Stijn van Roessel1, Eran van Veldhuisen1, Sjors Klompmaker1,2, Quisette P Janssen3, Mohammed Abu Hilal4,5, Adnan Alseidi6,7, Alberto Balduzzi8, Gianpaolo Balzano9, Claudio Bassi8, Frederik Berrevoet10, Morgan Bonds6, Olivier R Busch1, Giovanni Butturini11, Marco Del Chiaro12, Kevin C Conlon13, Massimo Falconi9, Isabella Frigerio11, Giuseppe K Fusai14, Johan Gagnière15,16, Oonagh Griffin15, Thilo Hackert17, Asif Halimi18, Ulla Klaiber17, Knut J Labori19, Giuseppe Malleo8, Marco V Marino20,21, Michael B Mortensen22, Andrej Nikov23, Mickaël Lesurtel24, Tobias Keck25, Jörg Kleeff26, Rupaly Pandé27, Per Pfeiffer28, D Pietrasz29, Keith J Roberts27, Antonio Sa Cunha29, Roberto Salvia8, Oliver Strobel17, Timo Tarvainen30, Patrick M Bossuyt31, Hanneke W M van Laarhoven32, Johanna W Wilmink32, Bas Groot Koerkamp3, Marc G Besselink1. 1. Department of Surgery, Cancer Center Amsterdam, Amsterdam University Medical Center, University of Amsterdam, the Netherlands. 2. Department of Radiology, St Antonius Hospital, Nieuwegein, the Netherlands. 3. Department of Surgery, Erasmus University Medical Center, Rotterdam, the Netherlands. 4. Department of Surgery, University Hospital Southampton National Health Service, Southampton, Hampshire, United Kingdom. 5. Department of General Surgery, Istituto Ospedaliero Fondazione Poliambulanza, Brescia, Italy. 6. Department of Surgery, Virginia Mason Medical Center, Seattle, Washington. 7. Department of Surgery, University of California at San Francisco, San Francisco. 8. Department of General and Pancreatic Surgery, The Pancreas Institute, University of Verona Hospital Trust, Verona, Italy. 9. Pancreatic Surgery, Pancreas Translational & Clinical Research Center, San Raffaele Hospital, Milan, Italy. 10. Department of General and Hepatobiliary Surgery, Gent University Hospital, Gent, Belgium. 11. Department of Surgery, Pederzoli Hospital, Peschiera, Italy. 12. Department of Surgery, University of Colorado Hospital, Aurora. 13. Department of Surgery, Trinity College Dublin, Trinity Centre for Health Sciences, Dublin, Ireland. 14. Hepatobiliary Surgery and Liver Transplantation Unit, Royal Free Hospital, London, United Kingdom. 15. Department of Digestive and Hepatobiliary Surgery-Liver Transplantation, University Hospital of Clermont-Ferrand, Clermont-Ferrand, France. 16. Department of Surgery, Clermont-Auvergne University, Clermont-Ferrand, France. 17. Department of General, Visceral and Transplantation Surgery, Universitätsklinikum Heidelberg, Heidelberg, Germany. 18. Department of Surgery, Karolinska Institutet, Stockholm, Sweden. 19. Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Oslo, Norway. 20. General Surgery Department, Azienda Ospedaliera, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy. 21. Department of General Surgery, Hospital Universitario Marques de Valdecilla, Santander, Spain. 22. Department of Surgery, Odense Pancreas Center, Odense University Hospital, Odense, Denmark. 23. Department of Surgery, Charles University and Central Military Hospital, Prague, Czech Republic. 24. Department of Digestive Surgery and Liver Transplantation, Croix Rousse University Hospital, Hospices Civils de Lyon, University of Lyon, Lyon, France. 25. Department of Surgery, Universitaet zu Luebeck, Luebeck, Germany. 26. Department of Visceral, Vascular and Endocrine Surgery, Martin Luther University Halle-Wittenberg, Halle, Germany. 27. Department of Surgery, University Hospital Birmingham, Birmingham, United Kingdom. 28. Department of Medical Oncology, Odense University Hospital, Odense, Denmark. 29. Department of Hepato-Biliary-Pancreatic Surgery, Liver Transplant Center, Paul Brousse Hospital, Université Paris-Sud, Université Paris-Saclay, Villejuif, France. 30. Department of Gastroenterological Surgery, Helsinki University Hospital, Helsinki, Finland. 31. Department of Clinical Epidemiology, Amsterdam University Medical Center, University of Amsterdam, the Netherlands. 32. Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Center, University of Amsterdam, the Netherlands.
