bluuebunny/crossref_metadata_2025_split huggingface dataset:
Updated overall survival analysis of NAPOLI-1: Phase III study of nanoliposomal irinotecan (nal-IRI, MM-398), with or without 5-fluorouracil and leucovorin (5-FU/LV), versus 5-FU/LV in metastatic pancreatic cancer (mPAC) previously treated with gemcitabine-based therapy.
Authors: Wang-Gillam Andrea , Li Chung-Pin , Bodoky Gyorgy , Dean Andrew , Shan Yang-Shen , Jameson Gayle S. , Macarulla Teresa , Lee Kyung-Hun , Cunningham David , Blanc Jean-Frédéric , Hubner Richard , Chiu Chang-Fang , Schwartsmann Gilberto , Siveke Jens T , Braiteh Fadi S. , Moyo Victor M. , Belanger Bruce , Bayever Eliel , Von Hoff Daniel D. , Chen Li-Tzong 
Published: February 2017

417 Background: NAPOLI-1 is a global, randomized Phase 3 study evaluating nal-IRI—a nanoliposomal irinotecan—with or without 5-FU/LV in 417 patients with mPAC previously treated with gemcitabine-based therapy. Primary survival analysis was based on 313 events. Nal-IRI+5FU/LV significantly improved overall survival (OS, primary endpoint), 6.1 months (mo) vs 4.2 mo; with 5-FU/LV (unstratified hazard ratio [HR] = 0.67; P = 0.012). Primary endpoint was supported by improved progression-free survival, time to treatment failure, objective response and CA19-9 tumor marker response rates, and manageable toxicities. An updated analysis of OS, 6- and 12-month-survival estimates, and safety is presented. Methods: The updated descriptive analysis of OS, based on 378 events (25 May 2015), includes data from all randomized patients across the 3 arms. Results: After 378 OS events, nal-IRI+5-FU/LV (n = 117) retained an OS advantage relative to 5-FU/LV (n = 119): 6.2 mo (95% confidence interval [CI], 4.8–8.4) vs 4.2 mo (95% CI, 3.3–5.3) with an unstratified HR of 0.75 (P = 0.0417). In contrast, there was no OS advantage with nal-IRI monotherapy (n = 151) vs 5-FU/LV (n = 149): 4.9 mo [95% CI, 4.2–5.6] vs 4.2 mo [95% CI, 3.6–4.9], HR = 1.08; P = 0.5. Six-month survival estimates were 53% (95% CI, 44–62%) for nal-IRI+5-FU/LV vs 38% (95% CI, 29–47%) for 5-FU/LV; 12-month survival estimates were 26% (95% CI, 18-35%) for nal-IRI+5-FU/LV vs 16% (95% CI, 10–24%) for 5-FU/LV. With events in nearly all patients, the OS curves converge at ~20 mo with 19 patients (16.2%) surviving beyond 20 mo. This is a reason for attenuation of the HR estimate and unstratified log rank p-value. The most common grade 3+ adverse events occurring at a ≥ 2% incidence in the nal-IRI-containing arms were neutropenia, diarrhea, vomiting, and fatigue. Conclusions: In an updated analysis, the median OS benefit for nal-IRI+5FU/LV over 5-FU/LV was maintained, with a similar safety profile. Nal-IRI+5-FU/LV may be a new standard of care for patients with mPAC previously treated with gemcitabine-based therapy. Clinical trial information: NCT01494506.
RAINIER: A randomized, double-blinded, placebo-controlled phase II trial of gemcitabine (gem) plus nab-paclitaxel (nab-P) combined with apatorsen (A) or placebo (Pl) in patients (pts) with metastatic pancreatic cancer (mPC).
Authors: Ko Andrew H. , Murphy Patrick B. , Peyton James D. , Shipley Dianna , Al-Hazzouri Ahmed , Rodriguez Frank A. , Womack Mark S. , Xiong Henry Q. , Waterhouse David M. , Tempero Margaret A. , Bendell Johanna C. 
