bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase II study of anlotinib with cediranib as a second-line treatment for patients with advanced biliary tract cancers (aBTCs).
Authors: Zhao Ruihua , Zong Hong , Jin Shuiling , Zhong Qian , Jiang Miao , Jin Ming , Li Rui , Jiang Guozhong
Published: May 2020

e16712

Background: Gemcitabine combined with cisplatin (GP) is currently used as a standard first-line chemotherapy regimen for aBTCs, However, the median overall survival (mOS) is only about 11.7 months, and there is no standard treatment option for patients who failed GP therapy. In this study, we aimed to investigate the efficacy and safety of anlotinib with cediranib as a second-line treatment for patients with aBTCs. Methods: A monocenter single-arm phase II study was conducted at the First Affiliated Hospital of Zhengzhou University. Patients with measurable aBTCs and progressed on GP were enrolled in this study. Patients received cediranib 200mg, on day1 + anlotinib 12mg on day1-14, Q3W until disease progression, intolerance of toxicity, investigator/patient decision to withdraw or other reasons specified in the protocol. Response (RECIST1.1) was assessed every 8 weeks. Plasma, stool and tumor tissues were collected for exploratory analyses. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR) and drug safety. Results: We planned to include 20 patients. So far 9 patients were enrolled in this study, 66.7% (6/9) were men, 33.3% were women. The median age was 56y (43y-61y). The primary sites of the tumor were intrahepatic biliary (66.7%, 6/9) and gallbladder (33.3%, 3/9). At data cutoff (Dec 14, 2019), the median duration of follow-up was 2.5mos (range, 1.2 to 4) and all of the patients were still under treatment. 8 patients have undergone at least one efficacy evaluation, of which 2 (25%) PR, 5 SD (62.5%), DCR was 87.5% ((7/8). An SD patient had a long-term intermittent fever, which considered to be tumor fever, the body temperature returned to normal after 1 cycle of treatment. 1 patient was considered to be undefined because, at the first evaluation, the liver lesions were reduced however the lymph nodes in the retroperitoneum were enlarged. The median PFS and OS not yet reached. Grade 3-4 treatment-related adverse events (TRAEs) occurred in 11.1% (1/9) of patients. TRAEs led to discontinuation in 1 patient (grade 3 hypertension). TRAEs led to dose reduction of anlotinib in 2 patients. No TRAEs were fatal. Conclusions: The primary result showed that the combination of anlotinib and cediranib was well tolerated and demonstrates encouraging efficacy than historical control in second-line treatment for aBTC. Updated data, including safety, efficacy, and biomarkers will be presented. Clinical trial information: ChiCTR1900022003 .
Changes on functional capacity after impact of oncological digestive surgery: Reality in Chilean patients at Clinical Oncology Institute Arturo López Pérez Foundation.
Authors: Hurtado Veronica , Brito Felipe , Carrera David , Penjean Marcela
Published: May 2020

e16714

Background: Currently Chile does not have a database of functional capacity (FC) in cancer patients. Our purpose is to assess the impact of oncological digestive surgery in FC in Chilean patients at the Clinical Oncology Institute Foundation Arturo López Pérez (FALP) through the 6 minutes walking test (6MWT), which allows objectifying the FC based within the meters walked for 6 minutes by the patient. Methods: It’s a retrospective study of data analysis. The 6MWT was assessed on the day of admission to FALP and discharge. The FC was measured by the distance walked in 6 minutes. Inclusion criteria were male and female candidates for elective oncological digestive surgery from December 2018 - January 2020 and eligible for the 6MWD. We compared the result of the 6MWD baseline admission against an expected reference value according to age, weight and height, and were classified according to whether they were above or below the reference level; their change was also evaluated after surgery, estimated as a percentage of change. Digestive interventions were classified according to site. A P < 0.05 was considered significant. Results: 108 patients were included; the mean age was 57.8 years and the average body mass index (BMI) 26.6. Upon admission 40.7% (N = 44) were above the reference value and 59.3% (N = 64) below it. Regarding the length of hospital stay, we observed an average 8.97 days (Men = 9.96; women = 7.96; P = 0.008). At discharge in 6MWD an average decrease of 149.6 meters (admission = 502.2 mts; Discharge = 352.6 mts.) is seen. At admission, men with age < 40 years (P = 0.031) and subjects with BMI < 30 (P = 0.039) walked a greater distance. There are no significant differences by surgery classification. Regarding the percentage loss of FC, women are more affected (P < 0.001). Conclusions: Based on the results obtained in the 6MWT, we can conclude that the surgery has an impact on patient’s FC. Note that over 50% of patients had a lower value than the base reference. Therefore, we believe it is important to make a multidisciplinary approach at the time of cancer diagnosis to evaluate and optimize the FC baseline before surgery. Clear examples of this approach are the prehabilitation programs. More studies are required in Chilean patients for more conclusive data.
Identification of malignant ascites using MR-based T1 mapping.
Authors: Kuetting Fabian , Sprinkart Alois Martin , Faron Anton , Meffert Lisa , Jansen Christian , Luetkens Julian , Attenberger Ulrike , Kuetting Daniel
Published: May 2020

