bluuebunny/crossref_metadata_2025 huggingface dataset:
Improved surgical margins with neoadjuvant versus adjuvant chemotherapy in clinical stage I resectable pancreatic adenocarcinoma: A National Cancer Database study.
Authors: Bellini Geoffrey , Datta Samit Kumar , Sich Nicholas , Singh Maharaj , Weese James Leighton , Sanchez Federico Augusto , Guda Nalini , Papenfuss Wesley Allan , Chevinsky Aaron
Published: February 2020

651

Background: A strengthening consensus exists for neoadjuvant therapy (NAT) in borderline resectable pancreatic adenocarcinoma (PA), but the utilization of NAT in resectable stage I PA remains controversial. Many cancer centers are using NAT for these patients (pts), but others continue to offer upfront surgery and adjuvant therapy (AT). We hypothesized that NAT would improve margin negative resection in clinical stage I resectable PA. Methods: We utilized the IRB approved 2016 national cancer database for pancreas to establish a cohort of stage I PA pts. We divided this subset into pts who underwent NAT vs AT. We compared demographics. Primary endpoint was surgical margins. Results: 10,453pts from 2004 to 2016 had clinical stage I resectable PA: 8483pts (81.1%) AT and 1970pts (18.9%) total or partial NAT. There was a statistical difference in age (64.9 ± 9.9years NAT and 66.2 ± 9.9years AT, p<0.001), but no difference in Charlson comorbidity score (p=0.1693). NAT pts had significantly higher margin negative resection rates (84.5%) than AT pts (79.4%) (p<0.0001). Final pathologic staging was available for 10,237 pts: 8369 (81.8%) AT and 1868 (18.2%) NAT. Significantly fewer pts were upstaged on final pathology to stage II or greater (73.5%) in the NAT group than the AT group (84.1%) (p<0.001). Conclusions: NAT leads to significantly higher margin negative rates for resectable clinical stage I PA than surgery followed by AT. The majority of pts for both groups were upstaged suggesting that we continue to clinically understage the majority of pts. Overall, total or partial NAT for clinical stage I resectable PA provides a better chance for margin negative resection. Further study in the form of a randomized control trial is necessary. [Table: see text]
An institutional series of early-onset pancreatic cancer (EOPC): Clinical outcomes and genetic and supportive care referral patterns.
Authors: Kadakia Kunal C. , Trufan Sally Jeanne , Jagosky Megan , Worrilow William Mills , Harrison Bradley W. , Broyhill Katherine , Gower Nicole Lee , Coley Harris , Hwang Jimmy J. , Musselwhite Laura W. , Nazemzadeh Reza , Chai Seungjean , Salmon John Stuart , Kim Edward S. , Salem Mohamed E.
Published: February 2020

652

Background: The incidence of EOPC is rising and is associated with substantial implications for affected individuals and their families. Little is known about the extent of physician referrals of these patients (pts) to genetic, supportive care, and hospice services. Methods: Pts with EOPC (≤50 years) were identified using the institutional tumor registry for years 2011-2018 and retrospectively reviewed. Clinical data and rates of referral to supportive, genetic and hospice services were retrieved. Descriptive analyses were performed with 25-75% interquartile ranges (IQR) where appropriate. Overall survival (OS) was assessed using Kaplan-Meier curves and Cox Proportional Hazards modeling. Results: In total, 113 pts with EOPC and a median age of 47 years (range, 28-50) were analyzed. Of these 113 pts, 43% were female, 27% were black, and 45% had metastatic disease at initial presentation. The most commonly administered first line chemotherapy was FOLFIRINOX, with gemcitabine/nab-paclitaxel reserved for the second line. The median OS of pts with metastatic disease was 5.8 compared to 15.8 months for those without metastases. Only 28% of pts were referred to genetic services, and 72% of these underwent genetic testing. Out of the genetically tested pts, pathogenic germline mutations were confirmed for 33%. Of the original 113 pts, 41% received concurrent palliative care, which was provided at a median of 2.4 mos. (IQR, 0.7-6.8) preceding death. The median time between last chemotherapy administered and death was 2 mos. (IQR, 1-4.4), with 23% receiving treatment within the last month of life. Only 55% used hospice services prior to death for a median duration of 0.5 mos. (IQR, 0.2-1.4). Conclusions: Our study suggests that there is a tendency for late utilization of supportive and hospice care in pts with EOPC, possibly due to the desire of both pts and physicians to be more aggressive given the young age. Larger studies are warranted to elucidate barriers to concurrent supportive care, and whether formation of specialized young patient supportive care clinics would aid this situation and to avoid the use of unnecessary chemotherapy near the end of life.
Real-world eligibility of advanced pancreatic (APC) patients for maintenance olaparib.
Authors: Batra Atul , Cheung Winson Y. , Tang Patricia A.
Published: February 2020

653

Background: The POLO trial demonstrated an improvement in progression free survival (PFS, 7.4 months vs. 3.8 months; hazard ratio, HR, 0.53; 95% confidence interval, 95% CI, 0.35 to 0.82; P=0.004) with olaparib compared to placebo, as maintenance therapy in APC patients with germline BRCA 1/2 mutations with disease control after 16 weeks (DC16) of platinum-based first-line therapy. This study aims to identify the proportion of real-world APC patients eligible for olaparib, and to determine the PFS and overall survival (OS) after DC16. Methods: APC patients treated with first-line FFX in Alberta were identified (2011-2018). We conducted an analysis of baseline characteristics to identify factors associated with DC16. Results: We identified 165 APC patients treated with FFX with unknown BRCA 1/2 status, of which 56% were males and median age at diagnosis was 59 years (interquartile range 38-75 years). Of these, 72 (44%) had DC16. Normal LDH and ALP, and albumin more than 35 g/L were associated with a higher likelihood of having DC16 (table). The PFS of patients with DC16 was significantly higher than those with DC<16 weeks (9.3 vs 2.5 months, HR=0.22, 95% CI 0.15-0.32, P<0.001). In patients who had DC16, median PFS and OS from that point were 5.6 months and 17.9 months, respectively. Conclusions: Less than half of real-world patients treated with first-line FFX would be eligible for olaparib by the criteria of DC16 with FFX. Median PFS after DC16 is 5.6 months with FFX in patients with unknown BRCA 1/2 status. This provides a baseline for future trials evaluating maintenance strategies. Patients with APC and higher disease burden (higher ALP and LDH) and low albumin are less likely to have DC16. [Table: see text]
Gemcitabine and nab-paclitaxel in older adults with metastatic pancreatic cancer: Are two doses per cycle enough?
Authors: Winer Arthur , Handorf Elizabeth A. , Dotan Efrat
Published: February 2020

