bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of prior irinotecan exposure on outcomes of metastatic pancreatic cancer (mPC) patients.
Authors: O'Reilly Eileen Mary , Surinach Andy , Dillon Allison , Cockrum Paul , Yu Kenneth H.
Published: February 2020

667

Background: Published data suggests prior exposure to irinotecan infers a lower likelihood of benefit to liposomal irinotecan. This analysis seeks to expand this hypothesis by evaluating U.S. patterns of care to understand how prior irinotecan therapy impacts outcomes in mPC. Methods: Using the Flatiron Health database, data were extracted and analyzed for treated mPC patients (pts) in the 2L+ setting between Jan 1, 2014 and Jun 30,2019. Therapies of interest included: gemcitabine/ nab-paclitaxel (GnP), FOLFOX, FOLFIRI, FOLFIRINOX (FFX), and liposomal irinotecan/5-FU/LV (nal-IRI). The reference date for each treatment group was the date of treatment initiation. Prior irinotecan was defined as any irinotecan given in a prior regimen in mPC diagnosis. Cox proportional hazard (PH) methods were used to calculate mortality hazard ratios (HRs). HRs were adjusted to account for demographics and relevant covariates. Pts with prior exposure to irinotecan were used as the reference population for the Cox PH model (an HR < 1 represents worse survival for exposed pts relative to the unexposed). Results: N = 1,978 were included in this analysis. The median age at treatment initiation, and the proportion of pts previously treated with irinotecan are reported in table. Crude mortality was: GnP pts, HR 0.93 [95% CI: 0.77 – 1.11, adjusted HR, 0.94, 0.76 – 1.15]; nal-IRI pts, HR 0.81 [0.64 – 1.02, adjusted HR: 0.89, 0.67 – 1.19]; HR for FOLFOX was 0.55 [0.38 – 0.78, adjusted HR: 0.51, 0.33 – 0.79]. HRs are not reported for FFX and FOLFIRI due to the small numbers with prior irinotecan exposure. Conclusions: In mPC, prior irinotecan treatment may not preclude benefit from later treatment with nal-IRI or GnP as can be seen from the adjusted and unadjusted HRs. These findings are hypothesis-generating and need to be considered in the context of wide CI’s, retrospective nature and the limitations of such data. Further study is required to understand the less-favorable signal observed with FOLFOX and prior irinotecan.[Table: see text]
Distinct clinical characteristics of young-onset pancreatic cancer patients.
Authors: Goksu Suleyman Yasin , Kazmi Syed Mohammad Ali , Sanford Nina Niu , Aguilera Todd Anthony , Hsieh David , Sanjeevaiah Aravind , Verma Udit , Kainthla Radhika , Khosama Leticia , Maxwell Mary Claire , Fangman Benjamin David , Bleeker Jonathan Scott , Beg Muhammad Shaalan , Atiq Muslim
Published: February 2020

674

Background: Young-onset pancreatic adenocarcinoma (YOPC) is uncommon but there are limited studies for these patients. We used a population based registry to compare the characteristics and outcomes of young-onset vs. older patients with pancreatic adenocarcinoma. Methods: We selected the patients with pancreatic adenocarcinoma from the SEER registry diagnosed between 2004 and 2015. Cases with age of diagnosis less than 50 were termed young-onset pancreatic cancer. Stage 4 patients were excluded. We compared baseline characteristics of YOPC vs. older using Chi-square. Kaplan Meier and Cox regression were used for survival analysis of these patients. Results: Of 28,904 patients, 1,415 (4.9%) had YOPC while 27,489 (95.1%) were older. YOPC were more likely to have stage 3 compared to older patients with PC (31.6% vs. 25.3%). YOPC had a higher rate of surgery than older patients (40% vs. 29.1%, p < 0.001), were more likely to be male, black and of Hispanic ethnicity. The primary tumor location was not different between the two groups. Overall survival (OS) was higher in YOPC versus older patients (12 vs. 9 months, p < 0.001). The analysis of multivariable Cox regression confirmed that there is a significant association between survival and YOPC group after adjusting for stage, grade, gender, ethnicity, surgery and race (HR 1.23, 95% CI: 1.13-1.33, p < 0.001). Conclusions: Patients with non-metastatic YOPC represent a group of patients with distinct clinical characteristics. YOPC have a higher rate of surgery and better overall survival compared to older patients. [Table: see text]
Clinicopathological features of pancreatic cancer-related diabetes.
Authors: Lee Michael , Wong Hui-Li , Tsang Erica S. , Addison Sean McKay Fenlon , Topham James T. , Karasinska Joanna , Kalloger Steve , Loree Jonathan M. , Schaeffer David F. , Renouf Daniel John
Published: February 2020

675

Background: Epidemiological studies suggest pancreatic ductal adenocarcinoma (PDAC) may be strongly interrelated with diabetes. However, little is known about the clinicopathological features of pancreatic cancer related diabetes. Methods: A retrospective chart review was undertaken of all patients with advanced PDAC treated with at least one cycle of palliative chemotherapy at BC Cancer, Vancouver between Jan 2012- Dec 2015. Diagnosis of diabetes was determined by consultation documentation and/or fasting glucose > 7mmol/L or HbA1c > 48mmol/L. Peripancreatic diabetes is defined as diabetes diagnosis < 3 years prior to PDAC diagnosis. Results: 578 patients were identified with median age 66 (49-81), 54.6% male, 39.5% non-smoker and 63.5% ECOG 0/1. 27.3% confirmed diabetics, of which 75.8% (119/157) have peripancreatic diabetes. At initial diagnosis, 11.2% were deemed upfront resectable, 44.0% borderline/locally advanced, and 55.1% metastatic. Median overall survival (OS) for the cohort based on stage of disease at initial diagnosis for borderline, locally advanced and metastatic was 22 months (16.1-27.9), 12 months (10.1-13.9) and 6 months (5.0-7.0) respectively. There was no association with diabetes status and OS noted (p = 0.58). Statistical differences were noted in BMI (24.1 v 26.1, p = 0.003), and proportion of Charlson comorbidity index (CCI) of 2 (2.2 v 88.3%, p < 0.01) between non-diabetic and diabetic patients respectively. Statistical difference between peripancreatic diabetes compared to long-term diabetes were noted in resectable status (18.6 v 7.6%, p = 0.048), weight loss > 2kg (78.6 v 60.5%, p = 0.035), hypertension (25.9 v 59.8%, p = 0.002) and dyslipidemia (18.5 v 42.7%, p = 0.024). Conclusions: The majority of patients diagnosed with advanced PDAC with diabetes appeared to develop diabetes within 3 years prior to diagnosis. Further studies to assess the potential role of pancreatic cancer screening investigations in newly diagnosed diabetics are warranted.
Changing the landscape of germline testing in patients with pancreatic adenocarcinoma.
Authors: Athens Aly , Amacker-North Lisa , Warsinske Kelly , Kadakia Kunal C. , Kim Edward S. , Salem Mohamed E. , Elrefai Sara
Published: February 2020