e16719

Background: Non-invasive identification of malignant ascites is a challenge in clinical practice.Thus, we decided to assess if an MR-based T1 mapping approach allows non-invasive differentiation of malignant and non-malignant effusions. Methods: In-vitro and ex-vivo MR-examinations were performed on a clinical 1.5T MR-system. T1 mapping was performed with spectroscopy and an adapted modified Look-Locker inversion-recovery (MOLLI) acquisition. For in-vitro experiments 13 titrated solutions with varying albumin content (0 to 200 g/l) were examined. For ex-vivo evaluation 27 ascites/pleural effusion samples from patients with malignancy (19 with histologic tumor confirmation in effusion) and 18 samples from patients without malignancy were examined. All samples underwent histological and laboratory testing. Samples were classified as malignant-positive histology, malignant-negative histology and non-malignant negative histology. Lab values were correlated with T1 maps and receiver operating characteristic (ROC) analysis was used to determine the optimal T1-value threshold to differentiate malignant and non-malignant ascites. Results: In in-vitro analysis both methods showed a high correlation with albumin-content (MOLLI: r = -0.97; Spectroscopy: -0.98). T1-values derived from the reference standard (Spectroscopy) and the MOLLI technique had a high agreement (intraclass correlation single measures: 0,9889, 95% CI: 0,52 to 0,99; average measures: 9,994, 95% CI 0,69 to 0,99). Bland-Altman analysis showed a strong agreement between both methods: 62.5 ± 35 (95% CI: 41.2 to 83.8) Ex-vivo analysis revealed significant differences between T1 values from patients with malignant+ histology (median: 2237; IQR: 2132 to 2327.5) and patients with non malignant- negative histology (median: 2611; IQR: 2548 to 2803, p < 0.0001) as well as between malignant+ histology and all other included patients (median: 2585; IQR: 2503 to 2710, p < 0.0001) Multiple regression analysis of in-vivo results revealed that only albumin content correlated with MOLLI based T1 measurements (p < 0.0001; r = -0.65) ROC analysis for differentiation between malignant and non-malignant effusions (malignant+ histology vs. all other) showed an AUC of 0.897; 95% CI: 0.769 to 0.967). Malignant+ histology vs. non-malignant- histology showed an AUC of 1.000 (cut off Lolli > 2419; 95% CI: 0.905 to 1). Conclusions: T1 Mapping shows excellent correlation with protein content of fluids.MR- T1 mapping allows for non-invasive differentiation of malignant and non-malignant effusions in an ex-vivo set up.
Analysis of statistics of pancreatic cancer in Ukraine for a period of 10 years.
Authors: Zrielykh Liliia
Published: May 2020

e16721

Background: Pancreatic cancer (PC) is the 7th leading cause of cancer death in both sexes and 12th most common cancer worldwide. The estimated 5-year survival rate for it is nearly 5% both in developed and in developing countries. Methods: Analysis of data of National and regional cancer registries. Results: Number of new PC cases in 2003 in Ukraine was 4837 ( men – 2666, women – 2171), in 2013 – 5296 ( men – 2877, women – 2419). So the number of PC cases increased by 8,7% ( by 7,3% in men, by 10,3% in women) in 2013 in comparison to 2003. Number of deaths from PC in 2003 was 4115 (men – 2291, women – 1824), in 2013 – 4307 ( men – 2328, women – 1979). The number of PC deaths increased by 4,5% ( by 1,6% in men, by 7,8% in women). Incidence of PC in children population (age 0-17 years) in 2003 was 0, in 2013 – 4 ( men – 0, women – 4). Age-standardised incidence rate (world standard) of PC in 2003 was 5,9 ( 8,6 in men; 4,0 in women), in 2013 – 6,8 ( 9,8 in men; 4,7 in women). Age-standardised mortality rate (world standard) in 2003 was 5,0 ( men – 7,4; women – 3,4), in 2013 – 5,5 ( men – 7,9; women – 3,9). Patients diagnosed during the preventive medical examinations in 2003 were 3.8% ( men – 3,6%, women – 4,1%), in 2013 - 3.2% ( men – 3,2%, women – 3,3%). Newly diagnosed patients received the special treatment in 2003 were 27,6% (men – 28,7%, women – 26,1%), in 2013 - 26% (men – 25,5%, women – 26,6%). From among them surgical treatment only received 60.8% in 2003, 45.9% in 2013, Combined or complex scheme of treatment received 10.1% in 2003, 10.5% in 2013. The percentage of histologically verified PC in 2003 – 28,4%, in 2013 was 33,6%. Conclusions: There is a tendency of increase of incidence and mortality rates of PC in Ukraine. There have been cases of morbidity in children in 2013 compared with 2003. The number of patients revealed during preventive medical examinations remains low in 2013 and in 2003 due to low health financing, low coverage of preventive medical examinations. The number of patients who received special treatment remains low during 10 years. This is mainly due to lack of access to medical care, high cost of treatment, diagnosis of PC at an advanced stage.
Differentiation of liposomal irinotecan from dose-dense non-liposomal irinotecan in patient-derived pancreatic cancer xenograft tumor models.
Authors: Barbier Sandrine , Lezmi Stephane , Beaufils Benjamin , Lortie Adreanne , Hillairet de Boisferon Marc , Chaumeron Sophie , Espirito Anne , Klinz Stephan G , Thiagalingam Arunthathi , Meyer-Losic Florence
Published: May 2020