Published: February 2017

419 Background: Heat shock protein 27 (Hsp27) is over-expressed in PC, enabling tumor growth and metastasis. A is an antisense oligonucleotide that binds to Hsp27 mRNA and inhibits production of Hsp27 protein. This randomized phase II trial evaluates the efficacy of gem/nab-P plus A or Pl in pts with mPC. Methods: Pts with untreated mPC were randomized 1:1 to Arm A (gem, nab-P, A) or Arm B (gem, nab-P, Pl). 3 loading doses of 600mg A IV or Pl IV were given, then 600 mg A or Pl weekly with chemotherapy in 28 day cycles. Both arms received gem 1000mg/m2 IV, nab-P 125mg/m2 IV days 1, 8, and 15. Restaging was every 2 cycles. Serum Hsp27 levels were collected at baseline and on treatment. Primary endpoint compared overall survival (OS); secondary endpoints were progression free survival (PFS), response rate (RR), CA 19-9 response, and toxicity. Results: 132 pts were randomized: median age 66 yrs, 57% male, 47% ECOG 0. Demographics were similar for both arms. 36% of pts on Arm A and 48% of pts Arm B discontinued due to progressive disease, and 24% and 14% due to adverse events (AEs). There was a higher incidence of ≥Grade (G) 4 and serious adverse events (SAEs) in Arm A. The most frequently reported G 3/4 treatment-related AEs were anemia (20%), neutropenia (17%), and fatigue (16%) on Arm A and anemia (27%), neutropenia (19%), and thrombocytopenia (13%) on Arm B. Overall RR was 18% on each arm. With a median f/u of 9.1 mos, median PFS and OS are 2.7 and 5.2 mos on Arm A and 3.8 and 6.9 mos on Arm B (p=NS). Correlative analyses between Hsp27 expression and clinical outcomes will be presented. In a statistical model using only Arm B data, 3 base attributes, ECOG >0, liver mets, and neutrophil levels had a strong prognostic relationship to OS. Conclusions: This study showed no improvement in clinical outcomes adding A to gem plus nab-p. G 4 AEs and SAEs were increased with A. We await analysis for Hsp 27 and CA 19-9 levels and further analysis to identify any pt subgroup who might have benefited from the experimental treatment. Clinical trial information: NCT01844817.
Safety and efficacy of dose-modified FOLFIRINOX on toxicity and effectiveness in Japanese patients with unresectable pancreatic cancer (PC).
Authors: Uesugi Kazuhiro , Asagi Akinori , Terasawa Hiroyuki , Nadano Seijin , Ishii Hiroshi 
Published: February 2017

422 Background: FOLFIRINOX has been shown superior to GEM in terms of OS, PFS and/or RR for treatment of metastatic PC in Accord 11, and this regimen has become the standard of care for the first-line chemotherapy. However, the major disadvantage of FOLFIRINOX is significantly higher toxicity, and, in particular, quite higher incidence of neutropenia (78%) and febrile neutropenia (22%) was observed in the PII clinical trial of FOLFIRINOX performed in Japan (LOHP-PII-05, JSCO 2013). Thus, in clinical practice for the Japanese patients, it should be needed to make modification on this regimen in terms of dose reduction without compromising in its effectiveness. We evaluated the safety and efficacy of modified (m) FOLFIRINOX in Japanese patients with unresectable locally advanced PC (LAPC), metastatic PC (MPC), and/or postoperative recurrence. Methods: The modifications to FOLFIRINOX include discontinuation of the bolus 5-FU and dose-reduction (25%) of irinotecan. 36 patients with unresectable LAPC, MPC and postoperative recurrence were treated with mFOLFIRINOX, and toxicity and efficacy were evaluated. Results: Patient characteristics were as follows: LAPC/MPC/Postoperative recurrence 6/20/10; median age 65 years (range 39-75); male/female 27/9. Median number of cycles was 5 (range 1-28). Grade 3/4 toxicities included neutropenia (16.7%), leukopenia (13.9%), diarrhea (13.9%) and enteritis (11.1%) in order. Febrile neutropenia was only in 2 patients (5.6%). Both hematologic and non-hematologic toxicities were reduced, although diarrhea was observed in a bit higher incidence compared to those in LOHP-PII-05. The response rate and disease control rate evaluated in 28 patients were favorable, in LAPC, MPC and/or post operative recurrence, which were similar to those in LOHP-PII-05. In response of CA19-9 was evaluated in 26 patients. 20 patients (76.9%) showed a decline in CA19-9 levels from baseline, and a greater than 50% decline was noted in 15 patients (57.7%). Conclusions: mFOLFIRINOX has an improved safety profile with maintained efficacy in the selected population of MPC. mFOLFIRINOX has promising activity also in LAPC with respect to RR.