676

Background: Results from the POLO trial demonstrated the benefits of PARP inhibition in patients (pts) with germline BRCA-mutated metastatic pancreatic cancer (PC). In 2018, ASCO and NCCN updated their guidelines to recommend that pts with a personal history of PC undergo germline testing. We examined referral patterns and frequency of germline pathogenic variants in pts with PC. Methods: A retrospective review was performed of PC pts seen at the Levine Cancer Institute (LCI) Center for Genetics between January 2010 and September 2019. Descriptive analyses were completed on demographics and appointment outcomes. Results: A total of 201 PC pts were referred; 20 canceled and 14 no-showed their appointment. The remaining 167 were seen and included in this analysis. Most pts (59%) were referred after July 2018. The median age was 65 years (range 32-90) and 19% were < 50 years. The majority of pts were female (61%). Race was most often reported as white (72%) followed by black (20%). Reported family histories were as follows: 28 (17%) claimed at least one first-degree relative with PC; 54 (32%) claimed a first, second, or third-degree relative with PC; 24 (14%) had no known family history of PC; and 95 (57%) claimed a first-degree relative with another cancer (breast [37], prostate [25], colon [18], ovarian [9], uterine [6], and gastric [2]). Germline testing was pursued by 138 (83%) pts: 25 (18%) were found to have a pathogenic variant and 50 (36%) a variant of uncertain significance. Pathogenic variants were most commonly identified in ATM (24%), BRCA2 (20%), PALB2 (12%), and CDKN2A (8%). Variants were also observed in DIS3L2, HOXB13, MITF, MUTYH (heterozygote), NTHL1 (compound heterozygote), RAD50, PRSS1, and SDHA. Among pts that had a pathogenic variant, cascade testing was performed in 11 families (44%) for 29 individuals. Conclusions: Our data suggest that the referral of PC pts to genetics has increased following updated ASCO/NCCN guidelines. However, improved adherence to genetic counseling is needed. ATM and BRCA2 were the most common germline mutations observed. More effort to increase awareness of genetic testing and its potential implications for pts and their families is warranted and might reduce cancellations and missed visits.
Case series examining somatic test results for patients with hereditary cancer syndromes associated with gastrointestinal cancer risk.
Authors: Pauley Kristen , Koptiuch Cathryn , Greenberg Samantha , Amanda Gammon , Nevala-Plagemann Christopher , Vagher Jennie , Espinel Whitney , Gilcrease Glynn Weldon , Kohlmann Wendy , Garrido-Laguna Ignacio
Published: February 2020

680

Background: Somatic tumor testing may identify germline pathogenic variants (PV) associated with cancer predisposition syndromes. Labs differ whether they offer somatic only or paired germline analysis. Methods used by somatic testing labs, even those that include germline analysis, differ from designated germline labs that have optimized the identification of germline PV. Methods: Chart reviews were performed for patients who had testing through both somatic and designated germline laboratories. Cases with discrepant results in which germline PV were not detected by the somatic laboratory are summarized. Results: Nine cases with discrepant results. Five had paired germline testing and 4 somatic testing only. All 9 patients met the criteria to undergo designated germline testing, either for Lynch syndrome (3) or BRCA1/2 testing (6), based on personal and/or family history. Designated germline testing identified 4 MLH1, 1 BRCA1, 2 ATM, 1 MUTYH and 1 RAD50 PV not reported by the somatic labs’ tumor or germline analysis; 2 MLH1 PV were called variants of uncertain significance by somatic testing but classified as PV by ClinVar and designated germline labs. Three PV identified by designated germline labs are targets for PARP inhibitors and resulted in different treatment options. Three of the MLH1 PV were identified in patients meeting Lynch Syndrome test criteria while 1 was identified in a patient meeting BRCA1/2 criteria. Among the 5 other patients meeting BRCA1/2 test criteria, 3 had PV in breast cancer genes (2 ATM, 1 BRCA1) and 2 had PV in other cancer genes ( MUTYH and RAD50) not reported by the somatic labs, highlighting the importance of panel testing. Conclusions: Methods used by somatic labs, regardless of inclusion of germline analysis, are not equivalent to those of designated germline labs. Overlooked germline PV may miss identification of hereditary syndromes and targeted therapy opportunities (e.g. Anti-PD1 immunotherapy, PARP inhibitors). Patients meeting criteria for genetic evaluation should be referred for designated germline testing regardless of somatic testing outcomes.
Tumor downsizing following neoadjuvant therapy for borderline-resectable pancreatic adenocarcinoma.
Authors: Reza Joseph Arturo , Monreal Alberto , Meyer Patrick Hunter , Patel Swati , Zakari Ahmed , de la Fuente Sebastian
Published: February 2020

