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      Total neoadjuvant FOLFIRINOX versus neoadjuvant gemcitabine-based chemoradiotherapy and adjuvant gemcitabine for resectable and borderline resectable pancreatic cancer (PREOPANC-2 trial): study protocol for a nationwide multicenter randomized controlled trial

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          Abstract

          Background

          Neoadjuvant therapy has several potential advantages over upfront surgery in patients with localized pancreatic cancer; more patients receive systemic treatment, fewer patients undergo futile surgery, and R0 resection rates are higher, thereby possibly improving overall survival (OS). Two recent randomized trials have suggested benefit of neoadjuvant chemoradiotherapy over upfront surgery, both including single-agent chemotherapy regimens. Potentially, the multi-agent FOLFIRINOX regimen (5-fluorouracil with leucovorin, irinotecan, and oxaliplatin) may further improve outcomes in the neoadjuvant setting for localized pancreatic cancer, but randomized studies are needed. The PREOPANC-2 trial investigates whether neoadjuvant FOLFIRINOX improves OS compared with neoadjuvant gemcitabine-based chemoradiotherapy and adjuvant gemcitabine in resectable and borderline resectable pancreatic cancer patients.

          Methods

          This nationwide multicenter phase III randomized controlled trial includes patients with pathologically confirmed resectable and borderline resectable pancreatic cancer with a WHO performance score of 0 or 1. Resectable pancreatic cancer is defined as no arterial and ≤ 90 degrees venous involvement; borderline resectable pancreatic cancer is defined as ≤90 degrees arterial and ≤ 270 degrees venous involvement without occlusion. Patients receive 8 cycles of neoadjuvant FOLFIRINOX chemotherapy followed by surgery without adjuvant treatment (arm A), or 3 cycles of neoadjuvant gemcitabine with hypofractionated radiotherapy (36 Gy in 15 fractions) during the second cycle, followed by surgery and 4 cycles of adjuvant gemcitabine (arm B). The primary endpoint is OS by intention-to-treat. Secondary endpoints include progression-free survival, quality of life, resection rate, and R0 resection rate. To detect a hazard ratio of 0.70 with 80% power, 252 events are needed. The number of events is expected to be reached after inclusion of 368 eligible patients assuming an accrual period of 3 years and 1.5 years follow-up.

          Discussion

          The PREOPANC-2 trial directly compares two neoadjuvant regimens for patients with resectable and borderline resectable pancreatic cancer. Our study will provide evidence on the neoadjuvant treatment of choice for patients with resectable and borderline resectable pancreatic cancer.

          Trial registration

          Primary registry and trial identifying number: EudraCT: 2017–002036-17.

          Date of registration: March 6, 2018.

          Secondary identifying numbers: The Netherlands National Trial Register – NL7094, NL61961.078.17, MEC-2018-004.

          Supplementary Information

          The online version contains supplementary material available at 10.1186/s12885-021-08031-z.

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          Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey.

          Daniel Dindo, Nicolas Demartines, Pierre-Alain Clavien (2004)
          Although quality assessment is gaining increasing attention, there is still no consensus on how to define and grade postoperative complications. This shortcoming hampers comparison of outcome data among different centers and therapies and over time. A classification of complications published by one of the authors in 1992 was critically re-evaluated and modified to increase its accuracy and its acceptability in the surgical community. Modifications mainly focused on the manner of reporting life-threatening and permanently disabling complications. The new grading system still mostly relies on the therapy used to treat the complication. The classification was tested in a cohort of 6336 patients who underwent elective general surgery at our institution. The reproducibility and personal judgment of the classification were evaluated through an international survey with 2 questionnaires sent to 10 surgical centers worldwide. The new ranking system significantly correlated with complexity of surgery (P < 0.0001) as well as with the length of the hospital stay (P < 0.0001). A total of 144 surgeons from 10 different centers around the world and at different levels of training returned the survey. Ninety percent of the case presentations were correctly graded. The classification was considered to be simple (92% of the respondents), reproducible (91%), logical (92%), useful (90%), and comprehensive (89%). The answers of both questionnaires were not dependent on the origin of the reply and the level of training of the surgeons. The new complication classification appears reliable and may represent a compelling tool for quality assessment in surgery in all parts of the world.
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            FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer.

