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      Nab-paclitaxel plus gemcitabine for metastatic pancreatic adenocarcinoma after Folfirinox failure: an AGEO prospective multicentre cohort

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          Abstract

          Background:

          There is currently no standard second-line treatment for metastatic pancreatic adenocarcinoma (MPA), and progression-free survival is consistently <4 months in this setting. The aim of this study was to evaluate the efficacy and tolerability of Nab-paclitaxel plus gemcitabine (A+G) after Folfirinox failure in MPA.

          Methods:

          From February 2013 to July 2014, all consecutive patients treated with A+G for histologically proven MPA after Folfirinox failure were prospectively enrolled in 12 French centres. A+G was delivered as described in the MPACT trial, until disease progression, patient refusal or unacceptable toxicity.

          Results:

          Fifty-seven patients were treated with Nab-paclitaxel plus gemcitabine, for a median of 4 cycles (range 1–12). The disease control rate was 58%, with a 17.5% objective response rate. Median overall survival (OS) was 8.8 months (95% CI: 6.2–9.7) and median progression-free survival was 5.1 months (95% CI: 3.2–6.2). Since the start of first-line chemotherapy, median OS was 18 months (95% CI: 16–21). No toxic deaths occurred. Grade 3–4 toxicities were reported in 40% of patients, consisting of neutropenia (12.5%), neurotoxicity (12.5%), asthenia (9%) and thrombocytopenia (6.5%).

          Conclusions:

          A+G seems to be effective, with a manageable toxicity profile, after Folfirinox failure in patients with MPA.

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          Most cited references15

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          EUROCARE-4. Survival of cancer patients diagnosed in 1995-1999. Results and commentary.

          EUROCARE-4 analysed about three million adult cancer cases from 82 cancer registries in 23 European countries, diagnosed in 1995-1999 and followed to December 2003. For each cancer site, the mean European area-weighted observed and relative survival at 1-, 3-, and 5-years by age and sex are presented. Country-specific 1- and 5-year relative survival is also shown, together with 5-year relative survival conditional to surviving 1-year. Within-country variation in survival is analysed for selected cancers. Survival for most solid cancers, whose prognosis depends largely on stage at diagnosis (breast, colorectum, stomach, skin melanoma), was highest in Finland, Sweden, Norway and Iceland, lower in the UK and Denmark, and lowest in the Czech Republic, Poland and Slovenia. France, Switzerland and Italy generally had high survival, slightly below that in the northern countries. There were between-region differences in the survival for haematologic malignancies, possibly due to differences in the availability of effective treatments. Survival of elderly patients was low probably due to advanced stage at diagnosis, comorbidities, difficult access or lack of availability of appropriate care. For all cancers, 5-year survival conditional to surviving 1-year was higher and varied less with region, than the overall relative survival.
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            Peripheral neuropathy induced by paclitaxel: recent insights and future perspectives.

            Paclitaxel is an antineoplastic agent derived from the bark of the western yew, Taxus brevifolia, with a broad spectrum of activity. Because paclitaxel promotes microtubule assembly, neurotoxicity is one of its side effects. Clinical use of paclitaxel has led to peripheral neuropathy and this has been demonstrated to be dependent upon the dose administered, the duration of the infusion, and the schedule of administration. Vehicles in the drug formulation, for example Cremophor in Taxol, have been investigated for their potential to induce peripheral neuropathy. A variety of neuroprotective agents have been tested in animal and clinical studies to prevent paclitaxel neurotoxicity. Recently, novel paclitaxel formulations have been developed to minimize toxicities. This review focuses on recent advances in the etiology of paclitaxel-mediated peripheral neurotoxicity, and discusses current and ongoing strategies for amelioration of this side effect.
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              Levels of gemcitabine transport and metabolism proteins predict survival times of patients treated with gemcitabine for pancreatic adenocarcinoma.

