 3 (7.4%). 44 (65.6%) completed 4 cycles of PRRT per FDA approval while 10 received 3 cycles (14.9%). Median duration of follow up was 11.7 months. 53 patients received at least 2 doses and at least one imaging procedure post-PRRT. No complete responses were noted. 9 patients were found to have disease progression at last follow up. 1-year progression-free survival was 78% (95% CI 64-88%). 1-year overall survival was 88% (95% CI 75-94%). Of 23 patients who received fewer than 4 cycles, PRRT was discontinued in 4 (5.9%) due to myelosuppression, specifically thrombocytopenia grade 2 and above. 9 patients discontinued therapy due to change in clinical status or progression per treating physician, 2 experienced carcinoid crisis and 2 had renal function deterioration (preexisting renal disease). 5 patients had previously received PRRT with either Y90 or Lu 177 prior to FDA approval and were retreated in our cohort. 5 patients had preexisting renal disease, including one patient on peritoneal dialysis. Conclusions: We noted a higher rate of treatment discontinuation after 3 cycles, possibly due to heavy pretreatment or treatment of patients with advanced disease, not uncommon after a new therapy is approved and implemented into practice. Discontinuation due to myelosuppression or renal dysfunction was minimal, consistent with NETTER-1 data. Our cohort is unique as it included patients who had received prior PRRT as well as others with preexisting renal dysfunction. Despite this, treatment-related toxicity in our cohort was not significantly higher.
Molecular detection of pancreatic neuroendocrine tumors using methylated DNA markers: Discovery and tissue validation.
Authors: Majumder Shounak , Berger Calise K. , Foote Patrick H. , Cao Xiaoming , McGlinch Maria , Gysbers Brianna , Halfdanarson Thorvardur Ragnar , Graham Rondell P. , de la Fuente Jaime , Robran Mariah J , Doering Karen A , Burger Kelli , Mahoney Douglas W. , Taylor William R. , Petersen Gloria M. , Ahlquist David A. , Kisiel John B.
Published: May 2020

e16705

Background: The prevalence of pancreatic neuroendocrine tumors (PNETs) has increased in the last decade. Despite being clinically asymptomatic PNETs can be biologically aggressive. There is currently no reliable non-invasive diagnostic biomarker for PNETs. In this study we aimed to identify and validate methylated DNA marker (MDM) candidates that differentiate PNET from normal pancreas. Methods: For discovery, reduced representation bisulfite sequencing (RRBS) was performed on DNA extracted from frozen normal pancreas (n = 13) and PNET (n = 51) tissues. Area under the receiver operator characteristic curve (AUC), fold-change, and p-value criteria selected candidates MDMs for blinded validation in independent FFPE tissues from primary PNET (n = 67; solid = 50, cystic = 17), normal pancreas controls (n = 24), and normal buffy coat (n = 36) using methylation specific PCR. MDM distributions in primary PNETs were compared to primary lung (n = 36) and small bowel (n = 36) NETs and metastatic PNET tissue (n = 25). The discrimination accuracy of candidate markers was summarized as the AUC with corresponding 95% confidence intervals (CI). Results: From the RRBS discovery, 31 candidate MDMs were selected for validation. Four MDMs ( SRRM3, HCN2, SPTBN4 and TMC6) achieved individual AUCs ≥0.95 in the validation set (Table). These MDMs were similarly discriminant in metastatic PNET tissue and in primary lung and small bowel NETs. Three out of these 4 MDMs perfectly differentiated PNET tissue from buffy coat with AUC of 1 and may be ideally suited for further development of a blood-based assay. Conclusions: We identified and validated novel MDMs in tissue that discriminate PNETs from controls with normal pancreas and buffy coat with high accuracy. These MDMs also differentiated metastatic PNETs from normal pancreas tissue. Further exploration of these candidate tissue MDMs in plasma can potentially guide diagnosis and management of PNETs. Funding: P30DK084567. [Table: see text]
First-line fluoropyrimidine and oxaliplatin chemotherapy in gastro-entero-pancreatic grade III well-differentiated neuroendocrine tumors (NET G3).
Authors: Lamberti Giuseppe , Pusceddu Sara , Ibrahim Toni , Bongiovanni Alberto , Prinzi Natalie , Maggio Ilaria , Campana Davide
Published: May 2020