            Thierry Conroy, Françoise Desseigne, Marc Ychou … (2011)
            Data are lacking on the efficacy and safety of a combination chemotherapy regimen consisting of oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) as compared with gemcitabine as first-line therapy in patients with metastatic pancreatic cancer. We randomly assigned 342 patients with an Eastern Cooperative Oncology Group performance status score of 0 or 1 (on a scale of 0 to 5, with higher scores indicating a greater severity of illness) to receive FOLFIRINOX (oxaliplatin, 85 mg per square meter of body-surface area; irinotecan, 180 mg per square meter; leucovorin, 400 mg per square meter; and fluorouracil, 400 mg per square meter given as a bolus followed by 2400 mg per square meter given as a 46-hour continuous infusion, every 2 weeks) or gemcitabine at a dose of 1000 mg per square meter weekly for 7 of 8 weeks and then weekly for 3 of 4 weeks. Six months of chemotherapy were recommended in both groups in patients who had a response. The primary end point was overall survival. The median overall survival was 11.1 months in the FOLFIRINOX group as compared with 6.8 months in the gemcitabine group (hazard ratio for death, 0.57; 95% confidence interval [CI], 0.45 to 0.73; P<0.001). Median progression-free survival was 6.4 months in the FOLFIRINOX group and 3.3 months in the gemcitabine group (hazard ratio for disease progression, 0.47; 95% CI, 0.37 to 0.59; P<0.001). The objective response rate was 31.6% in the FOLFIRINOX group versus 9.4% in the gemcitabine group (P<0.001). More adverse events were noted in the FOLFIRINOX group; 5.4% of patients in this group had febrile neutropenia. At 6 months, 31% of the patients in the FOLFIRINOX group had a definitive degradation of the quality of life versus 66% in the gemcitabine group (hazard ratio, 0.47; 95% CI, 0.30 to 0.70; P<0.001). As compared with gemcitabine, FOLFIRINOX was associated with a survival advantage and had increased toxicity. FOLFIRINOX is an option for the treatment of patients with metastatic pancreatic cancer and good performance status. (Funded by the French government and others; ClinicalTrials.gov number, NCT00112658.).
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              The 2016 update of the International Study Group (ISGPS) definition and grading of postoperative pancreatic fistula: 11 Years After.