e16724

Background: Liposomal irinotecan (ONIVYDE) is approved with 5-fluorouracil/leucovorin for metastatic pancreatic ductal adenocarcinoma (PDAC) post progression on gemcitabine-based therapy. The liposomal formulation prolongs payload residence time in the circulation and tumor lesions, where local conversion to the active metabolite SN-38 is thought to occur. The effect of the liposomal formulation on therapeutic index (TI) was assessed in patient-derived xenograft PDAC models (IM-PAN-001 [untreated tumor] and SA-PAN-077) in severe combined immunodeficiency mice. Methods: Liposomal (2.5, 10 or 50 mg/kg, intravenous [IV] 1 x weekly) and non-liposomal irinotecan (2, 5 or 10 mg/kg, IV 5 x weekly) were administered for 3 weeks (n = 8/group). Maximum tolerated dose (MTD) and clinically-relevant weekly doses (10 mg/kg, liposomal; 33 mg/kg, non-liposomal) of irinotecan were evaluated. TI was the ratio of MTD/lowest dose with anti-tumoral activity; time to reach tumor volume of 600 mm3 (TTV600) was a proxy for overall survival. Tumor, plasma, gut and bone marrow were sampled for pharmacokinetics and safety assessment; DNA damage was evaluated via pH2AX and 53BP1 IHC. Results: The Table reports results of the more sensitive IM-PAN-001 model: TI of weekly liposomal irinotecan was 4-fold higher than for 5 x weekly non-liposomal irinotecan (TI was narrower for SA-PAN-077). For liposomal vs non-liposomal irinotecan in IM-PAN-001, TTV600 was longer at both MTD and clinically equivalent doses, and tumoral irinotecan levels were higher at MTD. High levels of DNA damage were present in most cancer cells in IM-PAN-001 compared to SA-PAN-077 one week after the last liposomal treatment cycle. Conclusions: In both PDAC models, TI was higher for weekly liposomal vs 5 x weekly non-liposomal irinotecan, suggesting potential benefits of the liposomal formulation in a clinical setting. [Table: see text]
Utilization of imaging in pancreatic adenocarcinoma patients status post Whipple procedure.
Authors: Shah Neal , Podury Ruchika , Kikano Elias , Smith Daniel Arnold , Ramaiya Nikhil H. , Tirumani Sree Harsha
Published: May 2020

e16725

Background: Pancreatic adenocarcinoma (PAC) remains the third leading cause of cancer death in the Western world. The 5-year survival of patients with PAC remains at 4%. Proper utilization of imaging to detect recurrence is necessary in patients who have undergone a Whipple procedure. Currently, Carbohydrate (CA) 19-9 is used for screening and is the only biomarker approved by the Food and Drug Administration (FDA). Sensitivity and specificity range from 79-81% and 82-90%. We intend to evaluate our single institute experience of imaging utilization, CA 19-9, and surgical specimen histopathologic features in the surveillance of PAC patients status post Whipple. Methods: Retrospective analysis of patients with a diagnosis of PAC who underwent imaging status post Whipple from 2008 - 2018 was completed. Cross-sectional imaging and clinical data was obtained from the electronic health record. Results: A total of 197 PAC patients status post Whipple were identified with mean age at diagnosis at 64.4 years and male to female ratio of 1.3. 85 patients were found to have died during treatment. The median survival for these patients was 68 years. Of the patients who died status post Whipple, postoperative CA 19-9 levels within 6 months of the procedure were elevated (p = 0.01). Patients who were found to have stage II to IV PAC at diagnosis were found to have a high CA 19-9 level within 6 months post-Whipple when compared to stage I patients (p < 0.05). Patients who were found to have less than 5 surveillance CTs status post Whipple were found to have higher CA 19-9 levels within 6 months status post Whipple (p < 0.01). There was no difference in number of CT scans between stages. Of those patients who died with stage I or II PAC at diagnosis, a large number were found to have less than 5 surveillance CT studies completed status post Whipple (p < 0.05). Furthermore, a higher cancer stage at diagnosis correlated with worse pathologic differentiation of the cancer (p < 0.001). Conclusions: Post Whipple CA 19-9 correlated with stage, recurrence, number of scans, and survival.
Morphological and biochemical heterogeneity in the tissue of pancreatic ductal adenocarcinoma (PDAC) according to structural and spectrometric MRI data.
Authors: Iozefi Dmitry Ya. , Vinidchenko Mikhail A. , Demchenko Nikolay S. , Kit Oleg I. , Fomenko Yuriy A. , Petrov Dmitry S.
Published: May 2020

e16727

Background: Comparing the MRI characteristics of pancreatic tissue in normal, solid adenocarcinomas and chronic pancreatitis in a multiparametric study, the radiologist needs tools that reduce the subjective component in making a diagnostic decision. The study is devoted to the assessment of structural heterogeneity, diffusion coefficient, lipid and lactate concentration according to MR spectroscopy in vivo. PDAС cells are proliferating and surviving within a particularly severe microenvironment characterized by relative hypovascularity, hypoxia, and nutrient deprivation. In this case cells have to show biochemical flexibility (survival phenotype) in order to adapt to unusual conditions. Methods: 20 patients with pancreatic adenocarcinomas (PDAC), 10 patients with chronic pancreatitis and 10 patients with unchanged pancreas were examined MRI using Signa HD 1.5 t General Electric. The results of their multiparametric imaging and NMR spectroscopy were investigated and compared.The heterogeneity coefficients (HC) were measured as ratio standard deviation in small region of interest to signal intensity in T1FS and T2. Lipid concentration was measured by Dixon method as the pancreatic -to-splenic attenuation ratio. Results: In a small sample, we observed a significant increase in HC in chronic pancreatitis, and in solid tissue in adenocarcinomas in comparison with normal tissue, depending on the main source of the MR signal (hydrogen in the macromolecules or hydrogen of water and fat). In adenocarcinomas, an increase in the signal from lipids (lip13a) peak was revealed, with a decrease in the total lipid concentration. A decrease in lipid concentration in the tumor in the presence of diffusion restriction (ADC 0,001-0,0016 мм2/s) and the appearance of a peak of lactate may be a biochemical marker of adenocarcinoma. In chronic pancreatitis, an increase in the mass fraction of lipids was revealed. Conclusions: The results obtained in current and future in-depth studies are promising for creation of a metabolically oriented diagnostic model of pancreatic cancer.
Association of fatty pancreas with increased risk of pancreatic adenocarcinoma.
Authors: El Kurdi Bara , Bataineh Adam , Babar Sumbal , El Iskandarani Mahmoud , Alomari Mohammad , Albawaliz Anas , Sanaka Madhusudhan
Published: May 2020