e16709

Background: The 2019 World Health Organization (WHO) classification of neuroendocrine neoplasia (NEN) introduced the new category of well-differentiated NEN with Ki67 proliferation index ≥20% (NET G3). Fluoropyrimidine-based regimens with oxaliplatin (FOLFOX/XELOX) were a treatment option in neuroendocrine carcinomas with low Ki67. However, FOLFOX/XELOX efficacy in this newly defined NET G3 category is unknown. Objective of this study was to describe FOLFOX/XELOX efficacy in NET G3 and identify factors associated with outcome. Methods: We retrospectively collected all metastatic gastro-entero-pancreatic NET G3 patients who received a fluoropyrimidine-based regimen with oxaliplatin (FOLFOX/XELOX) as first-line treatment at 4 NEN-dedicated Italian Centers. Concomitant somatostatin analog (SSA) treatment was allowed and recorded. Objective response rate (ORR) was defined according to RECIST criteria v1.1. Factors associated with progression-free survival (PFS), overall survival (OS), and ORR were analyzed. Results: Twenty-nine NET G3 patients (median age 57 years, range 18-79) matching inclusion criteria were identified. Twenty patients (69%) were of pancreatic origin, while 9 (31%) had gastrointestinal primary. Median Ki67 was 30% (range 21-50). Treatment was FOLFOX in 14 (48%) and XELOX in 15 patients (52%), while 12 (44%) received also concomitant SSA. After a median follow-up of 44.1 months, median PFS was 7.9 months (95%CI 6.2 -11.4) and median OS was 44.8 months (95%CI 37.1 - NA). The 12 patients whose tumor responded to treatment (44% [95%CI 26-65]) had longer PFS (26.5 vs 5.0 months; p = 0.004) and OS (194.0 vs 38.0 months; p = 0.04) compared to those who did not respond. Progressive disease was the best disease response in 7 patients (24%). Objective response was associated with a reduced risk for progression (HR: 0.22 [95%CI: 0.07-0.62]; p = 0.007) while higher Ki67 was associated with an increased risk for progression (HR: 1.11 [95%CI: 1.04-1.19]; p = 0.002) and for death (HR: 1.09 [95%CI: 1.01-1.17]; p = 0.017). After correcting for confounding factor, ORR (HR: 0.26 [95%CI: 0.08-0.83]; p = 0.023) and Ki67 (HR: 1.09 [95%CI: 1.02-1.16]; p = 0.009) retained their association with the risk for progression, but not with the risk for death. Conclusions: Fluoropyrimidine-based regimens with oxaliplatin (FOLFOX/XELOX) may be active and effective in NET G3 of gastroenteropancreatic origin.
Association of neoadjuvant chemotherapy on survival in locally advanced gallbladder cancer.
Authors: Kazmi Syed Mohammad Ali , Goksu Suleyman Yasin , Ozer Muhammet , Sanford Nina Niu , Porembka Matthew R. , Wang Sam C. , Mansour John C. , Hsieh David , Aguilera Todd Anthony , Sanjeevaiah Aravind , Khosama Leticia , Maxwell Mary Claire , Beg Muhammad Shaalan
Published: May 2020

e16716

Background: Gallbladder cancer (GBC) is an uncommon but highly fatal malignancy. Surgery remains the only potentially curative treatment for GBC. The role of neoadjuvant chemotherapy in patients with locally advanced GBC undergoing surgery is unknown. We studied the association of neoadjuvant chemotherapy on survival in locally advanced GBC patients who underwent resection. Methods: We identified adult patients with locally advanced (stage III-IV) GBC who underwent definitive surgery between 2004 and 2016 using the National Cancer Database. Treatment was categorized as neoadjuvant chemotherapy plus surgery (NAT), surgery plus adjuvant therapy (AT), and surgery alone (SA). Categorical variables were compared using the chi-square test with Bonferroni correction. Kaplan-Meier and Cox regression were used for survival analyses. We used 1:3 nearest neighbor propensity score matching based on NAT for each group. Results: Out of a total of 5,962 patients, 122 (2.2%) received NAT, 2934 (53.6%) AT, and 2421 (44.2%) SA. NAT was associated with private insurance and treatment at an academic/research facility (all p < .001) while SA patients were older, Hispanic, had government insurance, and higher comorbidities (all p < .001). Although all groups had similar lymph node assessment (NAT: 45%, AT: 46%, SA: 37%, p < .001), NAT was associated with lymph node negative disease (NAT 23%, AT 13.2%, SA 13.2%, p < .001). Median overall survival was higher in NAT compared to AT or SA (21 vs. 14 vs. 6 months, p < .001) which persisted after propensity score matching (21 vs. 15 vs. 9 months, p < .001) and multivariable regression analysis (Table). In node positive GBC, NAT was associated with improved median overall survival (NAT 24, AT 18, SA 8 months, p < .001). Conclusions: NAT is infrequently used in patients with locally advanced GBC. NAT is associated with improved median overall survival compared to AT and SA, and appears to be most beneficial in node positive disease. Prospective studies are needed to evaluate the role of neoadjuvant chemotherapy in locally advanced GB. [Table: see text]
Muscle impairment during follow-up as an independent prognostic factor for poor overall survival in pancreatic cancer.
Authors: Lambert Aurélien , Salleron Julia , Gavoille Céline , Viard Auréline , Ayav Ahmet , Conroy Thierry , Laurent Valérie
Published: May 2020

