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  • Labori, Knut JørgenDepartment of Hepato Pancreato Biliary Surgery, Oslo University Hospital ; Institute of Clinical Medicine, University of Oslo, Norway (författare)

Neoadjuvant FOLFIRINOX versus upfront surgery for resectable pancreatic head cancer (NORPACT-1) : a multicentre, randomised, phase 2 trial

  • Artikel/kapitelEngelska2024

Förlag, utgivningsår, omfång ...

  • The Lancet Group,2024
  • printrdacarrier

Nummerbeteckningar

  • LIBRIS-ID:oai:DiVA.org:his-23602
  • https://urn.kb.se/resolve?urn=urn:nbn:se:his:diva-23602URI
  • https://doi.org/10.1016/s2468-1253(23)00405-3DOI

Kompletterande språkuppgifter

  • Språk:engelska
  • Sammanfattning på:engelska

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  • Ämneskategori:ref swepub-contenttype
  • Ämneskategori:art swepub-publicationtype

Anmärkningar

  • Correspondence to: Prof Knut Jørgen Labori, Department of Hepato Pancreato Biliary Surgery, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, N-0372 Oslo, NorwayFunding: Norwegian Cancer Society, South Eastern Norwegian Health Authority, The Sjöberg Foundation, and Helsinki University Hospital Research Grants.
  • BackgroundIn patients undergoing resection for pancreatic cancer, adjuvant modified fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) improves overall survival compared with alternative chemotherapy regimens. We aimed to compare the efficacy and safety of neoadjuvant FOLFIRINOX with the standard strategy of upfront surgery in patients with resectable pancreatic ductal adenocarcinoma.MethodsNORPACT-1 was a multicentre, randomised, phase 2 trial done in 12 hospitals in Denmark, Finland, Norway, and Sweden. Eligible patients were aged 18 years or older, with a WHO performance status of 0 or 1, and had a resectable tumour of the pancreatic head radiologically strongly suspected to be pancreatic adenocarcinoma. Participants were randomly assigned (3:2 before October, 2018, and 1:1 after) to the neoadjuvant FOLFIRINOX group or upfront surgery group. Patients in the neoadjuvant FOLFIRINOX group received four neoadjuvant cycles of FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2, and fluorouracil 400 mg/m2 bolus then 2400 mg/m2 over 46 h on day 1 of each 14-day cycle), followed by surgery and adjuvant chemotherapy. Patients in the upfront surgery group underwent surgery and then received adjuvant chemotherapy. Initially, adjuvant chemotherapy was gemcitabine plus capecitabine (gemcitabine 1000 mg/m2 over 30 min on days 1, 8, and 15 of each 28-day cycle and capecitabine 830 mg/m2 twice daily for 3 weeks with 1 week of rest in each 28-day cycle; four cycles in the neoadjuvant FOLFIRINOX group, six cycles in the upfront surgery group). A protocol amendment was subsequently made to permit use of adjuvant modified FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 150 mg/m2, leucovorin 400 mg/m2, and fluorouracil 2400 mg/m2 over 46 h on day 1 of each 14-day cycle; eight cycles in the neoadjuvant FOLFIRINOX group, 12 cycles in the upfront surgery group). Randomisation was performed with a computerised algorithm that stratified for each participating centre and used a concealed block size of two to six. Patients, investigators, and study team members were not masked to treatment allocation. The primary endpoint was overall survival at 18 months. Analyses were done in the intention-to-treat (ITT) and per-protocol populations. Safety was assessed in all patients who were randomly assigned and received at least one cycle of neoadjuvant or adjuvant therapy. This trial is registered with ClinicalTrials.gov, NCT02919787, and EudraCT, 2015-001635-21, and is ongoing.FindingsBetween Feb 8, 2017, and April 21, 2021, 77 patients were randomly assigned to receive neoadjuvant FOLFIRINOX and 63 to undergo upfront surgery. All patients were included in the ITT analysis. For the per-protocol analysis, 17 (22%) patients were excluded from the neoadjuvant FOLFIRINOX group (ten did not receive neoadjuvant therapy, four did not have pancreatic ductal adenocarcinoma, and three received another neoadjuvant regimen), and eight (13%) were excluded from the upfront surgery group (seven did not have pancreatic ductal adenocarcinoma and one did not undergo surgical exploration). 61 (79%) of 77 patients in the neoadjuvant FOLFIRINOX group received neoadjuvant therapy. The proportion of patients alive at 18 months by ITT was 60% (95% CI 49–71) in the neoadjuvant FOLFIRINOX group versus 73% (62–84) in the upfront surgery group (p=0·032), and median overall survival by ITT was 25·1 months (95% CI 17·2–34·9) versus 38·5 months (27·6–not reached; hazard ratio [HR] 1·52 [95% CI 1·00–2·33], log-rank p=0·050). The proportion of patients alive at 18 months in per-protocol analysis was 57% (95% CI 46–67) in the neoadjuvant FOLFIRINOX group versus 70% (55–83) in the upfront surgery group (p=0·14), and median overall survival in per-protocol population was 23·0 months (95% CI 16·2–34·9) versus 34·4 months (19·4–not reached; HR 1·46 [95% CI 0·99–2·17], log-rank p=0·058). In the safety population, 42 (58%) of 73 patients in the neoadjuvant FOLFIRINOX group and 19 (40%) of 47 patients in the upfront surgery group had at least one grade 3 or worse adverse event. 63 (82%) of 77 patients in the neoadjuvant group and 56 (89%) of 63 patients in the upfront surgery group had resection (p=0·24). One sudden death of unknown cause and one COVID-19-related death occurred after the first cycle of neoadjuvant FOLFIRINOX. Adjuvant chemotherapy was initiated in 51 (86%) of 59 patients with resected pancreatic ductal adenocarcinoma in the neoadjuvant FOLFIRINOX group and 44 (90%) of 49 patients with resected pancreatic ductal adenocarcinoma in the upfront surgery group (p=0·56). Adjuvant modified FOLFIRINOX was given to 13 (25%) patients in the neoadjuvant FOLFIRINOX group and 19 (43%) patients in the upfront surgery group. During adjuvant chemotherapy, neutropenia (11 [22%] patients in the neoadjuvant FOLFIRINOX group and five [11%] in the upfront surgery group) was the most common grade 3 or worse adverse event.InterpretationThis phase 2 trial did not show a survival benefit from neoadjuvant FOLFIRINOX in resectable pancreatic ductal adenocarcinoma compared with upfront surgery. Implementation of neoadjuvant FOLFIRINOX was challenging. Future trials on treatment sequencing in resectable pancreatic ductal adenocarcinoma should be biomarker driven.

