title: FOLFIRINOX for locally advanced pancreatic cancer: a systematic review and patient-level meta-analysis.
abstract: BACKGROUND
  35% of patients with pancreatic cancer have unresectable locally advanced disease at diagnosis. Several studies have examined systemic chemotherapy with FOLFIRINOX (leucovorin and fluorouracil plus irinotecan and oxaliplatin) in patients with locally advanced pancreatic cancer. We aimed to assess the effectiveness of FOLFIRINOX as first-line treatment in this patient population.
  
  
  METHODS
  We systematically searched Embase, MEDLINE (OvidSP), Web of Science, Scopus, PubMed Publisher, Cochrane, and Google Scholar from July 1, 1994, to July 2, 2015, for studies of treatment-naive patients of any age who received FOLFIRINOX as first-line treatment of locally advanced pancreatic cancer. Our primary outcome was overall survival. Secondary outcomes were progression-free survival; rates of grade 3 or 4 adverse events; and the proportion of patients who underwent radiotherapy or chemoradiotherapy, surgical resection after FOLFIRINOX, and R0 resection. We evaluated survival outcomes with the Kaplan-Meier method with patient-level data. Grade 3 or 4 adverse events, and the proportion of patients who underwent subsequent radiotherapy or chemoradiotherapy or resection, were pooled in a random-effects model.
  
  
  RESULTS
  We included 13 studies comprising 689 patients, of whom 355 (52%) patients had locally advanced pancreatic cancer. 11 studies, comprising 315 patients with locally advanced disease, reported survival outcomes and were eligible for patient-level meta-analysis. Median overall survival from the start of FOLFIRINOX ranged from 10·0 months (95% CI 4·0-16·0) to 32·7 months (23·1-42·3) across studies with a pooled patient-level median overall survival of 24·2 months (95% CI 21·7-26·8). Median progression-free survival ranged from 3·0 months (95% CI not calculable) to 20·4 months (6·5-34·3) across studies with a patient-level median progression-free survival of 15·0 months (95% 13·8-16·2). In ten studies comprising 490 patients, 296 grade 3 or 4 adverse events were reported (60·4 events per 100 patients). No deaths were attributed to FOLFIRINOX toxicity. The proportion of patients who underwent radiotherapy or chemoradiotherapy ranged from 31% to 100% across studies. In eight studies, 154 (57%) of 271 patients received radiotherapy or chemoradiotherapy after FOLFIRINOX. The pooled proportion of patients who received any radiotherapy treatment was 63·5% (95% CI 43·3-81·6, I(2) 90%). The proportion of patients who underwent surgical resection for locally advanced pancreatic cancer ranged from 0% to 43%. The proportion of patients who had R0 resection of those who underwent resection ranged from 50% to 100% across studies. In 12 studies, 91 (28%) of 325 patients underwent resection after FOLFIRINOX. The pooled proportion of patients who had resection was 25·9% (95% CI 20·2-31·9, I(2) 24%). R0 resection was reported in 60 (74%) of 81 patients. The pooled proportion of patients who had R0 resection was 78·4% (95% CI 60·2-92·2, I(2) 64%).
  
  
  CONCLUSIONS
  Patients with locally advanced pancreatic cancer treated with FOLFIRINOX had a median overall survival of 24·2 months-longer than that reported with gemcitabine (6-13 months). Future research should assess these promising results in a randomised controlled trial, and should establish which patients might benefit from radiotherapy or chemoradiotherapy or resection after FOLFIRINOX.
  
  
  BACKGROUND
  None.
authors.affiliation: Department of Surgery, Erasmus University Medical Centre, Rotterdam, Netherlands.
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authors.lastname: Suker
authors.affiliation: Department of Surgery, Erasmus University Medical Centre, Rotterdam, Netherlands.
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authors.lastname: Beumer
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Eran
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authors.lastname: Sadot
authors.affiliation: Department of Hepatogastroenterology, Antoine Beclère Hospital, Assistance publique-Hôpitaux de Paris, Paris Sud University, Clamart, France.
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authors.lastname: Marthey
authors.affiliation: Department of Hematology-Oncology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Jason E
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authors.affiliation: Department of Radiation Oncology, H Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
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authors.affiliation: Department of Hematology and Medical Oncology, Emory University, Atlanta, GA, USA.
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authors.affiliation: Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA.
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authors.affiliation: Department of Medicine, Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA.
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authors.affiliation: Department of Medicine, Division of Medical Oncology, University of Kentucky-Markey Cancer Center, Lexington, KY, USA.
authors.forename: Peter J
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authors.lastname: Hosein
authors.affiliation: Department of Medicine, The Royal Marsden National Health Service Foundation Trust, London and Surrey, UK.
authors.forename: Sing Yu
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authors.lastname: Moorcraft
authors.affiliation: Department of Medical Oncology, Institut de Cancérologie de Lorraine and Lorraine University, Vandoeuvre-lès-Nancy, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Conroy
authors.affiliation: Department of Hematology, Medical Oncology, Hemostasis, Rheumatology and Infectious Diseases, Paracelsus Medical University of Salzburg, Salzburg, Austria.
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authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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authors.affiliation: Department of Gastroenterology and Digestive Oncology, Georges Pompidou European Hospital, Assistance publique-Hôpitaux de Paris, Sorbonne Paris Cité, Paris Descartes University, Cancer Research Personalized Medicine (CARPEM), Paris, France.
authors.forename: Julien
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authors.affiliation: Department of Hematology-Oncology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Theodore S
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authors.affiliation: Department of Radiation Oncology, Florida Hospital Cancer Institute, Orlando, FL, USA.
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authors.affiliation: Department of Medicine, The Royal Marsden National Health Service Foundation Trust, London and Surrey, UK.
authors.forename: Ian
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authors.lastname: Chau
authors.affiliation: Department of Surgery, Erasmus University Medical Centre, Rotterdam, Netherlands.
authors.forename: Casper H
authors.initials: CH
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authors.affiliation: Department of Surgery, Erasmus University Medical Centre, Rotterdam, Netherlands. Electronic address: b.grootkoerkamp@erasmusmc.nl.
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mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D017024:Chemotherapy, Adjuvant; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin / Q000008:administration & dosage; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011379:Prognosis; D015996:Survival Rate; D000093542:Gemcitabine
chemical_list: D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D003841:Deoxycytidine; D000077146:Irinotecan; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin; D000093542:Gemcitabine