e16726

Background: We aimed to assess that muscle impairment during follow-up is as an independent prognostic factor for poor overall survival in pancreatic cancer (PC) and is more accurate than a single muscle mass evaluation. Methods: Data from all patients with pancreatic adenocarcinoma at our center from 2009 to 2015 were retrieved (N = 114). A retrospective review of the total psoas area (TPA) was performed using manual segmentation on a single cross-sectional image through the third lumbar vertebrae for each available scan (N = 713, median number of scans per patient was 6 [3; 8]). For each patient, when at least two CT scans were available, the decrease in the TPA from baseline (Muscle Impairment) was expressed by a percentage. Results: In the univariate analysis, a TPA level under 420 mm2/m2 during the follow-up, with a HR = 3.419 ([2.168; 5.394]; 95% CI; p < 0.0001) and a TPA decrease of more than 20% from the baseline with a HR = 7.169 ([4.526; 11.353]; 95% CI; p < 0.0001) were prognostic factors for death. The multivariate analysis confirmed the results with a HR = 5.799 ([3.418; 9.839]; 95% CI; p < 0.0001) in the non-surgery group and a HR = 8.089 ([2.157; 30.339]; 95% CI; p = 0.0019) in the surgery group for a decrease in the TPA of more than 20% from the baseline. Conclusions: Muscle impairment during follow-up is a strong and independent prognostic factor for poor overall survival in patients with PC. It is in favor of a higher risk of death.
A single institution experience of brain metastases and pancreatic adenocarcinoma: Patients' treatments and outcomes.
Authors: Gouton Etienne , Chanez Brice , Launay Simon , Loir Elika , Moureau-Zabotto Laurence , Turrini Olivier , Gilabert Marine
Published: May 2020

e16737

Background: Brain metastases (BM) occur extremely rare in pancreatic adenocarcinoma (PDAC) and few data are available regarding those patients‘ care and outcomes. Methods: We performed a retrospective monocentric analysis of our database to identify patients (pts) diagnosed with PDAC and BM from July 1997 to December 2019. Results: 16 pts were eligible among 4900 pts diagnosed with PDAC in our institution (0.3%). Median age was 64 years (38.2-74.6) with 50% female. At diagnosis, 68.8% were metastatic including 27.3% with synchronous BM. About 1/3 pts had ≥ 2 lines of chemotherapy before BM. BM were discovered from neurological symptoms in 62% of cases and either with systematic brain CT/MRI or unknown in 19% for both. BM treatment was: surgery (25%), whole brain radiation therapy (RT) (43.8%), stereotactic RT (6.3%), radiosurgery (6.3%), best supportive care (BSC) or unknown (6.3%). At follow-up cutoff date (01/01/2020), most of pts were dead (75%), 2 were alive and 2 lost of follow-up. Mean interval between initial diagnosis and BM was 9.9 months (mths) (0-73). Median time to develop BM was different between pts with non-metastatic or metastatic disease at diagnosis: 16.3 mths (6.5-44) and 4.2 mths (0-36.1), respectively (HR = 0.43 (CI95: 0.14-1.09; p = 0.09)). Median overall survival (mOS) was 14.5 mths (1.6-80.2). Definitely, the non-metastatic group at diagnosis had better survival with mOS of 40.2 mths (24.7-80.2) compared to 6.5 mths (1.7-49.8) for the metastatic group (HR = 0.24 (CI95: 0,06-0,63; p = 0.012)). The median survival period after diagnosis of BM was only 3.4 mths (0.5-13.7). Pts who underwent BM surgery had better survival with a median survival from surgery of 5.5 months (4-13.7) compared to RT (0.8 mths (0.4-2)) or BSC (0.6 mths (0.5-5.9)). HR for surgery versus RT was 0.12 (CI95: 0.02-0.31; p = 0.003). After BM diagnosis, 43.8% of patients had a systemic chemotherapy, without objective response on BM. One interesting metastatic pt with BRCA1 mutation achieved a complete response (CR) after FOLFIRINOX. One BM occurred 2 years after diagnosis, was treated with surgery + RT but relapsed 4.5 mths later with new BM. Extra-cranial CR was persistent. This pt, still alive, had the longest survival period after diagnosis of BM (13.7 mths) and OS (49.8 months). Conclusions: To our knowledge, this is one of the largest cohort reported of BM in PDAC. Very few cases exist to guide therapy. Surgery appears to be the best treatment for BM, when feasible. Further investigations are still needed to understand the pathogenicity of BM in pancreatic cancer.
Germline mutations in Brazilian pancreatic carcinoma patients.
Authors: Rodrigues Livia Munhoz , Maistro Simone , Katayama Maria Lucia Hirata , Leite Luiz A.Senna , Glasberg Joao , Ribeiro Ulysses , Guindalini Rodrigo Santa Cruz , Koike Folgueira Maria A. A.
Published: May 2020

