Universität zu Köln

Kunzmann, Volker, Siveke, Jens T., Alguel, Hana, Goekkurt, Eray, Siegler, Gabriele, Martens, Uwe, Waldschmidt, Dirk, Pelzer, Uwe ORCID: 0000-0001-9213-2737, Fuchs, Martin, Kullmann, Frank, Boeck, Stefan, Ettrich, Thomas J., Held, Swantje, Keller, Ralph, Klein, Ingo, Germer, Christoph-Thomas, Stein, Hubert, Friess, Helmut, Bahra, Marcus, Jakobs, Ralf, Hartlapp, Ingo and Heinemann, Volker (2021). Nab-paclitaxel plus gemcitabine versus nab-paclitaxel plus gemcitabine followed by FOLFIRINOX induction chemotherapy in locally advanced pancreatic cancer (NEOLAP-AIO-PAK-0113): a multicentre, randomised, phase 2 trial. Lancet Gastroenterol. Hepatol., 6 (2). S. 128 - 139. SAN DIEGO: ELSEVIER INC. ISSN 2468-1253

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Abstract

Background The optimal preoperative treatment for locally advanced pancreatic cancer is unknown. We aimed to compare the efficacy and safety of nab-paclitaxel plus gemcitabine with nab-paclitaxel plus gemcitabine followed by fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) as rnultidrug induction chemotherapy regimens in locally advanced pancreatic cancer. Methods In this open-label, multicentre, randomised phase 2 study, done at 28 centres in Germany, eligible patients were adults (aged 18-75 years) with an Eastern Cooperative Oncology Group performance status of 0 or 1 and histologically or cytologically confirmed, treatment-naive locally advanced pancreatic adenocarcinoma, as determined by local multidisciplinary team review. After two cycles of nab-paclitaxe1125 mg/m(2) plus gemcitabine 1000 mg/m(2) (administered intravenously on days 1,8, and 15 of each 28-day cycle), patients without progressive disease or unacceptable adverse events were randomly assigned (1:1) to receive either two additional cycles of nab-paclitaxel plus gemcitabine (nab-paclitaxel plus gemcitabine group) or four cycles of sequential FOLFIRINOX (oxaliplatin 85 mg/m(2), leucovorin 400 mg/m(2), irinotecan 180 mg/m(2), fluorouracil 400 mg/m(2) by intravenous bolus followed by a continuous intravenous infusion of 2400 mg/m(2) for 46 h on day 1 of each 14-day cycle; sequential FOLFIRINOX group). Randomisation was done by the clinical research organisation on request of the trial centre using a permuted block design (block size 2 and 4). Patients, investigators, and study team members were not masked to treatment allocation. The primary endpoint was surgical conversion rate (complete macroscopic tumour resection) in the randomised population by intention-totreat analysis, which was assessed by surgical exploration in all patients with at least stable disease after completion of induction chemotherapy. This trial is registered with ClinicalTrials.gov, NCT02125136. Findings Between Nov 18, 2014, and April 27,2018,168 patients were registered and 130 were randomly assigned to either the nab-paclitaxel plus gemcitabine group (64 patients) or the sequential FOLFIRINOX group (66 patients). Surgical exploration after completed induction chemotherapy was done in 40 (63%) of 64 patients in the nabpaclitaxel plus gemcitabine group and 42 (64%) of 66 patients in the sequential FOLFIRINOX group. 