690

Background: Downstaging of pancreatic adenocarcinoma in patients presenting with nonmetastatic, unresectable disease has proven to be associated with improved clinical outcomes. Efforts at rescuing these patients to become surgical candidates are commonly attempted with a combination of systemic and radiation strategies. In this study, we aimed to determine tumor downsizing in patients that underwent neoadjuvant systemic therapy followed by a curative-intended surgical resection. Methods: A retrospective review of consecutive patients that underwent surgical resection for pancreatic adenocarcinoma following a course of neoadjuvant therapy was performed. Basic demographics, endoscopic ultrasound (EUS) findings, chemotherapy regimens and duration, rates of radiotherapy, type of surgical procedure and pathologic results were recorded. Tumor response to neoadjuvant therapy was established by correlating EUS- to pathologic tumor dimensions. Analysis of the data was done using Mann-Whitney U test, Pearson correlation and Chi-square when indicated. Results: A total of 97 patients were analyzed; 40 underwent neoadjuvant chemotherapy (13 patients also received concurrent radiation therapy). In those 57 patients that were resected upfront, EUS tended to underestimate tumor sizes significantly compared to pathologic dimensions, with an average difference between dimensions of 0.66 cm (p = 0.0004). Within the group treated with neoadjuvant chemotherapy, 90% of patients had downsizing at an average of 8% of tumor size. There were no differences in rates of tumor downsizing between FOLFIRINOX or Gemcitabine/Nac-paclitaxel treated patients. In addition, there were no correlations in margin status (R0) based on chemotherapy used, with both regimens achieving a similar rate of R0 resections (mean 61%). The type of chemotherapy regimen used did not affect the ratio of positive lymph nodes harvested. Conclusions: In patients that present with borderline resectable pancreatic adenocarcinoma, a course of neoadjuvant therapy results in tumor downsizing in a significant number allowing for margin negative resections. These results were seen regardless of the chemotherapeutic regimens utilized.
The surgical outcomes of borderline resectable or locally advanced pancreatic cancer.
Authors: Okamura Yukiyasu , Sugiura Teiichi , Ito Takaaki , Yamamoto Yusuke , Ashida Ryo , Ohgi Katsuhisa , Uesaka Katsuhiko
Published: February 2020

691

Background: Advances in multidisciplinary treatment for pancreatic cancer (PC) have increased surgical opportunities for initially unresectable locally advanced (UR-LA) or borderline resectable PC. In order to obtain a high rate of R0 resection, it is important to select an appropriate approach according to the infiltration site of the artery that can determine whether curative surgery is possible or not at early phase of the operation. Methods: From April 2012 to December 2018, 81 patients who were scheduled for curative resection for UR-LA or borderline resectable PC that contact the main artery (BR-A). In our institution, if a tumor is in contact with the superior mesenteric artery (SMA), we select the mesenteric approach. And if a tumor is in contact with the common hepatic artery (CHA) and/or celiac artery (CA), we open the lesser omentum and then dissect from the cranial side of pancreas to the diaphragm leg to judge the resectability before dividing the stomach. When arterial plexus infiltration is observed during surgery, we abandoned curative surgery or we performed combined resection of CHA and reconstruction if possible. Results: There were 69 BR-A and 12 UR-LA patients. Macroscopic curative resection was performed in 67 (83%) of 81 patients, and 14 patients were unresectable. Pancreatoduodenectomy was performed in 54 patients, distal pancreatectomy (DP) in 8, and DP with celiac axis resection in 7. There were 67 patients with vascular resection / reconstruction. R0 resection was obtained in 64 of 67 patients among curative resection. The median blood loss, operation time, and length of hospital stay were 714 mL, 439 minutes, and 19 days, respectively. The complications of Clavien-Dindo grade 3a or higher were observed in 18 patients (27%). There were no post-operative deaths. The 3-year survival rate after surgery was 70.3%, and there was no significant difference between BR-A and UR-LA (P = 0.701). The 3-year recurrence-free survival rate after surgery was 34.4%, which was not significantly different between the two groups (P = 0.816). Conclusions: A high R0 resection rate (96%) was obtained by an appropriate approach that can determine the resectability at early stage of operation, and high R0 rate leads to good outcomes.
Use of gastrin vaccine to increase gamma-delta and NKT cells and alter pancreas tumor microenvironment to improve survival.
Authors: Smith Jill P , Osborne Nicholas , Sundseth Rebecca , Cao Hong , Gay Martha D , Tucker Robin D. , Kroemer Alexander H , Sutton Lynda Youngpeter , Cato Allen
Published: February 2020