655

Background: The dosing of Gemcitabine and Nab-Paclitaxel (GA), a frontline regimen to treat metastatic pancreatic cancer (mPC), is frequently altered from the traditional dosing schedule (TDS) of day 1, 8, and 15 of a 28 day cycle to a modified dosing schedule (MDS) of 2 doses/cycle. Previous work showed that overall survival (OS) was similar between patients (pts) treated with the MDS vs the TDS. We sought to analyze a larger real-world database to assess these trends. Methods: We retrospectively analyzed de-identified pts with mPC ≥ 65 y/o treated with GA in the Flatiron Health nationwide EHR-derived database. Demographics, treatments (tx), and outcomes were collected. Pts were grouped as either starting with the TDS or MDS. Analysis included time on treatment (TOT) as well as OS. A Cox model was used to test non-inferiority of the MDS vs the TDS for both TOT and OS, adjusting performance status, age, race, gender, and line of therapy (LOT). The upper bound for non-inferiority was a Hazard Ratio (HR) = 1.2. Results: 1497 pts were treated between 1/1/14-5/31/19; 883 pts with the TDS and 614 with the MDS. Median TDS age was 72 (65-85) and MDS was 73 (65-84) (p<0.001). 1237 pts received first- line GA; 60% received the TDS, 40% the MDS. The use of the TDS vs MDS did not vary significantly by LOT, gender, or race, but more pts with a PS of ≥2 received the MDS (p=0.03). In the first-line, outcomes were better for the TDS vs the MDS (unadjusted median TOT 5.3 vs 3.2 mo, p<0.001, OS 9.2 vs 5.3 mo; p<0.001), with consistent results in the ≥ second-line. The MDS did not meet its non-inferiority boundary: first-line TOT HR=1.4 [95% CI 1.2-1.6]; second+ line TOT HR=1.3 [95% CI 1.0-1.7]; first-line OS HR=1.6 [95% CI 1.4-1.8]; second+ line OS HR=1.3 [95% CI 1.0-1.8]. Results were consistent when additionally stratified by PS 0-1 vs 2+. Conclusions: In this large real-world cohort, first-line GA tx with a MDS did not meet criteria for non-inferiority for TOT and OS vs a TDS in older adults with mPC. With the caveats of potential confounding that exist in a de-identified retrospective database, these results suggest that dose intensity may be important in pts with mPC. Further prospective studies are necessary to ensure we utilize effective tx strategies in older adults with mPC.
Blood-based detection of early-stage colorectal cancer using multiomics and machine learning.
Authors: Putcha Girish , Liu Tzu-Yu , Ariazi Eric , Bertin Marvin , Drake Adam , Dzamba Michael , Hogan Greg , Kothen-Hill Steven , Liao Jeffrey , Li Kang , Mahajan Shivani , Palaniappan Krishnan , Sansanwal Poonam , St John John , Ulz Peter , Wan Nathan , Warsinske Hayley , Weinberg David , Yang Rui , Lin Jimmy
Published: February 2020

66

Background: Despite population screening efforts, screening rates for colorectal cancer (CRC) remain suboptimal. A non-invasive, blood-based screening test with high sensitivity and specificity in early-stage disease should improve adherence and ultimately reduce mortality; however, tests based only on tumor-derived biomarkers have limited sensitivity. Here we used a multiomic, machine learning platform to discover, refine, and combine tumor- and immune-derived signals to develop a blood test for the detection of early-stage CRC. Methods: Samples from 591 participants enrolled in a prospective study including average-risk screening and case-control cohorts (NCT03688906) were included in this analysis (CRC: n = 43; colonoscopy-confirmed CRC-negative controls: n = 548). Participants with CRC were 60% male with a mean age of 63, and controls were 55% male with a mean age of 60. Stage distribution was 54% early (I/II) and 34% late (III/IV) with 11% unknown. Plasma was analyzed by whole-genome sequencing, bisulfite sequencing, and protein quantification methods. Computational methods were used to assess and infer the performance of individual and combined assays. Results: For colorectal adenocarcinoma, which represents ~95% of all CRCs, our multiomic test achieved a mean sensitivity of 92% in early stage (n = 17) and 84% in late stage (n = 11) at a specificity of 90%. Across all CRC pathological subtypes, our test achieved a mean sensitivity of 80% in early stage (n = 19) and 83% in late stage (n = 12) at a specificity of 90%; the test detected the single squamous cell carcinoma but missed both neuroendocrine tumors. Individual assays achieved a mean sensitivity of 50% in early stage and 66% in late stage at a specificity of 90%. Conclusions: In a prospective cohort, we demonstrated high sensitivity and specificity for early-stage adenocarcinoma by combining tumor- and immune-derived signals from cfDNA, epigenetic, and protein biomarkers. While most CRCs are adenocarcinomas, detection of all pathological subtypes is required to maximize sensitivity in a screening population. Further analysis of molecular and pathological subtypes, as well as the entire ~3000 patient cohort, is underway. Clinical trial information: NCT03688906.
Observational retrospective evaluation of treatment with liposomal irinotecan plus fluorouracil/leucovorin for metastatic pancreatic cancer patients: An Italian large real-world analysis.
Authors: Pellino Antonio , Manai Chiara , Merz Valeria , Scartozzi Mario , Milella Michele , De Vita Ferdinando , Antonuzzo Lorenzo , Zichi Clizia , Satolli Maria Antonietta , Panebianco Michele , Noventa Silvia , Giordano Guido , Nappo Floriana , Zecchetto Camilla , Puzzoni Marco , Vaccaro Vanja , Pappalardo Annalisa , Giommoni Elisa , Melisi Davide , Lonardi Sara
Published: February 2020