23 patients in the nab-paclitaxel plus geincitabine group and 29 in the sequential FOLFIRINOX group had complete macroscopic tumour resection, yielding a surgical conversion rate of 35.9% (95% CI 24.3-48-9) in the nab-paclitaxel plus gemcitabine group and 43.9% (31.7-56.7) in the sequential FOLFIRINOX group (odds ratio 0.72 [95% CI 0.35-145]; p=0.38). At a median follow-up of 24.9 months (95% CI 21.8-27.6), median overall survival was 18.5 months (95% CI 14.4-21.5) in the nab-paclitaxel plus gemcitabine group and 20.7 months (13.9-28.7) in the sequential FOLFIRINOX group (hazard ratio 0.86 [95% CI 0-55-1.36]; p=0-53). All other secondary efficacy endpoints, such as investigator-assessed progression-free survival, radiographic response rate, CA 19-9 response rate, and RO resection rate, were not significantly different between the two treatment groups except for improved histopathological downstaging in evaluable resection specimens from the sequential FOLFIRINOX group (ypN2 stage: 20 [69%] of 29 patients in the sequential FOLFIRINOX group vs four [17%] of 23 patients in the nabpaclitaxel plus gemcitabine group, p=0.0003; ypN0 stage: 15 [52%] of 29 patients in the sequential FOLFIRINOX group vs four [17%] of 23 patients in the nab-paclitaxel plus gemcitabine group, p=0.02). Grade 3 or higher treatmentemergent adverse events during induction chemotherapy occurred in 35 (55%) of 64 patients in nab-paclitaxel plus gemcitabine group and in 35 (53%) of 66 patients in the sequential FOLFIRINOX group. The most common of which were neutropenia (18 [28%] in nab-paclitaxel plus gemcitabine group, 16 [24%] in the sequential FOLFIRINOX group), nausea and vomiting (two [3%] in nab-paclitaxel plus gemcitabine group, eight [12%] in the sequential FOLFIRINOX group), and bile duct obstruction with cholangitis (six [9%] in nab-paclitaxel plus gemcitabine group, seven [1.1%] in the sequential FOLFIRINOX group). No deaths were caused by treatment-related adverse events during the induction chemotherapy phase. Interpretation Our findings suggest that nab-paclitaxel plus gemcitabine is similarly active and safe as nab-paclitaxel plus gemcitabine followed by FOLFIRINOX as multidrug induction chemotherapy regimens for locally advanced pancreatic cancer. Although conversion to resectability was achieved in about a third of patients, additional evidence is required to determine whether this translates into improved overall survival. Copyright (C) 2020 Elsevier Ltd. All rights reserved.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Kunzmann, Volker UNSPECIFIED UNSPECIFIED UNSPECIFIED Siveke, Jens T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Alguel, Hana UNSPECIFIED UNSPECIFIED UNSPECIFIED Goekkurt, Eray UNSPECIFIED UNSPECIFIED UNSPECIFIED Siegler, Gabriele UNSPECIFIED UNSPECIFIED UNSPECIFIED Martens, Uwe UNSPECIFIED UNSPECIFIED UNSPECIFIED Waldschmidt, Dirk UNSPECIFIED UNSPECIFIED UNSPECIFIED Pelzer, Uwe UNSPECIFIED orcid.org/0000-0001-9213-2737 UNSPECIFIED Fuchs, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Kullmann, Frank UNSPECIFIED UNSPECIFIED UNSPECIFIED Boeck, Stefan UNSPECIFIED UNSPECIFIED UNSPECIFIED Ettrich, Thomas J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Held, Swantje UNSPECIFIED UNSPECIFIED UNSPECIFIED Keller, Ralph UNSPECIFIED UNSPECIFIED UNSPECIFIED Klein, Ingo UNSPECIFIED UNSPECIFIED UNSPECIFIED Germer, Christoph-Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Stein, Hubert UNSPECIFIED UNSPECIFIED UNSPECIFIED Friess, Helmut UNSPECIFIED UNSPECIFIED UNSPECIFIED Bahra, Marcus UNSPECIFIED UNSPECIFIED UNSPECIFIED Jakobs, Ralf UNSPECIFIED UNSPECIFIED UNSPECIFIED Hartlapp, Ingo UNSPECIFIED UNSPECIFIED UNSPECIFIED Heinemann, Volker UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-603154
DOI:	10.1016/S2468-1253(20)30330-7
Journal or Publication Title:	Lancet Gastroenterol. Hepatol.
Volume:	6
Number:	2
Page Range:	S. 128 - 139
Date:	2021
Publisher:	ELSEVIER INC
Place of Publication:	SAN DIEGO
ISSN:	2468-1253
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language NEOADJUVANT THERAPY; CHEMORADIOTHERAPY; GUIDELINES Multiple languages Gastroenterology & Hepatology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/60315