696

Background: Pancreatic cancer (PC) has been called a “cold” tumor as it responds poorly to immune-based therapies. Strategies to render PC susceptible to immunotherapy are under investigation by methods that alter immune cell signatures such as increasing the population of double negative CD4-CD8-T-cells, or changing the polarization of tumor-associated macrophages (TAMs). Our current aim was to determine if a gastrin vaccine, Polyclonal Antibody Stimulator (PAS) influences double negative T-cell phenotype and polarization of TAMs to improve survival of PC. Methods: Two cohorts of C57BL/6 mice were injected either sc or orthotopically with syngeneic mT3 murine pancreatic cancer cells. After 1 week, groups were treated with PBS; PAS (100μg); PD-1 antibody (150μg); or the combination of PAS and PD-1 Ab. PAS was given ip at weeks 0, 1 and 3. Anti-PD-1 was given on days 0, 4, 8, 15 and 21. Spleens were collected from the sc experiment for T-cell surface analysis by flow cytometry. Orthotopic tumors were measured for growth rate, metastases, and stained for M1 (inos) and M2 (arginase) polarized TAMs, and mouse survival was analyzed. Results: PAS therapy increased expression of double negative T-cells. The percentage of gamma-delta T-cells in the (CD3+/CD4−/CD8−/CD44−/CD62L−) TEMRA subpopulation of mice treated with PAS or combinations of PAS with PD-1 Ab were increased approximately 40% compared to PBS-treated controls or PD-1 Ab-treated mice. NKT cells from PAS-vaccinated mice were 2.5-fold higher than controls. M2+ TAMS were significantly decreased in tumors of PAS treated mice compared to PBS treated mice (p = 0.017). PAS monotherapy resulted in a nearly 10-fold increase in M1 TAMs relative to controls (p = 0.002). PAS monotherapy decreased tumor metastases by 69% and prolonged survival. Primary tumor growth decreased with PAS in combination with PD-1 Ab (p=0.0025). Conclusions: PAS decreases PC tumor growth and metastases by increasing CD4-CD8-, gamma-delta, and NKT T-cell populations. Furthermore, PAS monotherapy significantly increases M1 and decreases M2 TAMs. These immune cell changes with PAS vaccination may render tumors more susceptible to other cancer therapies and improve survival.
Phase II study of preoperative chemotherapy with nab-paclitaxel and gemcitabine followed by chemoradiation for borderline resectable or node-positive pancreatic ductal adenocarcinoma.
Authors: Chen Emerson Yu-sheng , Tormoen Garth William , Kardosh Adel , Nabavizadeh Nima , Foster Bryan , Mayo Skye C. , Billingsley Kevin G. , Gilbert Erin W. , Lanciault Christian , Grossberg Aaron , Bensch Kenneth Gregory , Maynard Erin , Anderson Eric C. , Sheppard Brett C. , Thomas Charles R. , Lopez Charles D. , Vaccaro Gina M. ,   OHSU Gastrointestinal Cancer Disease Group
Published: February 2020

697

Background: Pre-operative therapy for resectable pancreatic ductal adenocarcinoma (PDAC) may eliminate micro-metastatic disease early and help achieve negative surgical margins. The present study is based on the hypothesis that gemcitabine/nab-paclitaxel chemotherapy followed by chemo-radiation with fluoropyrimidine is a feasible and efficacious pre-operative treatment for borderline resectable or node-positive PDAC. Methods: This is a single-arm phase II trial to evaluate pre-operative treatment with 2 cycles of gemcitabine 1000 mg/m2 and nab-paclitaxel 125 mg/m2 on days 1, 8, 15 every 28 days followed by 50.4 Gy of intensity-modulated radiation therapy over 28 fractions with concurrent 5-fluorouracil or capecitabine prior to pancreatic resection. Patients were eligible if they met borderline resectable criteria or had abnormal regional nodes visible on contrast CT. After surgery, they were eligible to receive up to 4 additional cycles of gemcitabine/nab-paclitaxel. The primary endpoint was the R0 resection rate. Secondary endpoints included response to pre-operative therapy, overall toxicities, relapse-free survival, and overall survival. Results: Nineteen of 24 screened patients have been enrolled. Median age was 68, 10 (53%) were female, and 4 (21%) were non-Caucasian. Eleven (78%) had head of pancreas cancers, 13 (68%) exhibited both arterial and venous involvement, and 12 (63%) had positive clinical nodes. All 19 patients received 2 months of gemcitabine/nab-paclitaxel, of which 17 patients continued to chemo-radiation (1 developed metastatic disease and 1 moved out of state). In the interval between chemo-radiation and surgery, 3 developed metastatic disease, 1 became unresectable, 1 withdrew from study, and 1 was deemed too frail for surgery. Nine have undergone successful pancreatic resection, and 2 are pending resection. Conclusions: Pre-operative gemcitabine/nab-paclitaxel followed by chemo-radiation with fluoropyrimidine is feasible in patients with borderline resectable PDAC and represents another strategy to FOLFIRINOX-based therapy. A planned interim analysis is ongoing. Clinical trial information: NCT02427841.
Phase II clinical trial of novel agent PBI-05204 in patients with metastatic pancreatic adenocarcinoma (mPDA).
Authors: Roth Marc Thomas , Cardin Dana Backlund , Borazanci Erkut Hasan , Steinbach Margaux , Picozzi Vincent J. , Rosemurgy Alexander , Wadlow Raymond Couric , Newman Robert A. , Berlin Jordan
Published: February 2020

698

Background: Survival statistics for mPDA are dismal and with limited treatment options novel agents are needed to improve disease outcomes. PBI-05204 (Phoenix Biotechnology, Inc., San Antonio, TX) is a modified supercritical carbon dioxide extract of Nerium oleander leaves. Oleandrin, the extract’s major cytotoxic component, has demonstrated anti-tumor activity in various tumor cell lines. In a human PDA orthotopic model, this preparation reduced tumor burden as monotherapy. Pharmacodynamic studies suggest that PBI-05204’s mechanism of action is through inhibition of the PI3k/Akt/mTOR pathway. Methods: A phase II single-arm, open-label study to determine the efficacy of PBI-05204 in patients (pts) with mPDA refractory to standard therapy was conducted. The primary endpoint was overall survival (OS) with the hypothesis that 50% of pts would be alive at 4.5 months. Secondary objectives included safety, progression-free survival (PFS), and overall response rate. Pts received oral PBI-05204 daily until progressive disease (PD), unacceptable toxicity, or pt withdrawal. Radiographic response was assessed every two cycles. Results: Forty-one pts were enrolled; two never received treatment and one was found to have a neuroendocrine tumor after pathological re-evaluation, leaving 38 pts for analysis. Median age at time of enrollment was 65.0 years. The median time from initial diagnosis to treatment was 16.9 months. The primary reason for withdrawal was PD (45.2%). Ten pts were alive at 4.5 months (26.3%) with a mPFS of 56 days (corresponding to first restaging). One objective response (2.6%) was observed for 162 days. Grade ≥3 treatment-emergent adverse events occurred in 63.2% of pts with the most common attributed to drug (all grades) being fatigue (36.8%), vomiting (23.7%), nausea (18.4%), decreased appetite (18.4%), and diarrhea (15.8%). Conclusions: PBI-05204 did not meet its primary endpoint for OS in this study. Recent preclinical data indicate an efficacious role for PBI-05204 against glioblastoma multiforme when combined with chemotherapy, such as temozolomide, and radiotherapy. A randomized Phase II trial is currently being designed. Clinical trial information: NCT02329717.
Attenuated regimen of biweekly gemcitabine/nab-paclitaxel in patients aged > 65 years with advanced pancreatic cancer (APC).
Authors: Rehman Hasan , Chi Jeffrey , Hakim Nausheen , Goyal Shreya Prasad , Olazagasti Coral , Jose Jyothi , Moriarty Linda , Saif Wasif M.
Published: February 2020