e16729

Background: Pancreatic adenocarcinoma (PADC) remains one of the most fatal malignancies with poor outcomes and prognosis. Several risk factors have been associated with its development such as smoking, age, obesity, chronic pancreatitis, diabetes mellitus and a family history of PADC. Furthermore, recent pathologic studies demonstrated that fatty infiltration of the pancreas (FP) is positively correlated with PADC development. We sought to systematically review the literature and perform the first meta-analysis to study the risk of PADC among patients with FP. Methods: We conducted a systematic search of the Pubmed, EMBASE, and Cochrane databases from inception through November-2019 for studies correlating FP with PADC. Relevant data was extracted and analyzed using comprehensive meta-analysis software. Random-effects model was used for all variables. Heterogeneity was assessed using the I2 measure and Cochrane Q-statistic. Publication bias was assessed using Egger’s test. Meta regression models accounting for independent variables such as age, sex, smoking, family history of PADC, chronic pancreatitis and method of FP diagnosis were constructed to explain heterogeneity. Results: Five observational case-control studies published between 2014 and 2019 including a total of 761 patients (320 PADC patients and 441 controls) were included. FP was associated with increased PADC with an OR 4.6 (CI 2.4-8.9) compared to controls with a considerable heterogeneity (I2= 69%). Meta regression analysis accounting for modality used to diagnose FP was able to explain 100% of the noted heterogeneity. Conclusions: While we noted FP to be significantly associated with increased PADC, heterogeneity in FP diagnostic approach resulted in significant inter-study variation. A consensus on a clear definition of FP with a standardized diagnostic approach is needed to better appraise literature on this emerging disease entity. Further prospective studies are needed to validate our results and explore the possible role for PADC screening in FP in addition to known factors such as family history and new-onset diabetes mellitus.
Endoscopic retrograde cholangiopancreatography (ERCP) findings to predict survival in patients with metastatic pancreatic adenocarcinoma.
Authors: Sridharan Vishwajith , Shafique Neha , Darnell Elijah , Wang Thomas , Hernandez-Barco Yasmin , Weniger Maximilian , Qadan Motaz , Fernandez Del-Castillo Carlos , Casey Brenna , Krishnan Kumar
Published: May 2020

e16734

Background: Chemotherapy is the primary therapy for patients with metastatic pancreatic ductal adenocarcinoma (PDAC), but response to therapy is variable. Patients with PDAC often develop jaundice and cholangitis and require endoscopic biliary stenting. Here, we investigate the association between ERCP findings, cholangitis, chemotherapy use, and survival in PDAC patients. Methods: We conducted a retrospective chart review of all patients who received metal stents for biliary obstruction with PDAC over a five-year period at the Massachusetts General Hospital. Only patients with metastatic cancer were included. Patients were stratified by whether or not they received chemotherapy, as well as the presence or absence of cholangitis. Associations between chemotherapy use and ERCP findings were investigated. Survival analyses were performed to compare patients by chemotherapy use, presence of cholangitis, and findings at ERCP. Results: A total of 126 patients were included; the average age of patients in our study was 69.9 ± 11.8. The average size of the primary lesion was 38.7 ± 14.4 mm. Sixty-nine percent of patients completed chemotherapy. The average number of stents for all patients was 2.5 ± 2.5, but was significantly higher in patients who experienced cholangitis (3.3 ± 2.8) as expected (p < 0.001). The majority of ERCP reports noted debris or sludge (44%), followed by presence of infiltrating or obstructing tumor (27%), stone (13%), pus or purulence (11%), and blood clot (5%). Patients who did not receive chemotherapy were more likely to have tumor obstruction noted on ERCP compared to those who received chemotherapy (p = 0.024). Patients undergoing chemotherapy were also more likely to have sludge noted on ERCP (p = 0.009) compared to those who did not have chemotherapy. There was no association between chemotherapy use and presence of stones (p = 0.94) or presence of purulence (p = 0.44) noted on ERCP. Among patients who received chemotherapy, those who had sludge or debris noted on their ERCP tended to have better survival compared to those where sludge was not noted on endoscopy (p = 0.038). Conversely, among patients who received chemotherapy, identification of an obstructing tumor on ERCP was prognostic of poorer survival (p = 0.037). Among patients who did not get chemotherapy, there was no survival difference between patients who had sludge or tumor and those who did not. Conclusions: Findings on ERCP may serve as a surrogate for chemotherapy response and be prognostic of survival in metastatic PDAC.
Use of a real-world data approach to rapidly generate outcomes data following a case study of a novel treatment combination in pancreatic adenocarcinoma.
Authors: Rahib Lola , Chen Karen , Ocean Allyson J. , Xie Changqing , Duffy Austin , Manji Gulam Abbas , Greten Tim F. , Shapiro Mark , Shrager Jeff , Hoos William , Federowicz Bryan , Kinsey Conan Grant
Published: May 2020