e16749

Background: Pancreatic cancer has the prospect of becoming the second leading cause of cancer death by 2030. The NCCN Guidelines recommend genetic testing for all patients with pancreatic cancer, however, the spectrum of germline mutations has not been extensively evaluated because recent studies with genetic testing have explored only a limited number of genes and have focused predominantly on Caucasian populations. Therefore, our objective is to evaluate the frequency and spectrum of germline mutations in unselected patients with pancreatic cancer in a multiethnic population. Methods: Patients from Instituto do Câncer do Estado de São Paulo (Brazil) with histopathological diagnosis of non-endocrine pancreatic carcinoma were included, regardless of the family history of cancer. These patients answered a life habits and family history of cancer questionnaire and supplied blood for the Next Generation Sequencing (MiSeq platform) with the TruSight Hereditary Cancer panel (Illumina), which includes 115 cancer predisposing genes. Variant analysis was performed with the VarStation, a Brazilian tool that offers post-sequencing computational support and aid for clinical interpretation. Results: To the present moment, 77 patients were evaluated. The mean age of the patients was 62 years (27-83), among whom, 13% with young age (≤50 years) and 47 women (61%). Thirty-eight patients (49%) reported cases of cancer in first-degree relatives. Regarding risk factors, 41 patients (53%) reported smoking, 19 (25%) alcohol ingestion and 20 (26%) had obesity. Seven out of 77 patients presented pathogenic variants in ATM (n = 2) , CHEK2, FANCM (n = 2) or PALB2 (n = 2) genes. Two of these patients ( CHEK2 and FANCM) had early onset pancreatic cancer (≤45 years), both denied smoking habit and family history of cancer in 1st degree relatives. Two patients, who were ATM mutation carriers, reported 1st or 2nd degree relatives with cancer and are alive after 4 and 8 years of diagnosis. Conclusions: In this unselected group of pancreatic cancer patients, 15% were young, almost half reported first-degree relatives with cancer and 9% were carriers of pathogenic variants in genes related with the homologous recombination DNA repair.
Trends in real-world clinical outcomes among patients (pts) with metastatic pancreatic adenocarcinoma (mPDAC) treated with liposomal irinotecan based regimens in the United States (US).
Authors: Koeller Jim M. , Cockrum Paul , Belanger Bruce , Corvino Frank A. , Surinach Andy , Kim George P.
Published: May 2020

e16751

Background: The NAPOLI-1 study, a randomized phase 3 study in pts with mPDAC previously treated with gemcitabine-based therapy, demonstrated an improvement in overall survival (OS) with liposomal irinotecan + 5-fluorouracil/ leucovorin (5-FU/LV) vs. 5-FU/LV. In this analysis we describe the trends in pt characteristics, real-world OS (rwOS), and real-world time to-treatment failure (rwTTF) among pts with mPDAC treated with liposomal Irinotecan based regimens overall and stratified by tx initiation prior to 2018 (pre-2018) or after 2018 (post-2018). Methods: This retrospective observational study used de-identified data from Flatiron Health EHR database from over 280 cancer clinics in the US. Pt characteristics, rwOS, and rwTTF were assessed in adult pts diagnosed with mPDAC who received liposomal irinotecan treatment (tx) between January 1, 2016 and October 31, 2019. Results: Of the 590 pts treated with liposomal irinotecan based regimens, 53% were male, 56% were initially diagnosed with Stage IV disease, 92% were treated in the community setting, and median age at tx initiation was 69 (IQR: 62 – 75) years. Among pts with available ECOG scores (N = 435), 77% had a score of 0 or 1. 43% (n = 254) initiated tx pre-2018 and 57% (n = 336) post-2018. Pre-2018, 106 (42%) pts initiated liposomal irinotecan in the third line metastatic setting or later (3rd line+), 125 (49%) had ECOG score of 0-1, and median age was 68 (62–74) years. Post-2018, 36% of pts initiated tx in 3rd line+, 211 (63%) had ECOG score of 0-1, and median age was 70 (63 – 75) years. Median rwOS was 4.4 months [95% CI: 4.3–6.2] pre-2018 and 5.2 mos [4.3–6.2] post-2018. rwTTF was 1.6 mos [1.4–1.9] pre-2018 and 2.1 mos [1.6–2.5] among pts post-2018. Among pts treated in first- or second-line, pre-2018 rwOS was 5.3 mos [3.9–6.4] and post-2018 rwOS was 6.3 mos [5.0– 7.6]. Conclusions: In this descriptive real-world study of pts with mPDAC receiving liposomal irinotecan based regimens, pts initiating treatment post-2018 appear to be less pre-treated, older, and have better performance status than pts pre-2018. Pts treated post-2018 experienced numerically longer rwTTF and rwOS than pts treated pre-2018.
Real-world survival outcomes of using neoadjuvant chemotherapy in pancreatic cancer patients: Findings from the PURPLE clinical registry.
Authors: Lee Belinda , Witmond Vincent , Pereira-Salgado Amanda , Degeling Koen , Shapiro Julia , Thomson Benjamin N , Ananda Sumitra S , McLachlan Sue-Anne , Knowles Brett , Fox Adrian , Wong Rachel , Burge Matthew E. , Clarke Kate , Pattison Sharon Tracy , Nikfarjam Mehrdad , Nagrial Adnan , Zielinski Rob , Chee Cheng Ean , Gibbs Peter , IJzerman Maarten J.
Published: May 2020