705

Background: Treatment with gemcitabine/nab-paclitaxel confers a survival benefit over gemcitabine monotherapy in APC. However, such treatment can be associated with significant toxicities especially in older patients and carries practical disadvantages related to a weekly schedule along with financial cost. We retrospectively analyzed patients > 65 years of age with APC who received a modified biweekly regimen of gemcitabine/nab-paclitaxel to evaluate efficacy and toxicity. Methods: Patients aged > 65 years with chemo-naive APC and ECOG PS < 2 were studied. Patients were treated with a modified regimen of gemcitabine 1000 mg/m2 and nab-paclitaxel 125 mg/m2 every 2 weeks on days 1 and 15 of a 28-day cycle. Patients were evaluated for progression-free survival (PFS) and overall survival (OS) with analyses performed using Kaplan-Meier method. Adverse events were recorded on the day of chemotherapy. CA19-9 was measured every cycle and restaging scans were performed every two cycles. Results: Seventy-three patients (median age: 73; range: 66 - 93) were treated with biweekly gemcitabine/nab-paclitaxel as first-line treatment. The median OS and PFS were 9.1 months and 4.8 months respectively. 66% of patients received growth factor support based on ASCO guidelines and no patients developed neutropenic fever. The incidence of grade > 3 toxicity for neutropenia, anemia, thrombocytopenia, and neurotoxicity were 2%, 7%, 3%, and 5% respectively. Dose reductions of gemcitabine/nab-paclitaxel were required in 10% and 4% patients respectively. Conclusions: In patients > 65 years of age with APC, a modified regimen of biweekly gemcitabine/nab-paclitaxel was found to be effective when compared with historical control from the MPACT study. This regimen allowed for less dose reductions, reduced healthcare costs from additional appointments, travel-related cost, as well as favorable side effect profile while maintaining efficacy. Though retrospective in nature, this study underlines the need for further investigation, particularly in elderly patients with APC and poor performance status. Better tolerability may allow for combination with a third agent, such as a targeted or immunotherapy.
Neoadjuvant therapy guideline adherence for locally advanced rectal cancers in a region with sociodemographic disparities.
Authors: Wong Denise , Hendrick Leah E. , Guerrero Whitney M. , Monroe Justin J. , Hinkle Nathan M. , Deneve Jeremiah Lee , Glazer Evan Scott , Shibata David
Published: February 2020

71

Background: Quality and practice guidelines from the American College of Surgeons Commission on Cancer (CoC) and the National Comprehensive Cancer Network (NCCN) recommend neoadjuvant chemoradiation (NCR) for locally advanced rectal cancer (LARC). We examined guideline adherence in a healthcare system serving a region with significant socioeconomic disparities and poor cancer outcomes. Methods: We performed a retrospective analysis of patients from 2005-2014 with stage II and III rectal cancer in our local 5- hospital healthcare system in the Mid-South region of the US. We examined the associations between guideline adherence and patient demographic, socioeconomic, and clinicopathologic data. Results: Of 157 stage II/III RC patients, 96 (61.1%) received NCR. By univariate analysis, factors associated with receipt of NCR included white race versus non-white (OR = 2.14, p = 0.024), private insurance versus no or public insurance (OR = 2.70, p = 0.005), employed status versus unemployed (OR = 2.29, p = 0.031), age at diagnosis (OR = 0.74, p = 0.032), and appropriate local staging with EUS or MRI (OR = 6.67, p = < 0.0001). Those who were diagnosed and treated later in the study period were more likely to get NCR (OR per 1 year = 1.20, p = 0.006). In addition, receipt of NCR was protective against death at time of follow up (OR = 0.41, p = 0.009). By multivariate analysis, those with private insurance (OR = 2.51, p = 0.023), younger age at diagnosis (OR per 10 years = 1.39, p = 0.048) and with appropriate local staging (OR = 6.67, p < 0.0001) were more likely to have received NCR. Conclusions: Guideline adherence for LARC in our system, which serves a population with socioeconomic disparities, is relatively low. Sociodemographic factors such as employment and race influenced receipt of NCR, while insurance status and age were independent determinants. Despite some increase in compliance over time, adherence to NCR for LARC remains lower than expected and represents an important target for improvement efforts.
Efficacy of SBP-101, in combination with gemcitabine and nab-paclitaxel, in first-line treatment of metastatic pancreatic ductal adenocarcinoma.
Authors: Kotasek Dusan , Nagrial Adnan , Lumba Sumit , Tebbutt Niall C. , George Thomas J. , Smith Sheri Lynn , Gagnon Suzanne , Cullen Michael T. , Walker Michael J.
Published: February 2020