Phase II study of individualized adaptive stereotactic body radiotherapy (SBRT) for patients at high risk for liver damage.
Authors: Feng Mary Uan-Sian , Suresh Krithika , Schipper Matthew J , Bazzi Latifa , Ben-Josef Edgar , Matuszak Martha , Parikh Neehar , Welling Theodore Hobart , Ten Haken Randall K , Lawrence Theodore Steven 
Published: February 2017

424 Background: Patients (Pts) with pre-existing liver dysfunction are at high risk for further damage after SBRT. We completed a phase 2 study of individualized SBRT, utilizing pre- and during-treatment indocyanine green (ICG) clearance to adapt treatment and maximize both safety and efficacy. Methods: From 5/10-10/14, pts with hepatocellular carcinoma (HCC) or metastases (mets) were enrolled and underwent SBRT planning up to a target dose of 50-60 Gy or as limited by a 15% normal tissue complication probability for radiation-induced liver disease (RILD). ICG retention at 15 minutes (ICGR15) was measured prior to and 1 month after 3 of 5 planned treatments. Using a Bayesian adaptive model, RT dose was scaled down as necessary for the final 2 treatments to keep ICGR15 < 44% after the full treatment and thus minimize toxicity. Follow up was every 3 months for 2 years. Results: 90 pts received SBRT to 116 tumors and had at least 1 year of potential follow up. Median age was 62 years, range 34-85. 69 had HCC, 4 intrahepatic cholangiocarcinoma, and 17 mets. 62 had cirrhosis, most commonly HCV and alcoholic. Median Child-Pugh (CP) score was 6, range 5-9. 20 pts were CP B/C. Median pre-RT ICGR15 was 22, range 4-75, normal 4-10. Pts had a median of 1.5 (range 0-6) prior liver-directed therapies, most commonly transarterial chemoembolization (70), prior RT (36), and radiofrequency ablation (13). Median tumor size was 3 cm, and 12 had portal vein involvement. 63 received all 5 fractions (48 full dose, 15 with dose reduction due to elevated ICGR15); 27 received only 3 treatments. Median prescription dose was 47 Gy. Treatment was well tolerated with no classical RILD and a lower complication rate than expected without adaptation. 4 pts had grade 3 ascites. 2 pts had GI bleed after SBRT. 14% and 10% of pts experienced at least a 1 or 2 point increase in CP 6 months post SBRT. Local control (95%CI) at 1 and 2 yrs was 99 (96,100)% and 90 (81,100)%. 4 recurrent tumors were 3 HCC and 1 met, measuring 26, 12, 30, 38mm; treated to 30, 50, 33, 30 Gy. Conclusions: Individualized adaptive SBRT, based on ICG clearance is a promising method of allowing pts to receive the maximally aggressive dose based on each pt’s individual tolerance to RT. Funded by P01 CA59827
Effect of baseline carbohydrate antigen 19-9 (CA19-9) level on overall survival (OS) in NAPOLI-1 trial: A phase III study of MM-398 (nal-IRI), with or without 5-fluorouracil and leucovorin (5-FU/LV), versus 5-FU/LV in metastatic pancreatic cancer (mPAC) previously treated with gemcitabine-based therapy.