e16755

Background: Only a minority of pancreatic cancer patients (pts) are surgical candidates at presentation. Neoadjuvant chemotherapy (NAT) is proposed to increase the proportion of surgical candidates. This study investigates the impact of NAT in routine care of pancreatic cancer. Three cohorts were analysed, patients with early-stage resectable (ER), borderline resectable (BR) and locally advanced (LA) pancreatic cancer. Within these groups, survival outcomes of those undergoing immediate resection (IR) was compared to those receiving NAT with nab-paclitaxel and Gemcitabine (nabPGem) and NAT with FOLFIRINOX. Methods: The PURPLE registry consists of 1492 pancreatic cancer pts from 27 hospitals in Australia, New-Zealand and Singapore, collated between 2016-2019. After exclusion of LA unresectable and metastatic pts (n = 809), 683 pts were included. Kaplan-Meir curves estimated survival between groups with 95% confidence intervals. Multivariable cox proportional hazards models adjusted for age, gender and ECOG performance status. Results: Of 683 pts, 107 received NAT and 576 underwent IR. Those in the NAT group had favourable characteristics, including younger age (mean 63 vs. 66 yrs, p < 0.01) and higher proportion of ECOG 0 vs. ≥1 (64% vs 46%) than those undergoing IR. Of those that received NAT, 64 received FOLFIRINOX and 35 nabPGem. Those receiving FOLFIRINOX were younger (mean: 60 vs. 67 yrs, p < 0.01) and were more likely ECOG 0 compared to those receiving nabPGem (72% vs. 46%, p = 0.02). Resection rates for pts undergoing IR vs. NAT were 88% vs. 50% in ER and 16% vs. 43% in BR. Rates of R0 resection margins in pts undergoing IR vs. NAT were 54% vs. 25% in ER and 6% vs. 21% in BT. Comparing ER to BR, mOS was 29.9 vs. 20.3 mths (HR: 0.54, p < 0.01). Within BR, mOS was 20.3 vs. 17.2 mths for NAT vs. IR (HR: 1.11, p = 0.74). Comparing those receiving FOLFIRINOX vs. nabPGem over all groups, mOS was 22 mths vs. 12 mths (HR: 0.31, p < 0.01). Conclusions: Real-world data confirms the use of NAT remains infrequent in this Asia-Pacific population. The use of FOLFIRINOX was associated with better survival than nabPGem based on this observational study. Improved methods for treatment selection are required. Potential biomarkers including circulating tumor DNA are being explored in the DYNAMIC-Pancreas clinical trial.
The role of response as predictor of improved outcome in advanced pancreatic cancer (APC) patients (pts) treated with first-line Gemcitabine plus Nab-paclitaxel (GemNab).
Authors: Bensi Maria , Di Stefano Brunella , Bagalà Cinzia , Spring Alexia , Chiaravalli Marta , Ribelli Marta , Camarda Floriana , Maratta Maria Grazia , Tortora Giampaolo , Salvatore Lisa
Published: May 2020

e16758

Background: GemNab is one of the first-line standard treatment (tx) of APC. To date, no predictive factors, both clinical and molecular, of benefit from this regimen exist. Two retrospective studies showed that early tumor shrinkage (ETS) can predict an improved outcome in APC pts receiving a first-line tx with FOLFIRINOX or GemNab. However, data regarding GemNab, limited to a small population of only 57 pts, seem to not confirm the association of ETS with a better outcome. Hence, we retrospectively analysed an homogeneous population of APC treated with first-line GemNab at our Institution, investigating the impact of several clinical factors, including response and ETS. Methods: APC pts receiving a first-line tx with GemNab were included in the analysis. The association of RECIST response and ETS with PFS and OS was evaluated. The following variables were collected: gender; age ( > vs ≤ 55 years and ≥ vs < 70 years ); baseline ECOG PS; Ca 19.9 baseline level (≥ vs < 200); anamnesis of diabetes; site of primary tumor (head/uncinate process vs body/tail); locally A vs metastatic (m) PC; synchronous vs metachronous; number of m sites (1 vs > 1); m sites (liver, peritoneum, lung, nodes); number of tx lines (1 vs > 1). Univariate and multivariate analyses for PFS and OS were performed. Results: A total of 184 APC pts receiving first-line GemNab at our Institution from February 2014 to May 2019 were included in the analysis. RR and ETS were assessed in 174 and 168 pts, respectively. RR was 30%, disease control rate (DCR) 63% and ETS was 24%. Responders had a significant better PFS (12.5 vs 5.7 months, p < 0.0001) and OS (25.1 vs 12.1 months, p < 0.0001). ETS was significantly associated with improved PFS (12.3 vs 6.2 months, p < 0.0001) and OS (24.0 vs 12.8 months, p < 0.0001). At the multivariate analysis a significant association with survival parameters was confirmed for RECIST response, but not for ETS. At the multivariate analysis, also metachronous disease and number of tx lines > 1 were independently associated with better OS. Conclusions: Despite its retrospective nature, this is one of the largest series of APC pts treated with first-line GemNab investigating the role of RECIST response and ETS in predicting outcome. On the basis of our results, RECIST response may be considered a positive prognostic factor, whereas ETS does not. In conclusion, achieving tumor shrinkage, not necessarily early, significantly delays PC progression and prolongs survival in pts treated with first-line GemNab.
The impact of 2nd-line treatment (tx) after 1st-line Gemcitabine plus Nab-paclitaxel (GemNab) in advanced pancreatic cancer (APC) patients (pts).
Authors: Di Stefano Brunella , Bensi Maria , Bagalà Cinzia , Spring Alexia , Chiaravalli Marta , Ribelli Marta , Maratta Maria Grazia , Camarda Floriana , Tortora Giampaolo , Salvatore Lisa
Published: May 2020