Abstract
IMPORTANCE: The benefit of adjuvant chemotherapy after resection of pancreatic cancer following neoadjuvant combination treatment with folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) is unclear. OBJECTIVE: To assess the association of adjuvant chemotherapy with overall survival (OS) in patients after pancreatic cancer resection and neoadjuvant FOLFIRINOX treatment. DESIGN, SETTING, AND PARTICIPANTS: This international, multicenter, retrospective cohort study was conducted from January 1, 2012, to December 31, 2018. An existing cohort of patients undergoing resection of pancreatic cancer after FOLFIRINOX was updated and expanded for the purpose of this study. All consecutive patients who underwent pancreatic surgery after at least 2 cycles of neoadjuvant FOLFIRINOX chemotherapy for nonmetastatic pancreatic cancer were retrospectively identified from institutional databases. Patients with resectable pancreatic cancer, borderline resectable pancreatic cancer, and locally advanced pancreatic cancer were eligible for this study. Patients with in-hospital mortality or who died within 3 months after surgery were excluded. EXPOSURES: The association of adjuvant chemotherapy with OS was evaluated in different subgroups including interaction terms for clinicopathological parameters with adjuvant treatment in a multivariable Cox model. Overall survival was defined as the time starting from surgery plus 3 months (moment eligible for adjuvant therapy), unless mentioned otherwise. RESULTS: We included 520 patients (median [interquartile range] age, 61 [53-66] years; 279 [53.7%] men) from 31 centers in 19 countries. The median number of neoadjuvant cycles of FOLFIRINOX was 6 (interquartile range, 5-8). Overall, 343 patients (66.0%) received adjuvant chemotherapy, of whom 68 (19.8%) received FOLFIRINOX, 201 (58.6%) received gemcitabine-based chemotherapy, 14 (4.1%) received capecitabine, 45 (13.1%) received a combination or other agents, and 15 (4.4%) received an unknown type of adjuvant chemotherapy. Median OS was 38 months (95% CI, 36-46 months) after diagnosis and 31 months (95% CI, 29-37 months) after surgery. No survival difference was found for patients who received adjuvant chemotherapy vs those who did not (median OS, 29 vs 29 months, univariable hazard ratio [HR], 0.99; 95% CI, 0.77-1.28; P = .93). In multivariable analysis, only the interaction term for lymph node stage with adjuvant therapy was statistically significant: In patients with pathology-proven node-positive disease, adjuvant chemotherapy was associated with improved survival (median OS, 26 vs 13 months; multivariable HR, 0.41 [95% CI, 0.22-0.75]; P = .004). In patients with node-negative disease, adjuvant chemotherapy was not associated with improved survival (median OS, 38 vs 54 months; multivariable HR, 0.85; 95% CI, 0.35-2.10; P = .73). CONCLUSIONS AND RELEVANCE: These results suggest that adjuvant chemotherapy after neoadjuvant FOLFIRINOX and resection of pancreatic cancer was associated with improved survival only in patients with pathology-proven node-positive disease. Future randomized studies should be conducted to confirm this finding.
IMPORTANCE: The benefit of adjuvant chemotherapy after resection of pancreatic cancer following neoadjuvant combination treatment with folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) is unclear. OBJECTIVE: To assess the association of adjuvant chemotherapy with overall survival (OS) in patients after pancreatic cancer resection and neoadjuvant FOLFIRINOX treatment. DESIGN, SETTING, AND PARTICIPANTS: This international, multicenter, retrospective cohort study was conducted from January 1, 2012, to December 31, 2018. An existing cohort of patients undergoing resection of pancreatic cancer after FOLFIRINOX was updated and expanded for the purpose of this study. All consecutive patients who underwent pancreatic surgery after at least 2 cycles of neoadjuvant FOLFIRINOX chemotherapy for nonmetastatic pancreatic cancer were retrospectively identified from institutional databases. Patients with resectable pancreatic cancer, borderline resectable pancreatic cancer, and locally advanced pancreatic cancer were eligible for this study. Patients with in-hospital mortality or who died within 3 months after surgery were excluded. EXPOSURES: The association of adjuvant chemotherapy with OS was evaluated in different subgroups including interaction terms for clinicopathological parameters with adjuvant treatment in a multivariable Cox model. Overall survival was defined as the time starting from surgery plus 3 months (moment eligible for adjuvant therapy), unless mentioned otherwise. RESULTS: We included 520 patients (median [interquartile range] age, 61 [53-66] years; 279 [53.7%] men) from 31 centers in 19 countries. The median number of neoadjuvant cycles of FOLFIRINOX was 6 (interquartile range, 5-8). Overall, 343 patients (66.0%) received adjuvant chemotherapy, of whom 68 (19.8%) received FOLFIRINOX, 201 (58.6%) received gemcitabine-based chemotherapy, 14 (4.1%) received capecitabine, 45 (13.1%) received a combination or other agents, and 15 (4.4%) received an unknown type of adjuvant chemotherapy. Median OS was 38 months (95% CI, 36-46 months) after diagnosis and 31 months (95% CI, 29-37 months) after surgery. No survival difference was found for patients who received adjuvant chemotherapy vs those who did not (median OS, 29 vs 29 months, univariable hazard ratio [HR], 0.99; 95% CI, 0.77-1.28; P = .93). In multivariable analysis, only the interaction term for lymph node stage with adjuvant therapy was statistically significant: In patients with pathology-proven node-positive disease, adjuvant chemotherapy was associated with improved survival (median OS, 26 vs 13 months; multivariable HR, 0.41 [95% CI, 0.22-0.75]; P = .004). In patients with node-negative disease, adjuvant chemotherapy was not associated with improved survival (median OS, 38 vs 54 months; multivariable HR, 0.85; 95% CI, 0.35-2.10; P = .73). CONCLUSIONS AND RELEVANCE: These results suggest that adjuvant chemotherapy after neoadjuvant FOLFIRINOX and resection of pancreatic cancer was associated with improved survival only in patients with pathology-proven node-positive disease. Future randomized studies should be conducted to confirm this finding.
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