710

Background: SBP-101, a polyamine metabolic inhibitor, inhibited growth in 6 human pancreatic ductal adenocarcinoma (PDA) cell lines and 3 murine xenograft tumor models of human PDA. SBP-101 monotherapy in heavily pre-treated PDA patients (> 2 prior regimens, N=4) showed a median survival of 5.9 months at the optimal dose level. Purpose: To assess the safety, tolerability, PK, and efficacy of SBP-101 in combination with gemcitabine (G) and nab-paclitaxel (A) in patients with previously untreated metastatic PDA. Methods: In a modified 3+3 dose escalation scheme, subcutaneous injections of SBP-101 were dosed at 0.2, 0.4 or 0.6 mg/kg days 1-5 of each 28-day cycle. G (1000 mg/m2) and A (125 mg/m2) were administered intravenously on Days 1, 8, and 15 of each cycle. Safety and tolerability were evaluated by clinical and laboratory assessments. PK was evaluated on day 1 of cycle 1. Efficacy was assessed by CA19-9 levels, objective response as assessed by RECIST criteria, progression-free survival (PFS) and overall survival (OS). Results: Fifteen patients have been enrolled in 3 cohorts (1: N=4, 2: N=7, 3: N=4) and received up to 6 cycles of treatment (7 subjects are ongoing in cohorts 2 and 3). The most common adverse events related to SBP-101 are fatigue (N=4), nausea (N=2) and injection site pain (N=2). There is no evidence of SBP-101-related bone marrow suppression or peripheral neuropathy. One patient in cohort 2 developed grade 3-4 reversible liver enzyme elevation. PK parameters in cohort 1 were below the limits of detection at most time points, but plasma Cmax and AUC0-t were measurable in cohorts 2 and 3. In those cohorts, CA19-9 levels decreased 76-95% in 7 of 8 evaluable subjects (1 additional subject TBD), with 5 patients achieving partial responses (4 ongoing) and 1 achieving stable disease. Median PFS and OS have not yet been reached. Conclusions: Preliminary results suggest SBP-101 is well tolerated when administered with G and A. Signals of efficacy support continued development of SBP-101 in combination first-line treatment for PDA. Clinical trial information: NCT03412799.
Modified FOLFIRINOX versus sequential chemotherapy (FOLFIRI/FOLFOX) as second-line treatment for advanced pancreatic adenocarcinoma: A real-world analysis.
Authors: Tezuka Shun , Ueno Makoto , Kobayashi Satoshi , Morimoto Manabu , Nagashima Shuhei , Sano Yusuke , Asama Hiroyuki , Kawano Kuniyuki , Tanaka Satoshi , Fukushima Taito
Published: February 2020

711

Background: Therapy options for second-line treatment of advanced pancreatic adenocarcinoma (PDAC) are limited and preferred regimens have not been established. This study compared the efficacy and safety of modified FOLFIRINOX (mFFX) and sequential chemotherapy (FOLFIRI/FOLFOX) as second-line treatment for advanced PDAC. Methods: This was a retrospective single-center analysis of all patients who received mFFX or sequential chemotherapy between December 2014 and May 2019 as second-line treatment for advanced PDAC. The sequential arm included all patients intended to be treated with sequential chemotherapy even if finished with either FOLFIRI or FOLFOX. For efficacy analysis, progression-free survival (PFS), overall survival (OS), and response rate (RR)of all the patients, excluding those with locally advanced pancreatic cancer (LAPC), were evaluated. For safety analysis, we evaluated the incidence of grade ≥3 adverse events in all the patients. Results: Seventy-four patients (mFFX 44; sequential 30) were included.The patients characteristics (mFFX/sequential) are as follows:median age 64/67 years, performance status (ECOG) 0 50%/53%, and LAPC 16%/13%. In contrast to sequential therapy, the mFFX group showed better OS and RR. However, there was no significant difference between mFFX and sequential therapy in PFS (median 4.4 [95% confidence interval (CI) 1.8-7.9] vs. 4.6 [95% CI 2.0-6.2] months; hazard ratio [HR] 0.88 [95% CI 0.51-1.56]; p = 0.657), OS (median 10.6 [95% CI 5.9-13.8] vs. 8.5 [95% CI 5.0-12.2] months; HR 0.71 [95% CI 0.37-1.41]; p = 0.318), and RR (8.1% vs. 3.8%; odds ratio 1.94 [95% CI 0.19-19.87]; p = 1.000). In the safety analysis, grade ≥3 rates of neutropenia, febrile neutropenia, and anorexia were 36.4%, 6.8%, and 16.0%, respectively, with mFFX and 0%, 0% and 3.3%, respectively, with sequential chemotherapy. Conclusions: Whereas certain trends were observed, there were no significant differences in efficacy between mFFX and sequential chemotherapy. Considering the incidence of grade ≥3 adverse events with mFFX, sequential chemotherapy could be considered as one of the second-line treatment options for advanced PDAC.
A phase I/II study combining a TMZ-CD40L/4-1BBL-armed oncolytic adenovirus and nab-paclitaxel/gemcitabine chemotherapy in advanced pancreatic cancer: An interim report.
Authors: Musher Benjamin Leon , Smaglo Brandon George , Abidi Wasif , Othman Mohamed , Patel Kalpesh , Jing James , Stanietzky Nir , Lu Jinyu (Jim) , Brisco Amanda , Wenthe Jessica , Brenner Benjamin , Eriksson Emma , Leen Ann M. , Hilsenbeck Susan G. , Ullenhag Gustav J. , Rowinsky Eric Keith , Grilley Bambj , Loskog Angelica Sara Ingrid
Published: February 2020