e16759

Background: Three main phase III randomized studies investigated the role of 2nd-line tx in APC pts. The PANCREOX study failed to demonstrate a survival advantage of mFOLFOX vs 5FU/LV. Conversely, the CONKO-003 and NAPOLI-1 trials, demonstrated a significant survival improvement from the combination regimen OFF and 5FU+Nal-IRI, respectively, in comparison to 5FU/LV alone. Recently, final OS analysis from NAPOLI-1 demonstrated an association of specific characteristics (ECOG PS, age, Ca 19.9 baseline level, neutrophil-to-lymphocyte ratio and no liver metastases (m)) with OS > 1 year. The main limit of all these studies was due to the period they were carried out: no pts received 1st-line GemNab. Hence, we retrospectively analysed an homogeneous population of APC treated with 1st-line GemNab at our Institution, investigating the impact of 2nd-line tx. Methods: APC pts receiving a 2nd-line tx after 1st-line GemNab were included in the analysis. The following variables were collected: gender; age ( > vs ≤ 55 years and ≥ vs < 70 years ); baseline ECOG PS (0-1 vs 2-3); Ca 19.9 baseline level (≥ vs < 200); anamnesis of diabetes; site of primary tumor (head/uncinate process vs body/tail); number of m sites (1 vs > 1); m sites (liver, peritoneum, lung, nodes); RECIST response and ETS during 1-line GemNab. Univariate and multivariate analyses for PFS and OS were performed. Results: Out of 167 APC pts progressed to 1st-line GemNab, 93 (56%) pts received a 2nd-line tx, specifically 58 pts received an oxa-based regimen, 11 FOLFIRINOX, 8 FOLFIRI and 16 pts received other tx. Median 2nd-line PFS and OS were 3.3 and 5.6 months, respectively. Out of 87 pts evaluable for response, 7 pts achieved a partial response and 27 a stable disease, with a RR and a disease control rate (DCR) of 8% and 39%, respectively. Pts with baseline ECOG PS 0-1 had a significant better outcome in comparison to pts with PS 3-4 (PFS 4.2 vs 1.2 months, p < 0.0001; OS 7.2 vs 2.6 months, p = 0.0001). This significant association with survival parameters and ECOG PS was confirmed at the multivariate analysis. Conclusions: Despite the limited number of pts evaluated and the restrospective nature of our analysis, our results are in line with previous evidences, confirming the importance of a 2nd-line combination tx, when feasible, as well in an homogeneous population of APC pts treated with 1st-line GemNab. On the basis of our results, ECOG PS may be considered a prognostic factor and the choice of 2nd-line tx should be guided in primis by the baseline general conditions of APC pts.
Liver-directed therapy (LDT) and systemic chemotherapy for pancreatic adenocarcinoma with liver metastases (PCLM): Experience of 12 years.
Authors: Goyal Shreya Prasad , Jose Jyothi , Greben Craig R. , Lobko Igor , Grimaldi Gregory Michael , Ghaly Maged , Daly Kevin P , Saif Wasif M.
Published: May 2020

e16768

Background: PCLM has a poor prognosis with a median survival of ≤6 months. Treatment options are limited as only few patients can undergo curative surgery, therefore locoregional therapies such as LDT offer an adjunct to systemic therapies. Combination of LDT and systemic therapies is a strategy to enhance the effect of radioembolization or chemotherapy alone, akin to the use of radiotherapy with chemotherapy. The purpose of this retrospective study was to evaluate the efficacy of incorporating trans-arterial radioembolization (TARE) with 90Y, trans-arterial chemoembolization (TACE), and radiofrequency ablation (RFA) with systemic chemotherapy in the treatment of PCLM. Methods: We retrospectively evaluated 42 patients, with data available on 39 patients, with PCLM who underwent LDT between February 2007 and March 2019. Patient outcomes were assessed using Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1 including disease response, median overall survival (mOS) from the time of diagnosis of metastatic disease, and mOS following receipt of LDT. Treatment-related adverse events were assessed using Common Terminology Criteria for Adverse Events (CTACE), Version 5.0. Results: Of 39 patients, 56% underwent TARE, 36% RFA, and 7.8% TACE. The selection of modality was based on institutional standards and at the discretion of the referring physician. The mOS was 5 months (range 4-5.5 months) from the application of LDT and the one-year mOS was 7.8 months (6.5-9.5 months). Overall and liver specific disease response assessed with follow-up imaging (range 4-12 weeks post therapy) was complete response in 2.5%, partial response in 59%, stable disease in 21%, and progression of disease in 18% of patients. The mean interval between the diagnosis and initial LDT was 6 months. All patients received single course of TARE for each diseased liver lobe. In 26% of patients who had bilobar liver disease, the combination treatments for both diseased lobes was defined a single course. The mean Y90 radiation dose delivered to the right lobe was 1.00 GBq and to the left lobe was 0.64 Gbq. Grade 3 toxicities included abdominal pain in 13%, hyperbilirubinemia in 7.7%, fever in 7.7%, abscess in 2.6%, and thrombocytopenia in 5.1% of patients. No treatment-related grade 4 or 5 toxicities were seen. Conclusions: LDT can be safely combined with systemic chemotherapy for the treatment of PCLM. Patient outcomes following this treatment strategy are promising but prospective evaluations are needed to validate these preliminary findings.
PhaseI/IIa Study evaluating the safety, efficacy of K-001 in advanced pancreatic ductal adenocarcinoma.
Authors: Cui Jiujie , Yang Haiyan , Chen Donghui , Hu Jiong , Zhang Haiyan , Jiao Feng , Liu Min , Liu Jue , Wang Li-Wei
Published: May 2020