Ämnesord och genrebeteckningar

Biuppslag (personer, institutioner, konferenser, titlar ...)

  • Bratlie, Svein OlavDepartment of Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden ; Department of Surgery, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Sweden (författare)
  • Andersson, BodilDepartment of Clinical Sciences Lund, Surgery, Lund University, Sweden ; Skåne University Hospital, Lund, Sweden (författare)
  • Angelsen, Jon-HelgeDepartment of Gastrointestinal Surgery, Haukeland University Hospital, Bergen, Norway ; Department of Clinical Medicine, University of Bergen, Norway (författare)
  • Biörserud, ChristinaDepartment of Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden ; Department of Surgery, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Sweden (författare)
  • Björnsson, BergthorDepartment of Surgery in Linköping, Linköping University, Sweden ; Department of Biomedical and Clinical Sciences, Linköping University, Sweden (författare)
  • Bringeland, Erling AudunDepartment of Gastrointestinal Surgery, St Olavs Hospital, Trondheim University Hospital, Norway ; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway (författare)
  • Elander, NilsDepartment of Biomedical and Clinical Sciences, Linköping University, Sweden ; Clatterbridge Cancer Centre NHS Foundation Trust, Liverpool, UK (författare)
  • Garresori, HerishDepartment of Hematology and Oncology, Stavanger University Hospital, Norway (författare)
  • Grønbech, Jon ErikDepartment of Gastrointestinal Surgery, St Olavs Hospital, Trondheim University Hospital, Norway ; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway (författare)
  • Haux, JohanHögskolan i Skövde,Institutionen för hälsovetenskaper,Forskningsmiljön hälsa, hållbarhet och digitalisering,Department of Oncology, Skaraborg Hospital Skövde, Sweden,Translational Medicine(Swepub:his)hauj (författare)
  • Hemmingsson, OskarDepartment of Surgical and Perioperative Sciences, Surgery, Umeå University, Sweden ; Wallenberg Centre for Molecular Medicine, Umeå University, Sweden (författare)
  • Gustafsson Liljefors, MariaDivision of Surgery and Oncology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden (författare)
  • Myklebust, Tor ÅgeDepartment of Registration, Cancer Registry of Norway, Oslo, Norway ; Department of Research and Innovation, Møre and Romsdal Hospital Trust, Ålesund, Norway (författare)
  • Nymo, Linn SåveDepartment of Gastrointestinal Surgery, University Hospital of North Norway, Tromsø, Norway ; Institute of Clinical Medicine, The Arctic University of Norway, Tromsø, Norway (författare)
  • Peltola, KatriinaComprehensive Cancer Center, Helsinki University Hospital, Finland (författare)
  • Pfeiffer, PerDepartment of Medical Oncology, Odense University Hospital, Denmark (författare)
  • Sallinen, VilleGastroenterological Surgery/ Transplantation and Liver Surgery, Helsinki University Hospital and University of Helsinki, Finland (författare)
  • Sandström, PerDepartment of Surgery in Linköping, Linköping University, Sweden ; Department of Biomedical and Clinical Sciences, Linköping University, Sweden (författare)
  • Sparrelid, ErnestoDivision of Surgery and Oncology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden (författare)