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Background: Pancreatic ductal adenocarcinoma (PDAC) has been highly resistant to immunotherapeutics to date. LOAd703, an oncolytic adenovirus with transgenes encoding TMZ-CD40L and 4-1BBL, has been shown to lyse tumor cells selectively, induce anti-tumor cytotoxic T-cell responses, reduce myeloid-derived suppressor cell (MDSC) infiltration, and induce tumor regression in preclinical studies. Methods: In this phase I/II trial, patients with unresectable or metastatic PDAC are treated with LOAd703 intratumoral injections and standard nab-paclitaxel/gemcitabine (nab-P/G) chemotherapy. Starting on cycle 1 day 15 of nab-P/G, LOAd703 is injected with image guidance into the primary pancreatic tumor or a metastasis every 2 weeks for 6 injections. In the event of sustained tumor control, subjects are eligible to receive 6 more injections. Three dose levels of LOAd703 are being investigated using a BOIN dose escalation design. Primary endpoints are safety and feasibility. Secondary endpoints include response rate and overall survival. Results: To date, 13 subjects are evaluable for safety and feasibility. Three patients were treated at dose 1 (5x10e10 VP), 4 subjects at dose 2 (1x10e11 VP), and 6 subjects at dose 3 (5x10e11 VP). The most common adverse events (AEs) attributed to LOAd703 have been fever, chills, nausea, and increased transaminases. AEs have been transient and grade 1-2, with the exception of a grade 3 transaminase elevation in 1 subject receiving dose 3 (the only dose-limiting toxicity observed thus far). During protocol treatment, circulating MDSCs decreased in 8/13 subjects while effector memory T-cells increased in 10/13. ELISPOT analyses showed a rise in tumor antigen-specific T-cells in 10/13 subjects. At the lowest dose level, best response was stable disease, and 6/10 patients who received higher LOAd703 doses have had partial responses. Only 1 patient has had progressive disease as best response. Conclusions: Adding LOAd703 to nab-P/G has been safe and feasible. Treatment-emergent immune responses have been demonstrated in most subjects, with a notable proportion having objective anti-tumor responses. Clinical trial information: NCT02705196.
Clinical and pathologic characteristics of early-onset colorectal cancer (EoCRC).
Authors: Arif Arif Ahmad , Chahal Daljeet , Speers Caroline , Gill Sharlene , Donnellan Fergal , Loree Jonathan M.
Published: February 2020

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Background: Although CRC incidence continues to fall in patients over 50 due to adoption of screening programs, there has been an increasing incidence in patients < 50 where screening does not occur. We investigated the clinical and pathologic characteristics of EoCRC in BC. Methods: We retrospectively analyzed 27612 patients diagnosed with CRC and referred to BC Cancer between 1990-2016. Patients < 50 were classified as early onset CRC and analyzed for baseline and disease characteristics. Results: In the 2540/27612 (9.2%) of patients < 50, patients were more likely to be female (OR 1.33, 95% CI 0.61-1.44, P < 0.0001), have left sided tumors (OR 1.50, 95% CI 1.35-2.01, P < 0.0001), have poorly differentiated tumors (OR 1.24, 95% CI 1.10-1.34, P = 0.0003), and more patients presented with metastatic disease (OR 1.26, 95% CI 1.15-1.38, P < 0.0001) compared to patients ≥50. At diagnosis, patients < 50 were more likely to have a significant complication related to the primary tumor (OR 1.18, 95% CI 1.06-1.32, P = 0.0041), specifically, greater rates of perforation (OR 1.84, 95% CI 1.47-2.31, P < 0.0001). Although high risk features used to guide adjuvant therapy decisions in patients < 50 with stage II CRC were not higher, with similar T4 prevalence, poor differentiation, lymphovascular and perineural invasion, and less inadequate lymph node harvesting (≤12) (all p > 0.05), rates of adjuvant therapy were higher (OR 2.39, 95% CI 1.91-3.00, P < 0.0001). This was also noted in stage III CRC (OR 4.11 95% CI 3.07-5.48, P < 0.0001). Age impacted overall survival, with younger patients of all stages living longer (HR 0.72, 95% CI 0.68-0.76, P < 0.0001). Similar findings were noted for stage I-III CRC (HR 0.54 0.50-0.58, P < 0.0001) and for patients once they became metastatic (HR 0.84 95% CI 0.75-0.93, P = 0.0025). To control for competing causes of death, we looked at disease specific survival, which continued to show improved outcomes for patients age < 50 in stage I-III (HR 0.88 95% CI 0.81-0.97, P = 0.0016) and stage IV (HR 0.77 95% CI 0.72-0.84, P < 0.0001) CRC. Conclusions: EoCRC patients present with unique clinical and pathologic characteristics which may impact outcome. While the population < 50 has comparable outcomes, they may undergo increased rates of treatment.
Efficacy and safety of mFOLFIRINOX in patients with borderline resectable and locally advanced unresectable pancreatic cancer: Intention-to-treat population analysis.
Authors: Hwang Inhwan , Yoo Changhoon , Kim Kyu-Pyo , Byun Jae Ho , Jeong Jae Ho , Chang Heung-Moon , Ryoo Baek-Yeol
Published: February 2020