660

Background: In the NAPOLI I phase III trial, Nanoliposomal irinotecan (nal-IRI) plus 5-fluorouracil/leucovorin (5-FU/LV) showed better outcome compared to 5FU/LV in patients with metastatic Pancreatic Cancer (MPC) progressed to 1st- line gemcitabine-based therapy. Aim of this study is to explore the real-world efficacy and safety of 5FU/LV-nal-IRI by a compassionate use programme and to identify potential prognostic factors that could affect survival in this setting. Methods: This is a retrospective multi-center analysis including patients with MPC who received 5FU/LV-nal-IRI after failure of a gemcitabine-based therapy. Survival analyses were carried out by the Kaplan-Meier method. Univariate and multivariate analyses were performed by using the log-rank test and the Cox regression. Results: A total of 296 pts (median age, 69 years, range 30-82; 50% male; ECOG PS 0, 44%) were treated at 11 Italian institutions from June 2016 and November 2018. 34% of the pts have been previously resected on their primary tumor, and 76% received gemcitabine-nabpaclitaxel as 1st - line treatment. 5FU/LV-nal-IRI has been administered as 2nd - line in 72% of the pts, while in 23% of the cases as 3rd - line or more. The median OS was 7.1 months [95% confidence interval (CI) 6.1 - 8.1] and the median PFS was 3.3 months (95% CI 2.9 - 3.6). At six months, OS and PFS rate were 53.4% and 31.4% respectively. ORR was 12% and DCR was 40%. 52% of pts received more than 4 cycle with dose reduction in 148 pts (50%). Most common grade 3 toxicities were neutropenia (14%), diarrhea (11%), anemia (3%), nausea (3%), fatigue (3%), mucositis (2%) and vomiting (1%). Baseline characteristics associated with better OS were ECOG PS 0, normal CEA, neutrophil-to-lymphocyte ratio ≤5 and haemoglobin ≥11 g/dL. Conclusions: These real-world data confirm the efficacy and safety of 5FU/LV-nal-IRI in patients with MPC progressed to a gemcitabine-based therapy, with outcome comparable to NAPOLI-1 even in a less selected population and with more active 1st - line combination therapy. In this cohort, well known prognostic markers has been confirmed, as expected.
Comparing survival outcomes for neoadjuvant therapy versus adjuvant therapy in the management of stage 1 pancreatic adenocarcinoma: A National Cancer Database study.
Authors: Datta Samit Kumar , Bellini Geoffrey , Singh Maharaj , Sich Nicholas , Weese James L. , Sanchez Federico Augusto , Guda Nalini , Papenfuss Wesley Allan , Chevinsky Aaron
Published: February 2020

664

Background: We are in the midst of a paradigm shift in the treatment of stage 1 pancreatic ductal adenocarcinoma (PDAC) from surgery first followed by adjuvant therapy (AT) to Neoadjuvant therapy (NAT) first followed by surgery and this is reflected in the current NCCN guidelines as well. Data comparing these two modalities are limited. AIM: To compare long term survival between Surgery + AT and NAT + Surgery in a large National Cancer Database for stage 1 PDAC. Methods: We identified patients with the NCDB with surgically resected AJCC clinical stage 1, 1A, and 1B PDAC between 2004-2016. Patients were stratified into two groups to assess outcomes: AT and NAT. Patients with incomplete survival and sequence of therapy were excluded. Baseline demographic data, 90-Day Mortality, Median survival, and Hazard ratios (HR) for survival was evaluated. Results: 9017 pts with Clinical stage 1, 1A, 1B PDAC between 2004-2016 were identified. Of these 7453 pts had surgery followed by AT; and 1564 pts had NAT followed by surgery. There was a statistically significant difference in age (66.0±9.9 years for AT vs. 64.7±9.78 years for NAT, p < 0.001) but no difference in Charlson Comorbidity Scoring (p = 0.618) or sex (p = 0.073). 90-Day Mortality was 0.35% in the AT group compared to 0.83% in the NAT group (p = < 0.001). Median survival was 28.5 (95% CI 26.5-29.9) months in the NAT group compared to 25.4 (95% CI 24.7-26.1) months in the AT group. With AT as the reference group for survival, there was a HR of 0.904 (95% CI 0.845-0.968, p = 0.003) for NAT. Conclusions: In this retrospective cohort of patients, NAT was associated with increased overall survival. However, NAT was associated with an increased 90 day mortality. A randomized, controlled trial is necessary to further support the superiority of NAT in the management of stage 1 PDAC.
Changes in glucose tolerance after pancreatectomy in patients with pancreatic ductal adenocarcinoma.
Authors: Shirakawa Sachiyo , Toyama Hirochika , Komatsu Shohei , Ishida Jun , Kido Masahiro , Fukumoto Takumi
Published: February 2020