e16735

Background: We use a real-world data approach to report on safety and benefits on metastatic pancreatic cancer pts who were treated with a MEK inhibitor plus hydroxychloroquine (HCQ) after exhausting all other treatment options. MEK inhibition acts on the KRAS pathway, which in turn increases autophagy as a resistance mechanism, furthermore, HCQ inhibits autophagy causing a cytotoxic effect. This combination was shown to diminish tumor volume in xenograft mouse models and a partial response in one heavily pre-treated patients was reported. Methods: XCELSIOR is an IRB approved, patient-centric, real-world data and outcomes registry for developing operational and analytic methods in precision oncology. Searching the XCELSIOR database, we identified 14 pts for whom this regimen had been considered. As part of their participation in XCELSIOR, these patients shared access to their full medical records, which were collected, processed, and abstracted into a 21 CFR 11 compliant database for analysis. We additionally collected de-identified data on 12 pts treated with this combination from five academic centers. Three more patients are expected to start treatment soon. Results: Between March 2018 and January 2020, 15 patients treated with the trametinib/HCQ combination and 3 patients treated with cobimetinib/HCQ were identified in XCELSIOR and five academic institutions. The median age at diagnosis was 64 (range 43-74) and 56% were male. For patients treated with trametinib/HCQ, the median time on treatment was 67 days (range 5-172 days), 11 patients were treated for more than 30 days (median time 97 days). The median PFS for this group was 2.9 months and the median OS was 7.4 months. The clinical benefit rate was 60% for the 10 evaluable patients treated with trametinib/HCQ, 1 patient had a partial response (previously published), 5 had stable disease (for at least 8 weeks) and 4 had progressive disease (physician reported). 2/3 patients treated with cobimetinib/HCQ were on treatment for more than 30 days and all three had progressive disease within 7 weeks. The most common side effects were Grade 1 fatigue and Grade 1/2 rash for both combinations. An additional 3 patients will start treatment soon and will be included in the analysis. Conclusions: Combinatorial MEK and autophagy inhibition was well tolerated in heavily treated metastatic pancreatic cancer patients. Trametinib/HCQ demonstrates some clinical benefit for this group. We demonstrate the feasibility of utilizing real-world data in precision oncology. Clinical trial information: NCT03793088 .
National Comprehensive Cancer Network (NCCN) category I/FDA-approved metastatic pancreatic adenocarcinoma (mPDAC) treatments in commercially insured patients: An analysis of inpatient (IP) and emergency room (ER) admissions.
Authors: Cockrum Paul , Surinach Andy , Arndorfer Stella , Koeller Jim M. , Kim George P.
Published: May 2020

e16739

Background: There are currently four NCCN category 1 systemic regimens approved in the United States for the treatment of mPDAC: FOLFIRINOX (FFX), gemcitabine+nab-paclitaxel (gem+nab-P), gemcitabine monotherapy (gem), and liposomal irinotecan + 5-fluorouracil/leucovorin (5-FU/LV) following progression with gem-based therapy. There is limited real-world research on the IP admissions and ER visit healthcare resource utilization (HRU) of patients receiving these treatments. Methods: Using the IQVIA PharMetrics Plus administrative claims database, data were analyzed for adult patients with mPDAC treated with NCCN category 1 regimens in first through fourth line of therapy between January 1, 2014 and May 31, 2019. For each line of therapy, continuous treatment was defined as the time from first administration of a therapy until the last administration. Mean all-cause and mPDAC-related IP admissions, ER visits, inpatient length of stay (LOS) during treatment were assessed. Results: Of the 2,731 patients with mPDAC included in the study, 101 (3.7%) were treated with a liposomal irinotecan based regimen, 1,316 (48.2%) were treated with gem+nab-P, 612 (22.4%) with FFX, and 624 (22.8%) with gem in any treatment line. The mean number of IP admissions was 1.2 for liposomal irinotecan treated patients, 1.5 for gem+nab-P, 1.5 for FFX, and 1.2 for gem. Among patients with at least one IP admission the mean LOS was 4.5 days for liposomal irinotecan, 5.4 days for gem+nab-P, 3.8 for FFX, and 5.1 for gem treated patients. Patients treated with liposomal irinotecan had a mean of 1.3 ER visits during treatment. Gem+nab-P, FFX, and gem-treated patients experienced 1.7, 1.4, and 1.8 mean ER visits, respectively. Mean mPDAC-related IP admissions ranged from 1.1 – 1.5, ER visits ranged from 1.1 – 1.7, and mean LOS ranged from 3.8 – 5.5 days. Conclusions: In this descriptive retrospective study patients receiving liposomal irinotecan, across all treatment episodes, generally experienced numerically lower mean IP admissions and ER visits. LOS was similar across all regimens. Further studies are necessary to characterize the IP and ER HRU burden among mPDAC patients treated with approved regimens.
Performance of neoadjuvant therapy in locally advanced adenocarcinoma of the pancreas: A single large volume center experience.
Authors: Lee Teresa , Zhan Tingting , Chanda Subikram , Barsouk Adam , Nauheim David , Renslo Bryan , Shergill Mandeep , Jiang Wei , Chao Timothy , Lavu Harish , Yeo Charles , Posey James
Published: May 2020