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Background: Borderline resectable pancreatic cancer (BRPC) and locally advanced unresectable pancreatic cancer (LAUPC) are heterogeneous disease entity with various prognosis. Based on the phase III PRODIGE trial, (m)FOLFIRINOX has been widely used for the management of patients with BRPC and LAUPC. Considering the lack of large phase 3 trial of (m)FOLFIRINOX for BRPC and LAUPC, real-life evidences of (m)FOLFIRINOX are needed. Methods: In this retrospective analysis, 199 patients who received at least one dose of (m)FOLFIRINOX between February 2013 and January 2017 were included. Endpoints of this study were objective response rates (ORR), surgical resection rate, progression-free survival (PFS) and overall survival (OS). Results: Median age was 60 years (range, 33-79) and 62.3% of patients were male. Pancreas head (n=112, 56.3%) was the most common primary tumor site, followed by body (n=42, 21.1%) and multifocal (n=34, 17.1%). By an independent radiology review, patients were classified to BRPC (n=75, 37.7%) and LAUPC (n=124, 62.3%). With median 40.3 months (95% CI, 36.7-43.8) of follow-up duration in surviving patients, ORR was 26.6% (n=53), median PFS and OS were 10.6 months (95% CI, 9.5-11.7) and 17.1 months (95% CI, 13.2-20.9), respectively. There was no difference in PFS and OS between BRPC and LAUPC (median PFS, 11.1 months [95% CI, 8.8-13.5] vs. 10.1 months [95% CI, 8.4-11.8], p=0.47); (median OS, 18.4 months [95% CI, 16.1-20.8] vs. 17.1 months [95% CI, 13.2-20.9], p=0.50). Curative-intent surgery (R0 and R1) was done in 63 patients (33.2%, 49 for R0 and 14 for R1) after treatment with (m)FOLFIRINOX. Resection rates were 58.2% in BRPC patients and 19.4% in LAUPC patients (p<0.001). In patients who underwent curative-intent surgery, median disease-free survival since surgery was 10.4 months (95% CI, 8.3-12.5 ) and there was no difference according to the baseline disease extent (BRPC vs. LAUPC): 10.0 months (95% CI, 7.5-12.5) vs. 12.0 months (95% CI, 3.7-20.3), p=0.37. Conclusions: (m)FOLFIRINOX is effective therapy for BRPC and LAUPC patients. Significant proportion of patients could receive curative-intent surgery.
Phase II trial of BPM31510-IV plus gemcitabine in advanced pancreatic ductal adenocarcinomas (PDAC).
Authors: Kundranda Madappa N. , Propper David , Ritch Paul S. , Strauss James , Hidalgo Manuel , Gillmore Roopinder , Sarangarajan Rangaprasad , Narain Niven R. , Kiebish Michael A. , Rodrigues Leonardo O , Granger Elder , Ramanathan Ramesh , Alistar Angela Tatiana , Bui Lynne A. , Chawla Sant P. , Niewiarowska Anna A.
Published: February 2020

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Background: BPM31510-IV is an Ubidecarenone (CoQ10) drug-lipid conjugate nanodispersion targeting metabolic machinery in cancer, shifting bioenergetics from lactate dependency towards mitochondrial OxPhos to generate ROS and activate apoptosis. An MTD of BPM31510-IV in combination with gemcitabine was established at 110mg/kg in a Phase I clinical trial, which determined the dose for the Phase 2 investigation. Methods: Eligible patients (aged ≥ 18 y) with relapsed/refractory PDAC to standard treatment (ST) and met inclusion/exclusion criteria were recruited. Patients received 110mg/kg IV BPM31510 in combination with gemcitabine in a 144-hour infusion. Tumor response was evaluated at week 10 and then every 8 weeks. Study endpoints assessed were Overall Response Rate (ORR), Overall Survival (OS), Progression-Free Survival (PFS), Time to Progression (TTP), Tumor Response using Adaptive Molecular Responses (multi-omic molecular profiling), changes in CA 19-9 levels and patient reported Quality of Life (QOL) using the validated FACT-HEP PRO. A comprehensive multi-omic profiling for identification of biomarkers for patient stratification was explored. Results: Of the 35 patients enrolled to receive therapy, 18 patients met criteria of an adequately treated cohort (ATC- received BPM31510-IV + gemcitabine for 30 days over 2 cycles and had a RECIST 1.1 evaluation) while remaining (n = 17) had progressive disease (PD). Half of the ATC population (n = 9/18, 50%) achieved best ORR of stable disease (SD); 10/18 (55 %) demonstrated SD as best response at target lesions and 8/18 demonstrated SD at end of Cycle 2. The mTTP was 121 days (70 – 147, 95% CI); PFS 118 days (70 – 131, 95% CI) and OS 218 days (131 – 228, 95% CI), respectively. Overall, BPM31510-IV was well tolerated; the most common AE’s were GI related. Conclusions: The efficacy signal observed in this heavily pretreated population in addition to the toxicity profile warrants further clinical investigation of BPM31510-IV + gemcitabine in advanced PDAC. Clinical trial information: NCT02650804 . [Table: see text]
A prospective trial of elemental enteral feeding in patients with pancreatic cancer cachexia (PANCAX-1).
Authors: Hendifar Andrew Eugene , Gresham Gillian , Kim Haesoo , Guan Michelle , Liu Jar-Yee , Minton Brian , Bhuiyan Diane , Langeslay Ruby , Rogatko Andre , Gong Jun , Placencio-Hickok Veronica
Published: February 2020

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Background: Unintentional weight loss affecting > 85% of pancreatic cancer (PC) patients contributes to low therapeutic tolerance, reduced quality of life, and overall mortality. Optimal treatment approaches have not been developed. We hypothesize that peptide-based enteral nutritional support in cachectic advanced PC patients, receiving palliative chemotherapy, results in improved weight, lean body mass (LBM), and hand-grip strength. Methods: Pancreatic adenocarcinoma patients with cachexia (> 5% unintentional weight loss within the previous 6 months) were provided a jejunal tube peptide-based diet for 3 months. Primary outcome was weight stability (0.1kg/BMI unit decrease). Secondary outcomes included changes from baseline in LBM, bone mineral density (BMD), total body fat mass (BFM), handgrip strength, physical activity (Fitbit), and CA19-9 and CRP. Planned interim analysis was performed after 14 patients completed treatment. Results: From 31 consenting patients, 16 were evaluable for the primary outcome. Patients receiving enteral therapy were 39% male, median age 69 (Range: 41 to 89 years), and 74% ECOG 1. A summary of change in outcomes at 3 months from baseline is shown in Table. The primary endpoint of weight stability in 10 (62.5%) patients was met, thus completing study. Overall survival was 6.5 months (n=31) and 9.9 months for evaluable patients (n=16). Weight stability was statistically associated with LBM (Pearson’s correlation: 0.87, p<0.001), but not survival (HR: 0.94, 95% CI 0.32, 2.83, p=0.92). Conclusions: Peptide-based enteral feeding resulted in weight stability and improvements in lean body mass and physical function. Further randomized trials assessing nutritional support in advanced patients are warranted. NIH/NCATS Grant # UL1TR000124. Clinical trial information: NCT02400398 . [Table: see text]