Authors: Chen Li-Tzong , Siveke Jens T , Wang-Gillam Andrea , Hubner Richard , Pant Shubham , Dragovich Tomislav , Chung Vincent M. , Chang David Z. , Ross Paul J. , Cooray Prasad , Tebbutt Niall C. , Franke Fabio A. , Belanger Bruce , Dhindsa Navreet , De Jong Floris , Mamlouk Khalid , Von Hoff Daniel D. 
Published: February 2017

425 Background: CA19-9 has been shown to correlate with response to therapy and OS in patients with mPAC. NAPOLI-1, a randomized phase 3 study evaluated nal-IRI, a nanoliposomal formulation of irinotecan, with or without 5-FU/LV vs 5-FU/LV in patients with mPAC previously treated with gemcitabine-based therapy. Nal-IRI+5-FU/LV significantly improved OS (primary endpoint) vs 5-FU/LV (6.1 mo vs 4.2 mo; unstratified hazard ratio [HR] = 0.67; P = 0.012). CA19-9 response (≥50% decline from baseline) was superior with nal-IRI+5FU/LV compared with 5-FU/LV (29% vs 9%; P=0.0006). Nal-IRI alone did not show a statistical improvement in survival. Methods: Patients with a recorded baseline CA19-9 measurement were divided into quartiles to evaluate the treatment effect pattern of CA19-9 from nal-IRI+5-FU/LV and 5-FU/LV arms. Quartile ranges were based on 404 available CA19-9 values from randomized patients (N=417). Unstratified Cox proportional hazards regression was used to estimate HRs and corresponding 95% CIs. Effect of baseline CA19-9 on time to response, progression-free survival, and response will be presented. Results: Of patients randomized to receive nal-IRI+5-FU/LV (n = 117) or 5-FU/LV enrolled contemporaneously (n = 119), 218 received study drug and had a baseline CA19-9 measurement. Results show a greater treatment effect on OS with higher CA19-9 level relative to 5-FU/LV. Conclusions: In patients with mPAC previously treated with gemcitabine-based therapy, nal-IRI+5-FU/LV significantly improved OS supported by progression free survival and objective response rate. The CA19-9 serum level can provide important information with regards to overall survival. Clinical trial information: NCT01494506. [Table: see text]
Multidisciplinary approach to patients with recurrent colorectal liver metastases.
Authors: Vigano Luca , Costa Guido , Comito Tiziana , Pedicini Vittorio , Poretti Dario , Scorsetti Marta , Solbiati Luigi , Torzilli Guido 
Published: February 2017

426 Background: Recurrence after liver resection (LR) for colorectal metastases (CLM) is common. Re-resection is the standard treatment. In unresectable patients, radiofrequency ablation (RFA) and stereotactic body radiation therapy (SBRT) have been proposed, but they did not show a clear survival benefit in comparison with chemotherapy alone. The present study aims to elucidate the outcome of patients with recurrent CLM according to the received treatment. Methods: A series of 323 consecutive patients undergoing first LR between 2004 and 2013 was considered. Of these, 206 (63.8%) had recurrence and were analyzed. Redo surgery was scheduled whenever possible. If surgery was excluded, RFA was considered for hepatic lesions, while SBRT for both hepatic and extra-hepatic lesions. Results: Among the 206 analyzed patients with recurrence, 72 underwent re-resection, 19 RFA and 14 SBRT. Liver-only recurrences were treated in 68.3% of cases (69/101, 47 surgery), pulmonary ones in 57.9% (22/38, 15 surgery) and other extra-hepatic ones in 20.9% (14/67, 10 surgery). After a median follow-up of 32 months, three-year survival after the diagnosis of recurrence (OS) was 42.2% (median 37.4 months). OS was associated with the administered treatment: at three years 70.5% if surgery, 53.8% if RFA/SBRT, and 15.0% if chemotherapy alone, p < 0.0001. The same association was observed focusing the analysis on patients with a total of three lesions in the liver and/or the lung (1-3 liver/lung group, n = 86): three-year OS was 82.6% if surgery, 55.8% if RFA/SBRT, and 29.2% if chemotherapy, p < 0.0001. Progression-free survival after the treatment of recurrence (PFS) was associated with the received treatment: at two years 29.0% if surgery, 14.4% if RFA/SBRT, and 2.6% if chemotherapy, p < 0.0001. The same result was observed in the “1-3 liver/lung” group: two-year PFS was 32.1% if surgery, 18.3% if RFA/SBRT, and 0% if chemotherapy, p = 0.001. RFA and SBRT groups had similar OS and PFS. Conclusions: Aggressive management of recurrent CLM prolongs OS and PFS. Surgery is the best treatment option. Despite potential selection biases, RFA and SBRT should be considered in unresectable patients because they are associated with better outcome than chemotherapy alone.