e16745

Background: Pancreatic adenocarcinoma (PC) is a disease with low 5-year survival rates even in patients who undergo surgical resection: ~10% overall and 20-35% in those with negative lymph nodes and R0 operation. Adjuvant chemotherapy (CT) has demonstrated benefit; however, not all patient are candidates for multi-agent CT post-op. Early use of systemic therapy might improve outcomes. As a leading referral center for pancreatic resection in a tri-state area, we present a single institution real-world experience of neoadjuvant CT (neo-CT) in PC patients principally with degrees of vascular abutment at presentation. Methods: We identified 90 patients scheduled for pancreatectomy from 2015 to 2019 who received neo-CT. Three had an aborted procedure due to occult metastatic disease. Of those who underwent resection (n = 87), most were borderline or locally advanced (n = 79) with a few deemed resectable (n = 5) or metastatic (n = 3) prior to CT. 80 patients (92%) had R0 resection, though final pathology showed R1 resection in 5 and distant metastases in 2 patients. 72% of patients (n = 63) received 5-FU-based neo-CT, while 28% (n = 24) received gemcitabine-based CT. 36% (n = 31) received neoadjuvant radiation (RT) (with or without concurrent CT) in addition to CT, and 43% (n = 37) had adjuvant therapy, either CT, RT, or a combination. 4 patients received additional therapies on clinical trial. 41 patients (47%) completed >6 months of peri-operative CT, with 23 of those (26%) completing 6 months prior to surgery. We evaluated pathologic regression scores and compared those with very good response (score 0-1) post-CT vs. partial (score 2) or no response (score 3). Results: Median progression-free survival (PFS) from start of treatment in our cohort was 1.9 years (95% CI 1.4-NR) while median overall survival (OS) was 3.0 years (95% CI 2.4-NR). Duration of neo-CT did not affect PFS or OS. Logrank tests of OS curves of the 3 pathologic response groups indicated a statistically-significant difference (p = 0.004), with longer OS in patients with score 0-1 and shorter OS in patients with score 3. Conclusions: This analysis involves patients treated in both community and academic settings. We observed improved survival among those with best pathologic responses. The majority of cases with lower residual tumor burden received FOLFIRINOX. We are analyzing molecular data in this cohort and will conduct adjusted analyses for clinical characteristics. The prospective selection of multiagent CT in PC may be influenced by molecular profile and early response assessment.
A phase II trial of cabozantinib and erlotinib for patients with EGFR and c-Met co-expressing metastatic pancreatic adenocarcinoma (PDAC).
Authors: Turk Anita Ahmed , Sehdev Amikar , Shahda Safi , O'Neil Bert , Helft Paul R. , Spittler Aaron John , Flynn Janet , Loehrer Patrick J.
Published: May 2020

e16764

Background: Both EGFR and the c-MET receptors are overexpressed in a majority of PDACs. Inhibition of both receptors simultaneously may be required for anti-tumor activity. Erlotinib, an EGFR inhibitor, has modest activity in metastatic PDAC and is approved by the FDA in combination with gemcitabine. Cabozantinib is a tyrosine kinase inhibitor targeting AXL, FLT-3, KIT, MER, MET, RET, ROS1, TIE-2, TRKB, TYRO3, and VEGFR-1, -2, and -3. Preclinical data suggests that the addition of cabozantinib to erlotinib leads to tumor shrinkage and improvement in survival in a KPC PDAC mouse model compared to gemcitabine alone. This phase II study tests this hypothesis in patients with metastatic PDAC that co-express c-MET and EGFR. Methods: Key eligibility includes patients (pts) with metastatic PDAC with EGFR and c-MET overexpression (as determined by centrally tested IHC of 2+ or greater) that have progression on one prior chemotherapy regimen. Patients were treated with cabozantinib (40mg daily) and erlotinib (100mg daily) continuously. This dosing is based on previous combination data in NSCLC. This is a single arm two-stage phase II study with a primary endpoint of overall response rate. Secondary endpoints include of PFS, DCR and OS. Results: From October 2017 to October 2019, 43 pts were screened with 7 pts (median age 62 [range 51-76)] enrolled and treated on study. Pts had a median of 1 line of prior systemic chemotherapy. Most common reason for screen failure was due to lack of co-expression of c-MET and EGFR. EGFR IHC expression was +2 in 4 pts, +3 in 3 pts; c-MET IHC expression was +2 in 5 pts and +3 in 2 pts. Most common any-grade adverse events attributable to cabozantinib and erlotinib include: diarrhea (71%), AST increase (43%), fatigue (43%), nausea (43%), and rash (43%). Only one grade 3 event of fatigue occurred. All pts had clinical and/or radiographic progression within 1-2 months after initiating study therapy. Conclusions: The combination of cabozantinib and erlotinib was well tolerated with manageable toxicity. Due to lack of clinical responses, this study has been terminated due to futility. Clinical trial information: NCT03213626 .
Sarcopenia and sarcopenic obesity in pancreatic ductal adenocarcinoma (PDAC) patients undergoing surgery after neoadjuvant therapy (NAT): Clinical implications.
Authors: Trestini Ilaria , Paiella Salvatore , Sandini Marta , Hank Thomas , Pollini Tommaso , Sperduti Isabella , Melisi Davide , Auriemma Alessandra , Soldà Caterina , Tregnago Daniela , Avancini Alice , Malleo Giuseppe , D'Onofrio Mirko , Gianotti Luca , Pilotto Sara , Bria Emilio , Salvia Roberto , del Castillo Carlos Fernandez , Bassi Claudio , Milella Michele
Published: May 2020

e16769

Background: Nutritional status may be markedly affected by NAT for PDAC. Sarcopenia and sarcopenic obesity have been studied in several types of cancers and have been reported to be associated with higher morbidity and mortality. The present study assessed the impact of sarcopenia/sarcopenic obesity and changes in body composition (BC) following NAT on surgical and survival outcomes in patients (pts) undergoing surgery for PDAC. Methods: PDAC pts with available CT-scans (both at diagnosis and preoperatively) undergoing surgical resection after NAT at two academic medical institutions from 2013 to 2015 were retrospectively evaluated. BC was assessed by analyzing axial L3 CT images before and after NAT. Data were correlated with overall survival (OS) using a Cox regression model. Kaplan-Meier curves were compared with Log-Rank test. Results: The final cohort consisted of 108 pts, with a median age of 63 years and a median follow-up of 16 months. Ninety-one pts (89.8%) received FOLFIRINOX. Sarcopenia and sarcopenic obesity were found at diagnosis in 41.7% and 16.7% of pts, respectively. After NAT, all body compartments significantly changed (p < 0.001); the prevalence of sarcopenia and sarcopenic obesity decreased to 30.5% and 10.2%, respectively, after NAT. These BC phenotypes were related to a higher overall complications rate after surgery (69.7% vs. 30.3%, p = 0.027 and 81.8% vs. 18.2% %, p = 0.048, respectively). Particularly, cardiac complications were associated with sarcopenia (9% vs. 0%, p = 0.028) and pts that developed postoperative complications had higher preoperative total adipose tissue (300 vs. 229 cm2, p > 0.05). With regards to OS, sarcopenic obesity at baseline (HR 3.45, p = 0.023) was found to be a significant independent predictor for OS at multivariate analysis. Conclusions: Our data provide evidence that BC impacts on both surgical and survival outcomes in PDAC pts undergoing NAT before resection. The associations with worse clinical outcomes emphasize the role of nutritional evaluation, as well as the need to develop appropriate evidence-based nutritional interventions during NAT.
New-onset diabetes mellitus and risk of pancreatic cancer: A systematic review and meta analysis.
Authors: Albawaliz Anas , Bataineh Adam , El Kurdi Bara , Babar Sumbal , Abonofal Abdulrahman , Alhabhbeh Ammar , Alomari Mohammad , Qasem Abdulraheem M.S. , Sanaka Madhusudhan
Published: May 2020