668

Background: Diabetes mellitus (DM) is reported to be related to pancreatic ductal adenocarcinoma (PDAC). Long-standing DM is a risk factor for PDAC, meanwhile, quite a few patients with PDAC develop DM as a paraneoplastic disorder and some papers reported that DM affected prognosis for PDAC. In this study, we investigated pre- and post-operative glucose tolerance in patients with pancreatectomy for PDAC or other disease. Methods: This single-center prospective study included 69 patients with pancreatectomy (40 pancreaticoduodenectomy (PD) and 29 distal pancreatectomy (DP) ) who received 75-g oral glucose tolerance test (OGTT) and glucagon test pre- and one month postoperatively. Plasma glucose, insulin, and C-peptide (CPR) at 0-, 30-, 60-, and 120-min during OGTT; and 0- and 6-min during glucagon test were obtained. These data and survival outcomes were analyzed. Results: There were 20 (29%) PDAC patients: 12 (30%) in PD group and eight (28%) in DP group. Nine patients with PDAC (45%) and seven patients (18%) without PDAC demonstrated DM type in preoperative OGTT. After pancreatectomy, 11 patients (55%) with PDAC and seven patients (15%) without PDAC experienced improvement in OGTT (P=0.0005). Greater improvement in homeostasis model assessment insulin resistance that were obtained by OGTT and used to measure insulin resistance, was noted after surgery in PDAC patients compared with non-PDAC patients (-1.4 vs -0.5 in PD group, P=0.07; -0.8 vs +0.06 P=0.05 in DP group). Delta CPRs obtained by glucagon test were significantly decreased postoperatively (3.0 to 1.1 ng/mL, P<0.0001 in PD group; 3.3 to 1.8 ng/mL, P<0.0001 in DP group). In survival analysis, fasting plasma glucose >110 mg/dL (HR 3.9, 95%CI 1.5-10, P=0.005) and the average of plasma insulin > 25 µIU/mL during OGTT (HR 0.36, 95%CI 0.14-0.93, P=0.035) were significant prognostic factor for PDAC. Conclusions: Pancreatectomy impaired insulin secretion and improve insulin resistance especially in PDAC patients. About half of PDAC patients demonstrated the improvement of glucose tolerance after surgery. Of note, glucose tolerance differed between PDAC and other disease, and affect the survival outcome for PDAC patients.
A multicenter clinical randomized phase II study of investigating duration of adjuvant chemotherapy with S-1 (six versus 12 months) for patients with resected pancreatic cancer: PACS-1 study.
Authors: Yamashita Yo-ichi , Itoh Shinji , Shimokawa Mototsugu , Takamori Hiroshi , Fukuzawa Kengo , Ninomiya Mizuki , Araki Kenichiro , Kajiyama Kiyoshi , Sugimachi Keishi , Uchiyama Hideaki , Morine Yuji , Utsunomiya Tohru , Uwagawa Tadashi , Maeda Takashi , Adachi Eisuke , Ikeda Yasuharu , Yoshizumi Tomoharu , Baba Hideo , Mori Masaki
Published: February 2020

669

Background: Although adjuvant chemotherapy with S-1 has improved overall survival and progression-free survival (PFS) in patients with resected pancreatic cancer, the duration evaluation of adjuvant chemotherapy with S-1 have not established yet. Methods: We did a randomized, multicenter, phase 2 trial undertaken at 15 hospitals in Japan. Patients who were Eastern Cooperative Oncology Group performance states of 0 or 1 and aged 20 years or older were eligible. Patients with resected pancreatic cancer were randomly assigned (in a 1:1 ratio) to receive S-1 [40 mg, 50 mg, or 60 mg according to body-surface area, orally administered twice a day for 28 days followed by a 14 day rest, every 6 weeks [one cycle], for up to four cycles (6 months)] or up to eight cycles (12 months). The primary end point was overall survival rate. Secondary endpoints included PFS and safety. Results: The population consisted of 82 patients in the S-1 for 6 months group and 82 patients in the S-1 for 12 months group. The 2-year overall survival rate was 71.4% in the S-1 for 6 months group and 65.4% in the S-1 for 12 months, and the median overall survival was 31.0 months in the S-1 for 6 months group and 26.3 months in the S-1 for 12 months group [hazard ratio (HR) 1.23, 95% confidence interval (CI) 0.76-1.99, p = 0.377]. The PFS at 2 years was 56.8% in the S-1 for 6 months group, and 51.2% in the S-1 for 12 months. The HR for recurrence of S-1 for 6 months, compared with S-1 for 12 months, was 1.23 (95%CI 0.76-1.99, p = 0.392). Twenty-nine (35.3%) patients in the S-1 for 6 months group and 46 (56.0%) in the S-1 for 12 months group discontinued treatment before completion. In regard to patients completed treatment, the S-1 for 12 months group showed tendency to favorable prognosis on PFS compared with the S-1 for 6 months group (log-rank test; p = 0.175). Conclusions: In patients with resected pancreatic cancer, adjuvant chemotherapy with S-1 for 12 months is not superior to that for 6 months in terms of median overall survival and PFS. For patients who can tolerate adjuvant chemotherapy with S-1 for 6 months well, continuing treatment for up to 12 months may improve the prognosis.
Real-world rates of hematology lab abnormalities and associated cost among metastatic pancreatic cancer (mPC) therapeutic regimens.
Authors: Dieguez Gabriela , Surinach Andy , Mercer Daniel , Cockrum Paul , Kim George P. , Pelizzari Pamela
Published: February 2020

670

Background: Low hematologic counts are a common, costly side effect of chemotherapy. This observational study examines rates and associated cost to treat. Methods: Data on adverse events (AEs) were extracted from the clinical Flatiron Health database for mPC patients (pts) from 01/2014-01/2019. Anemia, neutropenia, and lymphopenia occurrence was assessed via diagnosis codes and structured lab data. Costs due to AEs were derived from a claims analysis of mPC pts from 2013-2017 in Medicare Limited Data Set claims. Mean adjusted incremental costs (ICs) were estimated by comparing 30-day costs of pts with and without AEs, with controls selected among pts without AEs with the same regimen and line of therapy, when at least 80 cases/controls were identified. Results: 4592 treated mPC pts were identified (median age at diagnosis: 68y, IQR: 61 – 75). 1138 pts were treated with FOLFIRINOX (FFX) in first-line (1L), 2295 pts with 1L gemcitabine plus nab-paclitaxel (gem-nab), 218 pts with second-line (2L) FOLFOX, 56 pts with 2L FOLFIRI, and 178 pts with 2L liposomal irinotecan (nal-IRI) based therapy. Observed rates of anemia and neutropenia are shown in the table below. Lymphopenia rates were similar across regimens and ICs were not statistically significant. ICs for patients with any grade anemia were $3864, $3818, $3536, $3978, and $2963 for FFX, gem-nab, FOLFOX, FOLFIRI, and nal-IRI treated pts, respectively. ICs for pts with any grade neutropenia were $2382 for FFX, $2440 for gem-nab, $2688 for FOLFOX, $3551 for FOLFIRI and $2307 for nal-IRI. Conclusions: Any grade anemia ICs ranged from $2963 [$1544, $4400] (nal-IRI) to $3978 [$2241, $5817] (FOLFIRI), and any grade neutropenia ICs ranged from $2307 [$703, $4313] (nal-IRI) to $3551 [$1227, $6039] (FOLFIRI). Pts treated with nal-IRI had similar any grade AE rates but lower ICs, which suggest lower severity of AEs. These results are consistent with Flatiron Health’s lower rates of grades 3+ neutropenia and anemia. [Table: see text]
Development and validation of a pancreatic cancer prediction model from electronic health records using machine learning.
Authors: Appelbaum Limor , Cambronero Jose Pablo , Pollick Karla , Silva George , Stevens Jennifer P. , Mamon Harvey J. , Kaplan Irving D. , Rinard Martin
Published: February 2020