Influence of pre-diagnosis statin use on survival among patients with pancreatic cancer.
Authors: Huang Brian Z , Chang Jonathan I , Wu Bechien U 
Published: February 2017

427 Background: Recent studies have suggested associations between statin use and enhanced survival among patients with pancreatic ductal adenocarcinoma (PDAC). We aimed to explore the impact of pre-diagnosis statin treatment on survival across different agents and exposure levels. Methods: We conducted a retrospective cohort study on 2,142 pancreatic cancer patients diagnosed from 2006-2014 in an integrated healthcare system. Patients were identified from an internal cancer registry and followed until censored at death, date of last contact, or end of study. We used electronic pharmacy records to abstract information on the type, length and dosage of all statin exposures in the year prior to diagnosis. The overall influence of statins as well as the individual effects of simvastatin, lovastatin, atorvastatin, pravastatin and rosuvastatin were assessed using Cox proportional hazards regression. All analyses were adjusted for age, race, stage, receipt of surgery, receipt of chemotherapy and Charlson comorbidity index. We further adjusted for cholesterol control to determine whether statins acted through a lipid-mediated pathway. Results: Overall statin use was associated with a 13% decrease in the risk of mortality (HR 0.87, CI 0.79-0.97). Specifically, those who had used statins for 9-12 months (HR 0.85, CI 0.75-0.95), received higher doses (40+ mg/day) (HR 0.86, CI 0.76-0.98) or were active users at diagnosis (HR 0.86, CI 0.78-0.96) all had better survival compared to non-statin users. When assessing the individual statins, we found similar improvements in survival only among simvastatin users. Further stratified analyses revealed that simvastatin decreased the risk of death by 26% in stage IV patients (HR 0.74, CI 0.64-0.85), but had no effect for stage I-III patients (pinteraction= 0.03). Cholesterol control did not impact any of the associations between statin use and survival. Conclusions: We found that pre-diagnosis statin use, specifically simvastatin, was associated with improved survival in pancreatic cancer patients.
The role of mTOR inhibitors in targeting a putative cancer stem cell-like population in esophageal cancer.
Authors: Wang Da , Chiu Roland , Plukker John Theodorus , Coppes Robert P. 