e16770

Background: K-001 is a potent, oral anticancer drug made from active ingredients of marine microorganisms. Its former phase I study did not observe the dose limited toxicity (DLT). Thus, further phase I/IIa trial was conducted to determine maximum tolerated dose (MTD), safety profile and antitumor effects of K-001 in advanced pancreatic ductal adenocarcinoma (PDAC). Methods: This open-label phase I/IIa study involved a dose-escalation to determine maximum tolerated dose (MTD), recommended dose (RD) of K001 in patients with pancreatic ductal adenocarcinoma, followed to obtain preliminary evidence of efficacy in patients who could potentially benefit from treatment. Results: Doses from 1350mg to 2160mg twice daily were evaluated. No dose-limiting toxic effects were observed. Totally, 47 adverse events (AE) were observed which included 27 (57.4%) grade 1 AEs, 17 (36.2%) grade 2 AEs and 3 (6.4%) grade 3 AEs. Only 2 AEs which were indigestion and gastrointestinal flatulence were affirmed to research drug and both grade 2. These two AEs were both symptoms of digestive system. For grade 3 AEs, The AEs were not dose dependent. Twelve patients were assessable for response. Clinical activity was observed at all doses tested with durable Response Evaluation Criteria in Solid Tumor (RECIST) . The objective RECIST response rate (ORR) was 0% (complete response + partial response) and the disease control rate (DCR) was 83.3% (10 of 12). Conclusions: K001 has promising efficacy and light side-effect profile. The activity observed demonstrates clinical benefit in pancreatic ductal adenocarcinoma, justifying the conduct of further studies. Clinical trial information: NCT02720666 .
Survival outcomes of neoadjuvant versus adjuvant chemotherapy in early-stage pancreatic adenocarcinoma: A subgroup analysis of the National Cancer Database.
Authors: Kumar Rohit , Bhandari Shruti , Singh Sunny R K , Malapati Sindhu Janarthanam , Rojan Adam
Published: May 2020

e16777

Background: Early-stage disease is diagnosed in 10-20% of patients with pancreatic adenocarcinoma (PAC). The current standard of care is upfront surgery followed by adjuvant chemotherapy (AC). The administration of the latter may be limited due to postoperative complications. The aim of this study is to determine the subgroups of patients with early-stage PAC who derive maximum benefit of neoadjuvant chemotherapy (NAC). Methods: Using the National Cancer Database 2004-15, we identified 20,003 patients with clinical stage I or II PAC who had surgery and received chemotherapy in any sequence. The baseline characteristics were compared using Pearson's chi‐square test between patients who received NAC versus AC. A separate multivariate Cox-proportional Hazard regression analysis was done for each subgroup to identify patients with the maximum survival benefit from NAC. Hazard ratio (HR) < 1 connotes survival benefit in favor of NAC. Results: Of the study population, 24% of the patients received NAC. The patients in the NAC group had more PAC of head (80% vs 73%), stage II disease (72% vs 53%), CA19-9 levels 50 U/ml (66% vs 59%), multiagent chemotherapy (68% vs 27%) and were treated at an academic facility (66% vs 52%) compared to the AC group. The p-value was < 0.001 for all comparisons. The age and sex distribution were similar in both groups. On multivariate survival analysis in the overall population, NAC had improved survival compared to AC (HR 0.88 95%CI 0.82-0.93, p < 0.001). Subgroup multivariate survival analysis is shown in the table. Conclusions: In early stage PAC, there is a trend towards survival benefit of NAC compared to AC in most subgroups. The maximum benefit is seen in younger patients with Stage II disease, high CA19-9 levels and fewer comorbidities who receive multiagent chemotherapy. This finding may partly be explained by better tolerability of preoperative compared to postoperative chemotherapy. A randomized clinical trial is needed to establish the optimal chemotherapy timing in patients with early-stage PAC who are treated with curative intent. [Table: see text]
Real-world dosing, management, and clinical outcomes of patients (pts) with metastatic pancreatic adenocarcinoma (mPDAC) treated with liposomal irinotecan.
Authors: Abushahin Laith I. , Cockrum Paul , Surinach Andy , Belanger Bruce
Published: May 2020