e16778

Background: Several epidemiologic studies have illustrated a general association between diabetes mellitus and pancreatic cancer (PC). Very few, however, described a temporal association between the new onset of diabetes mellitus, particularly within the first 2 years of diagnosis, and the development of PC. We sought to systematically review the literature and perform the first meta-analysis to study the risk of PC among patients with new-onset diabetes mellitus (NOD). Methods: A systematic literature search was conducted in PubMed, MEDLINE, EMBASE, and Cochrane databases from inception through November 2019 to identify studies evaluating the relationship between NOD and PC. NOD was defined as diabetes mellitus diagnosed within 3 years or less prior to diagnosis of PC. Studies were examined and relevant data was extracted and analyzed using Comprehensive Meta-Analysis software. A random effect meta-analysis approach was used to pool the data and odds ratio was used to calculate the overall effect estimate. Results: A total of 283 articles were identified by the search but only 4 relevant studies met our inclusion criteria and they examined a total of 42055 cases and 2402213 controls. The odds ratio of pancreatic cancer development among patients with NOD was 3.021 (CI 2.192- 4.165) compared to controls with significant heterogeneity (I2= 90%). Meta regression evaluating relevant variables such as mean age, race and smoking were not able to explain the heterogeneity. A meta-regression model accounting for sample size as an independent factor showed that sample size was inversely correlated to the OR of PC in patients with NOD and was able to explain 93% of the noted heterogeneity between studies. Conclusions: Our meta-analysis has shown a significant temporal association between NOD and pancreatic cancer. Diabetes mellitus, being mostly diagnosed in an outpatient setting by primary care physicians (PCPs), can be the first clue to detect pancreatic cancer at an early stage, and thus contribute to more favorable outcomes. These findings might guide PCPs to consider pancreatic cancer in the differential diagnosis in high risk patients. Further studies are needed to discern the role of NOD in pancreatic cancer screening. Attention is required to the possible inflationary effect of low sample sizes on the odds of developing PC after NOD.
Value-based estimate of market size and opportunity for economic benefit through innovative pancreatic cancer (PC) therapies.
Authors: Picozzi Vincent J. , Manax Victoria G. , Kim Semmie , Wintrob Zachary , Mandelson Margaret T. , Korfin Michele , Del Priore Giuseppe , Goldberg Robert
Published: May 2020

e16790

Background: Over the past 20 years, cancer drugs have contributed to increased life expectancy, reduced mortality, decreased hospitalization and decreased use of medical services. The economic value of these improvements is about as large as the value of the increase in the US gross domestic product during that time period. Recently, a health economic study presented at ASCO GI 2020 cited that every $1 (adjusted for inflation) spent on innovative PC treatments reduced non-drug expenditures by $9, thereby lowering the total cost of care for PC patients. Accordingly, the commercial opportunity of a new therapy should be measured by some combination of the clinical, economic and social value generated. We demonstrate the value of a novel PC drug from this perspective. Methods: Analysis of SEER survival and incidence data between 2008 and 2016 shows the introduction of new medicines for PC of all stages was associated with a cumulative increase of 26,456 life years, or 2.52 life years per patient. It was also associated with quality of life improvements, measured by a decline in hospitalizations rates and emergency room visits that can also lead to more days at work, at school and with family. Several studies have suggested the average value of an additional year of life, for the age of a typical patient diagnosed with PC, is at least $250,000. Using this figure, the value of 26,456 life years gained from 2008-2016 is $6.61 billion (26,456*$250,000) to patients, the healthcare system and society, as a result of advancing medical innovation for patients with PC. Results: The median annual list price of a life-enhancing cancer therapy is $150,000 per patient. Using the NCI treatment prevalence estimator (holding incidence constant), we estimate that between 2020-2025, there will be an additional 10,728 advanced PC patients requiring treatment who could benefit from innovative drugs. The total cost of these drugs for these patients would be $1.61 billion. However, the economic value of the life years saved would be $6.76 billion (10,728*2.52 life years*$250,000 = $6.76 billion). A review of cancer medicine payor coverage suggests a new PC therapy that produces such value would be able to obtain coverage from US payors given this value-based price. Conclusions: A value-based approach to estimating the opportunity for clinical and economic benefit reveals significant potential for new PC medicines.
Circulating tumor DNA analysis to detect minimal residual disease and predict recurrence in patients with resectable pancreatic cancer.
Authors: Yang Liu , Jiang Jiahong , Ye Song , Xu Yaping , Huang Dongsheng
Published: May 2020