679

Background: Pancreatic Adenocarcinoma (PDAC) is often diagnosed at an advanced stage. We sought to develop a model for early PDAC prediction in the general population, using electronic health records (EHRs) and machine learning. Methods: We used three EHR datasets from Beth-Israel Deaconess Medical Center (BIDMC) and Partners Healthcare (PHC): 1. “BIDMC-Development-Data” (BIDMC-DD) for model development, using a feed-forward neural network (NN) and L2-regularized logistic regression,randomly split (80:20) into training and test groups. We tuned hyperparameters using cross-validation in training, and report performance on the test split. 2. “BIDMC-Large-Data” (BIDMC-LD) to re-fit and calibrate models. 3. “PHC-Data” for external validation. We evaluate using Area Under the Receiver Operating Characteristic Curve (AUC) and compute 95% CI using empirical bootstrap over test data. PDAC patients were selected using ICD9/-10 codes and validated with tumor registries. In contrast to prior work, we did not predefine feature sets based on known clinical correlates and instead employed data-driven feature selection, specifically importance-based feature pruning, regularization, and manual validation, to identify diagnostic-based features. Results: BIDMC-DD included demographics, diagnoses, labs and medications for 1018 patients (cases = 509; age-sex paired controls). BIDMC-LD included diagnoses for 547,917 patients (cases = 509), and PHC included diagnoses for 160,593 patients (cases = 408). We compared our approach to adapted and re-fitted published baselines. With a 365-day lead-time, NN obtained a BIDMC-DD test AUC of 0.84 (CI 0.79 - 0.90) versus the previous best baseline AUC of 0.70 (CI 0.62 - 0.78). We also validated using BIDMC-DD’s test cancer patients and BIDMC LD controls. The AUC was 0.71 (CI 0.67 - 0.76) at the 365-day cutoff. NN’s external validation AUC on PHC-Data was 0.71 (CI 0.63 - 0.79), outperforming an existing model’s AUC of 0.61 (CI 0.52 - 0.70) (Baecker et al, 2019). Conclusions: Models based on data-driven feature selection outperform models that use predefined sets of known clinical correlates and can help in early prediction of PDAC development.
Extent of lymph node resection and effect on pancreatic cancer overall survival.
Authors: Cox Brian , Manguso Nicholas , Quadri Humair , Crystal Jessica , Atkins Katelyn Mae , Lee Jaewon , Hendifar Andrew Eugene , Kamrava Mitchell , Tuli Richard , Gong Jun , Gangi Alexandra
Published: February 2020

682

Background: Lymph node (LN) metastases affect overall survival (OS) in pancreatic cancer (PC). However, a LN sampling threshold does not exist. We examined the impact of nodal sampling on overall survival (OS). Methods: Patients with Stage I-III PC ≥55 years old who underwent curative resection from 2004-2016 were identified from the National Cancer Database (NCDB). After adjusting for age, gender, grade, stage, and Charlson-Deyo score, multiple binomial logistic regression analyses assessed the impact of the LN ratio (LNR) on OS. LNR was defined as the number of positive LN over the number of LN examined. Regression analyses, a Cox-Regression, and a Kaplan-Meier survival curve assessed how many LN should be sampled. Results: A total of 13,673 patients, median age 69 years (55-90), were included. Most were Caucasian (86.6%) males with Charlson-Deyo scores ≤ 1 (90.3%) and moderately to poorly differentiated PC (90.1%). Median number of LN examined was 15 (1-75) with a median of 1 positive LN (0-35). As expected, increased number of positive LNs was associated with reduced OS, p < 0.001. After data normalization, an increasing LNR was associated with a 12-fold likelihood of death [OR: 11.9, p < 0.001 (CI 6.0, 23.7)]. Subsequent regression models established evaluation of ≥ 16 LNs as the greatest predictor of OS. A regression model evaluating < or ≥ 16 lymph nodes was performed to ascertain the effects of age, gender, ethnicity, grade, stage, and LN examined on OS. The logistic regression model correctly classified 74.5% of cases with a specificity of 99.6% (p < 0.001). Examination of < 16 LN, Caucasian race, grade, stage, and higher Charlson-Deyo scores were significantly associated with decreased OS. If ≥ 16 LNs were examined, patients had a 1.5-fold likelihood of better OS, p < 0.001 (CI 1.4, 1.6). An adjusted Cox Regression showed increased HR of 1.2, p < 0.001 (CI 1.1, 1.2) and an unadjusted Kaplan Meier survival curve predicted ≥ 16 LN examined are associated with an increase in OS of 2.8 months [log-rank: 32.0, p < 0.001]. Conclusions: Patients undergoing curative intent resection for PC should have adequate nodal sampling. Stratification of patients by LNR may provide useful information of OS. Examination of ≥ 16 LNs impacts OS in patients with Stage I-III PC.
Goals of care designations in advanced pancreatic cancer patients undergoing palliative chemotherapy.
Authors: Anaka Matthew , Lee Minji , Lim Elisa , Ghosh Sunita , Cheung Winson Y. , Spratlin Jennifer L.
Published: February 2020