Published: February 2017

43 Background: Despite modern advances in the treatment of esophageal cancer (EC), using neoadjuvant chemoradiotherapy (CRT) and esophagectomy, most patients face poor outcome. Growing evidence indicates that cancer stem cells (CSCs) might contribute to the poor prospects. CSCs are usually resistant to CRT and ultimately can generate a new tumor. The mammalian target of rapamycin (mTOR) pathway is associated with cancer stemness. However, its role in EC CSC-like populations needs to be elucidated. Here, we investigate the role of mTOR pathway on the stemness of a putative CSC-like population. Methods: Previously, we identified a putative CSC-like population (CD44+/CD24-) in EC cell lines and in tumor biopsy from EC patients. qPCR was used to measure the expression of mTOR in CD44+/CD24- CSC-like population of OE21 squamous cell carcinoma and OE33 adenocarcinoma cell lines compared to controls, that consisted of solid tumors generated from the same cell lines obtained from xenografts. mTOR inhibitors rapamycin and torin-1 were used to see their effect on CD44+/CD24- expression and sphere formation. Results: mTOR expression was 2-fold up-regulated in the OE33 CD44+/CD24- CSC-like population compared to control. Furthermore, in OE21 this up-regulation was 1.9-fold. Surprisingly, inhibiting the mTOR pathway with rapamycin enhanced OE33 CD44+/CD24- expression compared to its control (p = 0.01). In pilot experiments this effect was dose dependent and cells treated with rapamycin formed more spheres than control. Rapamycin did not alter the expression of CD44+/CD24- in OE21. Inhibiting the mTOR pathway with Torin-1 enhanced OE21 CD44+/CD24- expression by 1.2-fold compared to control (N = 2). In another pilot experiment Torin-1 treated cells were able to form more spheres compared to control. Torin-1 did not have an effect on the expression of CD44+/CD24- in OE33. Conclusions: These findings indicate that inhibiting the mTOR pathway may enhance CSC-like properties in EC. Additional research needs to be done to further support this hypothesis and elucidate the mechanism in this process. Furthermore, the effect of mTOR pathway inducers in EC needs to be explored.
Comparative effectiveness and resource utilization of nab-paclitaxel plus gemcitabine (nab-P+G) versus FOLFIRINOX (FFX) in first-line treatment of advanced pancreatic adenocarcinoma (PDAC) in a U.S. community oncology setting.
Authors: Braiteh Fadi S. , Patel Manish , Parisi Monika , Ni Quanhong , Park Si yeon , Faria Claudio 
Published: February 2017

433 Background: Both nab-P+G and FFX demonstrated superior overall survival (OS) over gemcitabine monotherapy for the treatment of PDAC; but there is no real-world effectiveness and utilization study of nab-P+G vs. FFX. The objective of this study is to compare real-world treatment patterns of patients receiving nab-P+G vs. FFX as first-line treatment for advanced PDAC. Methods: A retrospective cohort study was performed using fully de-identified data from a nationally representative electronic medical record platform of 1,300 community oncology physicians. Patients diagnosed with PDAC between September 2013 and October 2014 who received either nab-P+G or FFX as 1st line therapy were included in the analysis. We calculated median time to treatment discontinuation (TTD) and database persistence (DP), a proxy for OS, using the Kaplan Meier method, and assessed supportive care usage with Poisson regression. Results: 202 (out of 851) patients met eligibility criteria (nab-P+G, n = 122; FFX, n = 80). Patients on nab-P+G were older than patients on FFX (mean age 67.0 v 61.4; p < 0.01), but other baseline characteristics were comparable. TTD (3.4 v 3.8 mos) and DP (8.6 v 8.6 mos) were not statistically different for nab-P+G and FFX, respectively. The rate of AE-related discontinuation was similar in patients on nab-P+G and FFX (18% v 21%); however patients on nab-P+G utilized less doses of granulocyte-colony stimulating factor (GCSF) agents (2.0 v 4.4; p < 0.01), but needed more doses of erythropoietin-stimulating agents (ESA) (0.9 v 0.1; p < 0.01) and steroids (7.9 v 5.8; p < 0.01) per 100 days. Conclusions: TTD and DP for patients with advanced PDAC did not differ significantly between nab-P+G and FFX, although supportive care medications differed. Patients treated with nab-P+G required fewer doses of GCSF and more doses of ESA and steroids, though AEs leading to discontinuation was not statistically different. Management of chemotherapy related toxicities may incur substantial burden on the U.S. healthcare system, especially if an alternative therapy exists with similar clinical outcomes.