e16780

Background: Pancreatic cancer remains one of the most lethal cancers in the United States (US) with a 5-year relative survival of 10%. Liposomal irinotecan is a topoisomerase inhibitor indicated, in combination with 5-fluorouracil and leucovorin, for pts with mPDAC following disease progression on gemcitabine-based therapy. This study examines the real-world use and therapeutic management of pts with mPDAC treated with liposomal irinotecan. Methods: This retrospective observational study utilized the Flatiron Health EHR-derived de-identified database from over 280 cancer clinics in the US. Data were analyzed for adult pts with mPDAC treated with liposomal irinotecan based regimens between Nov 2015 and Oct 2019. Pts were categorized into two starting dose groups: 70mg/m2 and < 65mg/m2. Pt characteristics, overall survival (OS), duration of treatment (DOT), and impact of dose reductions (DR, reduction ≥ 7mg/m2) were assessed among pts who received ≥3 cycles of treatment (tx). Results: Of the 532 pts (median age: 69y, IQR: 62-75) included in the study, 95 (18%) had an ECOG score of 2+ at tx initiation. Of the 184 pts (69y, 42 – 84) that did not receive 3 cycles of tx, 47 (25%) had an ECOG score of 2+ and 83 (45%) had two or more prior lines of tx. 348 pts (69y, 43 – 85) received ≥3 cycles of tx. 116 (33%) pts had two or more prior lines of tx, 209 (60%) had an ECOG score of 0-1, 48 (14%) had an ECOG score of 2+, and 91 (26%) had missing scores. 220 (63%) initiated tx at 70mg/m2 and 128 (37%) initiated at < 65mg/m2. 83 (38%) 70mg/m2 and 26 (20%) < 65mg/m2 pts experienced a DR during tx. 43 (52%) and 14 (54%) of the DRs occurred within the first 6 wks of tx in the 70mg/m2 and < 65mg/m2 cohorts, respectively. Median DOT was 12.6 weeks for 70mg/mg2 and 9.1 wks for < 65mg/m2 pts; DOT was longer among pts with a DR: 19.0 wks and 16.1 wks, respectively. Median OS (mOS) was 7.2 months (95% CI: 6.2 – 8.1) and 6.2 mos (5.0 – 7.4) for pts receiving 70mg/m2 and < 65mg/m2, respectively. mOS for pts with a DR was 8.9 mos (7.3 – 10.8) and 7.7 mos (5.0 – 14.9) for pts receiving 70mg/m2 and < 65mg/m2, respectively. mOS for pts with no DR was 6.0 mos (4.8 – 7.2) and 6.0 mos (4.7 - 7.2) for those receiving 70mg/m2 and < 65mg/m2, respectively. Conclusions: In this descriptive study among pts who were able to receive ≥3 cycles of liposomal irinotecan and remain on tx for ≥4 wks, DRs were effective in extending DOT and OS, independent of starting dose. The longest DOT and OS were observed in the pts who received 70mg/m2 with DRs. Pts who received 70mg/m2 and < 65mg/m2 had similar OS in the absence of DRs.
Effect of access to germline genetic testing on pancreatic cancer precision treatment across disease stage and ethnicity.
Authors: Esplin Edward D. , Truty Rebecca , Yang Shan , Nielsen Sarah M. , Klint Margaret , Lincoln Stephen E , Ngo Nhu , Das Kingshuk , Samadder Jewel , Nussbaum Robert Luke
Published: May 2020

e16783

Background: PARP inhibitor (PARPi) treatment was recently approved for pancreatic cancer (PaCa) patients with germline mutations in 2 DNA damage repair (DDR) genes. Despite criteria recommending germline multigene panel testing for all PaCa patients, barriers to testing remain, including among underserved populations, which limit access to precision therapies. We initiated a sponsored testing program that increases access to germline genetic testing for PaCa in two ways: 1) offering a comprehensive multigene panel, and 2) removing the barrier of cost. Here we present initial results from this program, including the diagnostic yield in patients across stages of PaCa and clinical utility of the findings. Methods: We retrospectively analyzed de-identified data from 966 PaCa patients tested on an 84 gene panel as part of the program to date. The only inclusion criterion was a willingness to participate in the sponsored program by the patient and the provider who ordered the testing. Data included likely pathogenic (LP) and pathogenic (P) mutations, disease stage and ethnicity. Results: In total, 166 (17%) patients were positive for P/LP germline mutations in 30 genes. Mutation rate by ethnicity was: Caucasian 17%, African American 12%, Hispanic 16%, Ashkenazi Jewish 20%, Asian 3%. Only 25% of patients with P/LP variants reported a family history of cancer. There was no statistical difference in mutation rates by stage (p = 0.11) [Table]. In positive patients, 83 (78%) had mutations conferring potential eligibility for DDR gene-specific precision therapies or clinical treatment trials. 28 (26%) were potentially eligible for olaparib due to BRCA1/2 mutations, 8 (7%) were potentially eligible for pembrolizumab, and 47 (44%) for PARPi clinical trials. Conclusions: This study found 8.5% of all PaCa patients tested are potentially eligible for germline-based precision therapies and/or clinical treatment trials. Of mutation positive patients, 75% did not report a family history of cancer. The positive rate was not statistically different between patients with stage I and stage IV PaCa, underscoring the recommendation to test all patients with PaCa. This program had a 1.5% increased relative uptake among African American patients compared to a standard insurance reimbursement delivery model. These data suggest reducing barriers improves PaCa patient access to genetic information that enables precision therapy. [Table: see text]