683

Background: Discussion of goals of care (GoC) is a key part of quality care for patients with palliative cancer. Numerous studies have shown that documentation of GoC in this population remains low. In 2014, Alberta Health Services launched a health-system wide initiative to provide patients with physical copies of their GoC designation intended to be available at all health-system interactions. Here we describe rates of GoC documentation in the period surrounding this initiative. Methods: This is a retrospective cohort analysis of 240 patients with locally advanced or metastatic pancreatic cancer treated with palliative chemotherapy from 2012-2015 in Alberta, Canada. Data were obtained from outpatient electronic medical record documentation and the provincial cancer registry. Results: 63.8% (153/240) of patients had a documented GoC discussion, with 60.4% (145/240) receiving a specific GoC designation. 59.6% (143/240) of patients were referred to palliative care, with 32.5% (78/240) seen by palliative care physician. Of 334 individual GoC discussions documented, 38.6% (129/334) were by medical oncologists, 2.3% (10/334) were by radiation oncologists, 27.2% (91/334) were by palliative care, and 19.2% (64/334) were by other inpatient physicians during hospital admissions. At least 9.6% (32/334) referenced discussions that occurred prior to initial consultation with an oncology physician. Conclusions: The majority of pancreatic cancer patients undergoing palliative chemotherapy had a documented GoC designation during the study period. Providing patients with physical copies of their GoC designation may therefore represent a simple but effective means of increasing GoC documentation in the outpatient oncology setting.
Risk factors for severe neutropenia among pancreatic cancer patients receiving nab-paclitaxel and gemcitabine combination therapy.
Authors: Kawakami Kazuyoshi , Ito Genta , Aoyama Takeshi , Yokokawa Takashi , Nakamura Masashi , Ozaka Masato , Sasahira Naoki , Kizaki Hayato , Hashiguchi Masayuki , Hama Toshihiro , Hori Satoko
Published: February 2020

684

Background: Albumin-bound paclitaxel (nab-paclitaxel) and gemcitabine combination therapy (GnP therapy) significantly extends overall survival in patients with metastatic pancreatic cancer, compared to conventional gemcitabine monotherapy. However, severe neutropenia (Grade ≥ 3) occurred in 67.6% of patients in the Japanese phase I/II trials of GnP therapy, and is often a limiting factor. The purpose of this study was to identify the risk factors for severe neutropenia in pancreatic patients receiving GnP therapy in clinical settings. Methods: A retrospective study of 222 consecutive patients with pancreatic cancer who received GnP therapy at the Cancer Institute Hospital from December 2014 to December 2016 was conducted. Univariate and multivariate analyses were used to compare blood test values and patients’ characteristics between patients with no neutropenia or Grade 1/2 (non-serious) neutropenia and those with Grade ≥ 3 (severe) neutropenia. Results: There were 19 patients (8.6%) with modified FOLFIRINOX in the previous treatment history. The median doses of nab-paclitaxel and gemcitabine were 192.5 mg (range 134-277.5) and 1,545 mg (range 1,000-2,220), respectively. Severe neutropenia and febrile neutropenia occurred in 118 patients (53.2%) and 15 patients (6.8%), respectively. Multivariate logistic regression analysis indicated that ANC (absolute neutrophil count) < 3.03 x 103 /μL (OR: 4.806, 95% CI: 2.416-9.558, p = 0.000), T-Bil ≥ 0.6 mg/dl (OR: 1.964, 95% CI: 1.040-3.708, p = 0.037) and CRP < 0.13 mg/dl (OR: 2.607, 95% CI: 1.331-5.106, p = 0.005) were significant risk factors for severe neutropenia. The incidence rate of severe neutropenia was 85.7% (18/21) in patients with all three identified factors, while it was 27.7% (13/47) in patients with none of them. Age was not a risk factor in either univariate or multivariate analysis. Conclusions: Low ANC, high T-Bil, and low CRP were found to be risk factors for severe neutropenia in patients receiving GnP therapy. It would be desirable to monitor patients with these risk factors carefully, even if their values are within the standard ranges.
Adverse events (AEs) with maintenance olaparib in patients with a germline BRCA mutation (gBRCAm) and metastatic pancreatic cancer (mPaC): Phase III POLO trial.
Authors: Reni Michele , Kindler Hedy L. , Hammel Pascal , Van Cutsem Eric , Macarulla Teresa , Hall Michael J. , Park Joon Oh , Hochhauser Daniel , Arnold Dirk , Oh Do-Youn , Reinacher-Schick Anke C. , Tortora Giampaolo , Algül Hana , O'Reilly Eileen Mary , McGuinness David , Cui Karen , Schlienger Katia , Locker Gershon Y. , Golan Talia
Published: February 2020

686

Background: In POLO (NCT02184195), maintenance olaparib was well tolerated and led to a significant progression-free survival benefit vs placebo in patients with a gBRCAm and mPaC whose disease had not progressed on first-line platinum-based chemotherapy (HR 0.53; 95% CI 0.35–0.82) (Golan et al. NEJM 2019). We analyzed common AEs and their management in POLO. Methods: Patients were randomized (3:2) to maintenance olaparib (tablets; 300 mg bid) or placebo until disease progression or unacceptable toxicity. AEs were graded using CTCAE v4.0. Results: Of 154 randomized patients, 151 were treated (olaparib, n=91; placebo, n=60) and included in safety analyses. Median treatment duration was 6.0 months (m) for olaparib and 3.7 m for placebo. Management of fatigue/asthenia, nausea, anemia and vomiting included supportive treatment and/or dose modification; few patients discontinued treatment due to AEs (Table). Of patients with anemia, 14 olaparib recipients received a blood transfusion while on study treatment; one olaparib recipient received epoetin beta. Conclusions: The AE profile of maintenance olaparib in patients with a gBRCAm and mPaC was consistent with that seen in other tumor types.Common AEs of fatigue/asthenia, nausea, anemia and vomiting occurred early, were manageable and led to few treatment discontinuations. Clinical trial information: NCT02184195 . [Table: see text]
Outcomes of advanced gastrointestinal (GI) cancer patients in relationship to opioid use: An individual patient data pooled analysis from eight clinical trials.
Authors: Abdel-Rahman Omar , Karachiwala Hatim , Easaw Jacob C.
Published: February 2020