e16799

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer death, partly due to the high recurrence rates for patients with resectable PDAC. Current postoperative surveillance methods including monitoring of clinical symptoms, tumor markers and CT imaging, lack sensitivity and specificity to identify minimal residual disease (MRD). Methods: We investigated whether the detection of circulating tumor DNA (ctDNA) could identify MRD and predict relapse in postoperative patients with PDAC. In this study, we performed panel-captured sequencing to detect somatic mutations. Matched tissue samples were obtained to verify mutation. Results: A total of 27 patients and 65 plasma samples were included. Among the somatic mutations, KRAS and TP53 were the most recurrent genes in both tissue and plasma samples. The detectable rate of ctDNA increased with the stage of PDAC. The maximal variant allele fraction (VAF) of ctDNA had a positive correlation with tumor largest diameter (p = 0.0101). Patients with ctDNA-positive status postoperatively had a markedly reduced disease-free survival (DFS) compared to those with ctDNA-negative status (HR, 5.20; p = 0.019). Positive vascular invasion significantly influenced disease-free survival (DFS) (p = 0.036), and positive postoperative ctDNA status was an independent prognostic factor for DFS (HR = 3.60; 95% CI, 1.15-11.28; p = 0.028). Conclusions: Postoperative ctDNA detection provides strong evidence of MRD and identifies patients with a high risk of relapse. ctDNA detection is a promising approach for personalized patient management during postoperative follow-up.
A novel prediction model to identify patients with early-stage pancreatic cancer.
Authors: Cherry Daniel R , Chen Qinyu , Murphy James Don
Published: May 2020

e16801

Background: Pancreatic cancer has an insidious presentation with four-in-five patients presenting with disease not amenable to potentially curative surgery. Efforts to screen patients for pancreatic cancer using population-wide strategies have proven ineffective. We applied a machine learning approach to create an early prediction model drawing on the content of patients’ electronic health records (EHRs). Methods: We used patient data from OptumLabs which included de-identified data extracted from patient EHRs collected between 2009 and 2017. We identified patients diagnosed with pancreatic cancer at age 40 or later, which we categorized into early-stage pancreatic cancer (ESPC; n = 3,322) and late-stage pancreatic cancer (LSPC; n = 25,908) groups. ESPC cases were matched to non-pancreatic cancer controls in a ratio of 1:16 based on diagnosis year and geographic division, and the cohort was divided into training (70%) and test (30%) sets. The prediction model was built using an eXtreme Gradient Boosting machine learning algorithm of ESPC patients’ EHRs in the year preceding diagnosis, with features including patient demographics, procedure and clinical diagnosis codes, clinical notes and medications. Model discrimination was assessed with sensitivity, specificity, positive predictive value (PPV) and area under the curve (AUC) with a score of 1.0 indicating perfect prediction. Results: The final AUC in the test set was 0.841, and the model included 583 features, of which 248 (42.5%) were physician note elements, 146 (25.0%) were procedure codes, 91 (15.6%) were diagnosis codes, 89 (15.3%) were medications and 9 (1.54%) were demographic features. The most important features were history of pancreatic disorders (not diabetes or cancer), age, income, biliary tract disease, education level, obstructive jaundice and abdominal pain. We evaluated model performance at varying classification thresholds. When applied to patients over 40 choosing a threshold with a sensitivity of 20% produced a specificity of 99.9% and a PPV of 2.5%. The model PPV increased with age; for patients over 80, PPV was 8.0%. LSPC patients identified by the model would have been detected a median of 4 months before their actual diagnosis, with a quarter of these patients identified at least 14 months earlier. Conclusions: Using EHR data to identify early-stage pancreatic cancer patients shows promise. While widespread use of this approach on an unselected population would produce high rates of false positives, this technique could be employed among high risk patients, or paired with other screening tools.
Similar response rates and survival with PARPi treatments for patients harboring somatic versus germline BRCA mutations: A meta-analysis and systematic review.
Authors: Mohyuddin Ghulam Rehman , Aziz Muhammad , Britt Alec , Wade Lee , Sun Weijing , Baranda Joaquina Celebre , Al-Rajabi Raed Moh'd Taiseer , Saeed Anwaar , Kasi Anup
Published: May 2020

e16802

Background: PARP inhibitor (PARPi) has recently been approved for various cancers. However, trials have mostly recruited pts with germline BRCA (gBRCA) mutations, and it is unclear whether PARPi have similar efficacy in pts with somatic BRCA (sBRCA) mutations. We aimed to determine the efficacy of PARPi in pts with sBRCA mutations. Methods: Per PRISMA guidelines, systematic review of PubMed, Embase, Cochrane RCT, and Web of Science Collection was performed from inception thru Jan 2020 to identify studies. Our inclusion criteria were clinical trials and retrospective studies that reported use of PARPi in pts with both s and g BRCA mutations. We performed a meta-analysis comparing overall response rate and PFS with PARPi in pts with s versus g BRCA mutations. Results: After screening, 18 studies met our criteria for including both s and g BRCA mutations. Only 8 studies reported response rates for both s and g BRCA mutations (Table). In those studies, 24 out of 43 pts with sBRCA mutations (55.8%), and 69 out of 157 (43.9%) pts with gBRCA had a response to PARPi (pooled OR 1.13, p value = 0.399, I2 = 0). In all five studies that reported PFS, there was no obvious difference in outcomes between sBRCA (HR in these studies ranged 0.23 to 0.27) versus gBRCA (HR ranged 0.17 to 0.27), however a precise statistical analysis could not be done. Conclusions: Our meta-analysis and systematic review of the literature indicates similar outcomes of PARPi therapy in pts with s and g BRCA mutations. Investigation of use of PARPi therapy in a broader patient population, and the inclusion of sBRCA mutations in future clinical trials is essential. [Table: see text]