              Claudio Bassi, Giovanni Marchegiani, CHRISTOS DERVENIS … (2017)
              In 2005, the International Study Group of Pancreatic Fistula developed a definition and grading of postoperative pancreatic fistula that has been accepted universally. Eleven years later, because postoperative pancreatic fistula remains one of the most relevant and harmful complications of pancreatic operation, the International Study Group of Pancreatic Fistula classification has become the gold standard in defining postoperative pancreatic fistula in clinical practice. The aim of the present report is to verify the value of the International Study Group of Pancreatic Fistula definition and grading of postoperative pancreatic fistula and to update the International Study Group of Pancreatic Fistula classification in light of recent evidence that has emerged, as well as to address the lingering controversies about the original definition and grading of postoperative pancreatic fistula.
              Article 0 comments Cited 812 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                B. Groot Koerkamp: b.grootkoerkamp@erasmusmc.nl
                Journal
                Journal ID (nlm-ta): BMC Cancer
                Journal ID (iso-abbrev): BMC Cancer
                Title: BMC Cancer
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1471-2407
                Publication date (Electronic): 23 March 2021
                Publication date PMC-release: 23 March 2021
                Publication date Collection: 2021
                Volume: 21
                Electronic Location Identifier: 300
                Affiliations
                [1 ]GRID grid.5645.2, ISNI 000000040459992X, Department of Surgery, , Erasmus MC University Medical Center, ; Rotterdam, The Netherlands
                [2 ]GRID grid.10419.3d, ISNI 0000000089452978, Department of Surgery, , Leiden University Medical Center, ; Leiden, The Netherlands
                [3 ]Department of Medical Oncology, Tjongerschans Hospital, Heerenveen, The Netherlands
                [4 ]GRID grid.413508.b, ISNI 0000 0004 0501 9798, Department of Surgery, , Jeroen Bosch Hospital, ; Den Bosch, The Netherlands
                [5 ]GRID grid.416213.3, ISNI 0000 0004 0460 0556, Department of Surgery, , Maasstad Hospital, ; Rotterdam, The Netherlands
                [6 ]GRID grid.413532.2, ISNI 0000 0004 0398 8384, Department of Surgery, , Catharina Hospital, ; Eindhoven, The Netherlands
                [7 ]GRID grid.440209.b, ISNI 0000 0004 0501 8269, Department of Surgery, Onze Lieve Vrouwe Gasthuis, ; Amsterdam, The Netherlands
                [8 ]GRID grid.10417.33, ISNI 0000 0004 0444 9382, Department of Surgery, , Radboud University Medical Center, ; Nijmegen, The Netherlands
                [9 ]GRID grid.452600.5, ISNI 0000 0001 0547 5927, Department of Surgery, , Isala Hospital, ; Zwolle, The Netherlands
                [10 ]GRID grid.415214.7, ISNI 0000 0004 0399 8347, Department of Surgery, Medisch Spectrum Twente, ; Enschede, The Netherlands
                [11 ]GRID grid.7692.a, ISNI 0000000090126352, Department of Surgery, Regional Academic Cancer Center Utrecht, , St. Antonius Hospital and University Medical Center Utrecht, ; Utrecht, The Netherlands
                [12 ]GRID grid.413711.1, Department of Medical Oncology, , Amphia Hospital, ; Breda, The Netherlands
                [13 ]GRID grid.412966.e, ISNI 0000 0004 0480 1382, Department of Internal Medicine, Division of Medical Oncology, , GROW - School for Oncology and Developmental Biology, Maastricht UMC+, ; Maastricht, The Netherlands
                [14 ]GRID grid.12380.38, ISNI 0000 0004 1754 9227, Department of Surgery, Cancer Center Amsterdam, , Amsterdam UMC, Vrije Universiteit, ; Amsterdam, The Netherlands
                [15 ]GRID grid.5645.2, ISNI 000000040459992X, Department of Medical Oncology, , Erasmus MC University Medical Center, ; Rotterdam, The Netherlands
                [16 ]GRID grid.7177.6, ISNI 0000000084992262, Department of Radiation Oncology, Cancer Center Amsterdam, , Amsterdam UMC, University of Amsterdam, ; Amsterdam, The Netherlands
                [17 ]GRID grid.7177.6, ISNI 0000000084992262, Department of Surgery, Cancer Center Amsterdam, , Amsterdam UMC, University of Amsterdam, ; Amsterdam, The Netherlands
                [18 ]GRID grid.7177.6, ISNI 0000000084992262, Department of Medical Oncology, Cancer Center Amsterdam, , Amsterdam UMC, University of Amsterdam, ; Amsterdam, The Netherlands
                Article
                Publisher ID: 8031
                DOI: 10.1186/s12885-021-08031-z
                PMC ID: 7989075
                PubMed ID: 33757440
                SO-VID: f7dde661-5336-4895-adc7-5a16d1c44750
                Copyright © © The Author(s) 2021
                License:

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                Date received : 23 October 2020
                Date accepted : 14 March 2021
                Funding
                Funded by: ZonMw (NL)
                Award ID: 843004108
                Funded by: FundRef http://dx.doi.org/10.13039/501100004622, KWF Kankerbestrijding;
                Award ID: 10955
                Categories
                Subject: Study Protocol
                Custom metadata
                issue-copyright-statement © The Author(s) 2021

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: neoadjuvant,folfirinox,gemcitabine,chemoradiotherapy,localized pancreatic cancer,intention-to-treat,randomized controlled trial,overall survival,quality of life
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: neoadjuvant, folfirinox, gemcitabine, chemoradiotherapy, localized pancreatic cancer, intention-to-treat, randomized controlled trial, overall survival, quality of life

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