687

Background: The current study aims at assessing the patterns of opioid use, and evaluating the impact of opioid use on survival outcomes among patients with advanced GI cancers who were included in eight clinical trials. Methods: De-identified datasets of eight clinical trials evaluating first-line systemic treatment for advanced GI cancers (NCT01124786; NCT00844649; NCT00290966; NCT00678535; NCT00699374; NCT00272051; NCT00305188; NCT00384176) were accessed from the Project Data Sphere platform. These trials evaluated patients with pancreatic, gastric, hepatocellular and colorectal carcinoma. Multivariable logistic regression analysis was used to evaluate factors predicting the use of opioids. Kaplan-Meier survival estimates were used to compare survival outcomes in each disease entity among patients who did or did not receive opioid treatment. Multivariable Cox regression analysis was used to assess the impact of opioid use on survival outcomes in each disease entity. Results: A total of 3441 participants were included in the current analysis. The following factors predicted a higher probability of opioid use within logistic regression analysis: younger age (P = 0.004), non-white race (P = 0.010), higher ECOG score (P < 0.001) and pancreatic primary site (P < 0.001). Use of opioids was consistently associated with worse overall survival in Kaplan-Meier survival estimates of each disease entity (for pancreatic cancer: P = 0.008; for gastric cancer: P < 0.001; for hepatocellular carcinoma: P < 0.001 and for colorectal cancer: P < 0.001). Within multivariable Cox regression analysis, opioid use was associated with worse overall survival among patients with pancreatic cancer (HR = 1.245; 95% CI: 1.063-1.459; P = 0.007), gastric cancer (HR = 1.725; 95% CI: 1.403-2.122; P < 0.001), hepatocellular carcinoma (HR = 1.841; 95 CI: 1.480-2.290; P < 0.001) and colorectal cancer (HR = 1.651; 95% CI: 1.380-1.975; P < 0.001). Conclusions: Opioid use is consistently associated with worse overall survival among patients with different GI cancers. Further studies are needed to evaluate the underlying mechanisms of this observation.
An exploratory study of metformin (Met) with or without rapamycin (Rapa) as maintenance therapy after induction chemotherapy in patients (Pts) with metastatic pancreatic adenocarcinoma (PDA).
Authors: Bever Katherine M. , Borazanci Erkut Hasan , Thompson Elizabeth , Wu Annie , Durham Jennifer N. , Liu Meizheng , Wilt Cara , Fu Wei , Leal Jeffrey P. , De Jesus-Acosta Ana , Wang Hao , Cosgrove David , Zheng Lei , Laheru Daniel A. , Von Hoff Daniel D. , Jaffee Elizabeth M. , Powell Jonathan , Le Dung T.
Published: February 2020

700

Background: Few studies have examined maintenance therapy in unselected pts with metastatic PDA (mPDA). mTOR signaling is central to several oncogenic pathways in PDA and also has a role in T cell differentiation and activation, and we hypothesized a role for mTOR inhibition (mTORi) in the maintenance setting. Methods: This was a randomized open-label study conducted at 2 sites. Eligible pts had mPDA with stable disease for ≥6 months on chemotherapy and ECOG PS 0/1. Pts were randomized 1:1 to Met 850mg BID alone (Arm A) or with Rapa 4mg daily (Arm B), stratified by prior FOLFIRINOX. Baseline and on-treatment PET scans and peripheral blood mononuclear cells were obtained for exploratory analyses. Results: 23 pts were randomized. Median age was 64 (range 34-77) and 82% had ECOG PS 1. 12 of 23 received prior FOLFIRINOX; 8 received >1 prior line of therapy. 22 subjects (11 per arm) were treated per protocol. Treatment related adverse events of Grade ≥3 were seen in 0% vs 27% of pts in Arm A vs B and were all asymptomatic hematologic or electrolyte abnormalities that were not clinically significant. Median PFS/OS were 3.5 (95% CI: 2.9-9.2)/13.2 mos (95% CI: 7.8 to not reached) respectively, with 2 yr OS rate of 37% (95% CI: 21-66%); there were no differences between treatment arms. As expected in the maximally debulked setting, no responses were observed by RECIST; however, decreases in FDG avidity and/or CA199 were observed in several long-term survivors. Better survival was associated with low baseline neutrophil to lymphocyte ratio, baseline lack of assessable disease by PET, and with expansion of dendritic cells following treatment. Compared to Met alone, Met + Rapa was associated with decreased mTOR activity on some immune cell subsets and decreased metabolic fitness, but this was not correlated with outcome. Conclusions: Met +/- rapa maintenance for mPDA was well-tolerated and several pts achieved stable disease associated with exceptionally long survival. Further prospective studies are needed to clarify the role of mTORi in the maintenance setting and to enhance pt selection for such approaches. Clinical trial information: NCT02048384.
Single institutional analysis of resectable pancreatic cancer.
Authors: Wiisanen Jeff , Navin Patrick , El Khatib Moustafa , Bamlet William R , Cleary Sean P. , McWilliams Robert R. , Truty Mark J. , Ho Thanh P. , Hartgers Mindy L. , Yadav Siddhartha , Mahipal Amit
Published: February 2020