  • Stenvold, HelgeDepartment of Oncology, University Hospital of North Norway, Tromsø, Norway (författare)
  • Søreide, KjetilDepartment of Clinical Medicine, University of Bergen, Norway ; Department of Gastrointestinal Surgery, Stavanger University Hospital, Norway (författare)
  • Tingstedt, BobbyDepartment of Clinical Sciences Lund, Surgery, Lund University and Skåne University Hospital, Lund, Sweden (författare)
  • Verbeke, CarolineDepartment of Pathology, Oslo University Hospital, Norway ; Institute of Clinical Medicine, University of Oslo, Norway (författare)
  • Öhlund, DanielWallenberg Centre for Molecular Medicine, Umeå University, Sweden ; Department of Radiation Sciences, Umeå University, Sweden (författare)
  • Klint, LeifDepartment of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden ; Department of Oncology, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Sweden (författare)
  • Dueland, SveinDepartment of Oncology, Oslo University Hospital, Norway (författare)
  • Lassen, KristofferDepartment of Hepato Pancreato Biliary Surgery, Oslo University Hospital, Norway ; Institute of Clinical Medicine, The Arctic University of Norway, Tromsø, Norway (författare)
  • Aahlin, Eirik KjusNordic Pancreatic Cancer Trial-1 study group (författare)
  • Bratthäll, CharlotteNordic Pancreatic Cancer Trial-1 study group (författare)
  • Halimi, AsifNordic Pancreatic Cancer Trial-1 study group (författare)
  • Hatlevoll, IngunnNordic Pancreatic Cancer Trial-1 study group (författare)
  • Heby, MargaretaNordic Pancreatic Cancer Trial-1 study group (författare)
  • Kokkola, ArtoNordic Pancreatic Cancer Trial-1 study group (författare)
  • Kordes, MaximilianNordic Pancreatic Cancer Trial-1 study group (författare)
  • Lindblad, StinaNordic Pancreatic Cancer Trial-1 study group (författare)
  • Lundgren, LindaNordic Pancreatic Cancer Trial-1 study group (författare)
  • Mortensen, Michael BauNordic Pancreatic Cancer Trial-1 study group (författare)
  • Mortensen, Kim ErlendNordic Pancreatic Cancer Trial-1 study group (författare)
  • Persson, JanNordic Pancreatic Cancer Trial-1 study group (författare)
  • Rangelova, ElenaNordic Pancreatic Cancer Trial-1 study group (författare)
  • Rønne, ElinNordic Pancreatic Cancer Trial-1 study group (författare)
  • Sandvik, Oddvar MathiasNordic Pancreatic Cancer Trial-1 study group (författare)
  • Søreide, Jon ArneNordic Pancreatic Cancer Trial-1 study group (författare)
  • Vilhav, CarolineNordic Pancreatic Cancer Trial-1 study group (författare)
  • Waardal, KimNordic Pancreatic Cancer Trial-1 study group (författare)
  • Wennerblom, JohannaNordic Pancreatic Cancer Trial-1 study group (författare)
  • Williamsson, CarolineNordic Pancreatic Cancer Trial-1 study group (författare)
  • Yaqub, SherazNordic Pancreatic Cancer Trial-1 study group (författare)
  • Department of Hepato Pancreato Biliary Surgery, Oslo University Hospital ; Institute of Clinical Medicine, University of Oslo, NorwayDepartment of Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden ; Department of Surgery, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Sweden (creator_code:org_t)

Sammanhörande titlar

  • Ingår i:The Lancet Gastroenterology & Hepatology: The Lancet Group9:3, s. 205-2172468-1253

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