              Patients who undergo surgery for pancreatic ductal adenocarcinoma (PDAC) frequently receive adjuvant gemcitabine chemotherapy. Key determinants of gemcitabine cytotoxicity include the activities of the human equilibrative nucleoside transporter 1 (hENT1), deoxycytidine kinase (dCK), and ribonucleotide reductase subunit 1 (RRM1). We investigated whether tumor levels of these proteins were associated with efficacy of gemcitabine therapy following surgery. Sequential samples of resected PDACs were retrospectively collected from 434 patients at 5 centers; 142 patients did not receive adjuvant treatment (33%), 243 received adjuvant gemcitabine-based regimens (56%), and 49 received nongemcitabine regimens (11%). We measured protein levels of hENT1, dCK, and RRM1 by semiquantitative immunohistochemistry with tissue microarrays and investigated their relationship with patients' overall survival time. The median overall survival time of patients was 32.0 months. Among patients who did not receive adjuvant treatment, levels of hENT1, RRM1, and dCK were not associated with survival time. Among patients who received gemcitabine, high levels of hENT1 and dCK were significantly associated with longer survival time (hazard ratios of 0.34 [P < .0001] and 0.57 [P = .012], respectively). Interaction tests for gemcitabine administration and hENT1 and dCK status were statistically significant (P = .0007 and P = .016, respectively). On multivariate analysis of this population, hENT1 and dCK retained independent predictive values, and those patients with high levels of each protein had the longest survival times following adjuvant therapy with gemcitabine. High levels of hENT1 and dCK in PDAC predict longer survival times in patients treated with adjuvant gemcitabine. Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Br J Cancer
                Br. J. Cancer
                British Journal of Cancer
                Nature Publishing Group
                0007-0920
                1532-1827
                29 September 2015
                15 September 2015
                : 113
                : 7
                : 989-995
                Affiliations
                [1 ]Department of Gastroenterology and Digestive Oncology, Georges Pompidou European Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris Descartes University , Paris, France
                [2 ]Department of Gastroenterology, Poitiers University Hospital , Poitiers, France
                [3 ]Methodological and Quality of Life Unit in Oncology, Quality of Life and Cancer Clinical Research Platform, Besançon University Hospital , Besançon, France
                [4 ]Department of Gastroenterology, Kremlin Bicêtre Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris Sud University , Le Kremlin Bicêtre, France
                [5 ]Department of Medical Oncology, Anticancer Center Leon Berard, Lyon I university , Lyon, France
                [6 ]Department of Digestive Oncology, Hospital Beaujon, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris Denis Diderot University , Clichy, France
                [7 ]Department of Hepato-Gastroenterology and Digestive Oncology, University Hospital of Tours, UMR CNRS 7192, François-Rabelais University , Tours, France
                [8 ]Gastroenterology and Endoscopy Unit, Cochin Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris Descartes University , Sorbonne Paris Cité, Paris, France
                [9 ]Department of Gastroenterology, La Pitié-Salpétrière Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Sorbonne University, UPMC University Paris 06 , Paris, France
                [10 ]Department of Hepatogastroenterology and Nutrition, Antoine-Béclère Hospital, Assistance publique-Hôpitaux de Paris (AP-HP), DHU Hepatinov , Clamart, France
                [11 ]Department of Gastroenterology, University Hospital La Timone, Aix-Marseille University , Marseille, France
                [12 ]Department of Gastroenterology and Digestive Oncology, Orleans Regional Hospital (CHRO) , Orleans, France
                [13 ]Department of Gastroenterology, Meaux Hospital , Meaux, France
                Author notes
                [14]

                These authors contributed equally to this work.

                Article
                bjc2015328
                10.1038/bjc.2015.328
                4651133
                26372701
                9e0e1d19-a12b-4a55-8e75-1f1bff68c361
                Copyright © 2015 Cancer Research UK

                From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/

                History
                : 28 April 2015
                : 07 July 2015
                : 13 August 2015
                Categories
                Clinical Study

                Oncology & Radiotherapy
                metastatic pancreatic cancer,nab-paclitaxel plus gemcitabine,second-line chemotherapy,folfirinox

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