706

Background: In recent years, there has been a shift towards neo-adjuvant treatment (NAT) of non-metastatic pancreas cancer in the hopes of improving negative margin rate, lymph node negativity, recurrence and survival. Even patients deemed resectable based on NCCN criteria are receiving NAT but data for these patients remains limited. This current study evaluated the outcomes of patients diagnosed with resectable pancreatic adenocarcinoma. Methods: Patients were retrospectively identified through the Mayo Clinic, Rochester SPORE pancreatic cancer registry as well as search of the electronic medical record via Advanced Cohort Explorer from May 2011 to 2016. Baseline demographics, tumor characteristics, treatments rendered, and outcomes were collected. Variables were analyzed for association with recurrence from time of surgery and survival from time of diagnosis using Kaplan-Meier curves and Cox proportional hazards regression. Results: A total of 520 patients with resectable pancreatic adenocarcinoma were identified. 72 patients received upfront chemotherapy with 44 (61.1%) proceeding to surgical resection. 62 patients received upfront chemotherapy followed by radiation with 33 (53.2%) proceeding to surgical resection. 12 patients received upfront radiation alone with 7 (58.3%) proceeding to surgical resection. 374 patients did not receive any NAT with 293 (78.3%) proceeding to surgical resection. In total, 377 (72.5%) went to resection. Median time to recurrence from surgery was 27.7 months vs. 21.7 months for NAT and upfront resection, respectively (HR 0.87, 95% CI 0.60-1.72, p = 0.48). Median overall survival from diagnosis for those receiving NAT was 40.6 months vs. 24.7 months for those receiving upfront resection (HR 0.62, 95% CI 0.41-0.92, p = 0.02). Conclusions: This study shows an approximate 16 month improvement in overall survival of patients receiving upfront NAT for resectable pancreatic adenocarcinoma. This might be due to a better selection of patients. It also highlights that not all patients with resectable cancer undergo resection. Further studies are warranted to identify why resectable patients are not proceeding to resection and which specific NAT approaches benefit patients the most.
Pancreatic ductal adenocarcinoma (PDAC), BRCA: Detailed analysis and outcomes of cohort from Memorial Sloan Kettering Cancer Center (MSK).
Authors: Momtaz Parisa , O'Connor Catherine Anne , Chou Joanne F. , Capanu Marinela , Yu Kenneth H. , Varghese Anna M. , Park Wungki , Zervoudakis Alice , Li Jia , Ku Geoffrey Yuyat , Reidy Diane Lauren , Shcherba Marina , Harding James J. , Goldberg Zoe , Abou-Alfa Ghassan K. , Stadler Zsofia Kinga , Salo-Mullen Erin E. , O'Reilly Eileen Mary
Published: February 2020

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Background: Given encouraging responses of platinum agents and poly-ADP ribose polymerase inhibitors (PARPi) in BRCA mutated (mut) PDAC, we sought to identify patients (pts) with BRCA mut PDAC treated at MSKCC and to evaluate outcome. Methods: Institutional database at MSK with IRB approval was queried for PDAC germline (g) or somatic (s) BRCA1/2 mut. Genomic profiling, clinicopathologic characteristics and outcomes were collected. Overall survival (OS) from diagnosis was estimated using Kaplan-Meier method. Results: n = 126 with BRCA1/2 mut PDAC were identified between 1/2011-12/2018. n = 77 (61%) male and median age of 62 (range 24-85) at diagnosis. n = 78 (62%) had g BRCA mut (n = 21 BRCA1; n = 57 BRCA2). n = 54 (43%) had a family history of BRCA-related malignancies; 35pts (28%) with a personal history of other BRCA-associated malignancy. n = 66 (52%) AJCC stage IV; of these 43pts (65%) received platinum-based therapy with a partial response (PR) in 35pts (81%); median duration 7 months (m) (range 0.5-39m). n = 40 (32%) received ≥ 4 lines of therapy (range 1-6 lines). n = 44 (35%) received PARPi and 11% (n = 14) received immunotherapy. Median OS for the entire cohort 32.1 m (95% CI 23.9, 42.6). Median OS for stage I-II 49.9m (95% CI 38.5,-); stage III 43m (95% CI 33.9,-) and stage IV 19.1m (95% CI 19.1 16.1,25.8). We did not observe a statistically significant difference in OS between BRCA1 vs BRCA2 pts. Conclusions: BRCA mut PDAC constitutes a small but likely distinct biologic subgroup. Improved OS was notable relative to historical data, possibly due to the integration of platinum and PARPi therapy and possibly due to contribution from disease biology. [Table: see text]
Clinical outcome of initially unresectable pancreatic cancer patients: Conversion surgery after modified FOLFIRINOX or gemcitabine nab-paclitaxel.
Authors: Ushida Yuta , Inoue Yosuke , Ito Hiromichi , Ono Yoshihiro , Sato Takafumi , Takahashi Yu
Published: February 2020

725

Background: Although pancreatic cancer (PC) is unfavorable clinical entity, the prognosis of resectable PC has been improving due to perioperative chemotherapy. Meanwhile, the prognosis of unresectable (UR) PC remains poor. In highly selected patients, however, conversion surgery (CS) has been performed with good outcome. Indication criteria of CS remain unestablished because the number of patients who underwent CS was very small in each institution. Methods: From 2014 to 2018, 485 consecutive patients with UR-PC who received modified FOLFIRINOX (mFFX) / Gemcitabine Nab-Paclitaxel (GnP) chemotherapy were reviewed. Among them, patients with disease control for more than 8 months were enrolled and divided into two groups; patients who underwent CS (CS group) and patients who did not undergo CS (non-CS group). We compared clinical characteristics and survival outcomes between groups. Our surgical indications were as follows: 1) Decreasing trend in CA19-9, 2) With response for chemotherapy in image, 3) Disease control more than 8 months, 4) Decision in Cancer board as for metastatic cases. Results: In UR-PC patients, 358 patients had distant metastasis (MPC) and 127 patients had locally advanced (LA) PC. The overall survival (OS), progression free survival (PFS) and conversion rate of LAPC were significantly better than MPC (OS; 21 vs. 13 months, PFS; 12 vs. 7 months, Conversion rate; 16 vs. 5 %, p < 0.001). Chemotherapy regimen (mFFX/GnP) had no significant difference in survival outcome. Between CS group (n = 39) with non-CS group (n = 160), age, sex, body mass index, location of lesion, CEA, CA19-9, regimen of chemotherapy and histology had no significant differences. The median survival time of CS group was significantly better than that of non-CS group (OS; NA vs. 21 months, p < 0.001, PFS; 24 vs. 14 months, p = 0.01). In CS group, median operative duration was 509 minutes, blood loss was 735 ml, hospital stay was 26 days, and there was no 90-days mortality case. Conclusions: In our retrospective study, CS for UR-PC can be safely performed, and among carefully selected patients, reasonable short and long term outcomes can be obtained without acceptable morbidity rate.