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Javed AA, Habib A, Mahmud O, Fatimi AS, Grewal M, Mughal N, He J, Wolfgang CL, Daamen L, Besselink MG. Prognostic factors in localized pancreatic ductal adenocarcinoma after neoadjuvant therapy and resection: a systematic review and meta-analysis. J Natl Cancer Inst 2025; 117:840-867. [PMID: 39563429 DOI: 10.1093/jnci/djae294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 10/29/2024] [Accepted: 11/06/2024] [Indexed: 11/21/2024] Open
Abstract
BACKGROUND Prognostic markers for overall survival in resected pancreatic ductal adenocarcinoma are well established but remain unclear following neoadjuvant therapy. This systematic review and meta-analysis aimed to determine factors associated with overall survival following neoadjuvant therapy in resected pancreatic ductal adenocarcinoma. METHODS The PubMed, Embase, Scopus, Web of Science, and Cochrane CENTRAL databases were systematically searched from January 2010 until May 2024. Studies that reported univariable and multivariable hazard ratios were included if patients underwent neoadjuvant therapy and resection for localized pancreatic ductal adenocarcinoma. Study quality assessment was performed using the Newcastle-Ottawa scale. Meta-analysis was performed using generic inverse-variance random-effects models. RESULTS Among 2208 unique articles identified by the search, 92 were included in the meta-analysis. Of these, 85 were of "good" and 7 of "poor" quality. The neoadjuvant therapy regimen was described in 84 studies of which 62 included patients treated with FOLFIRINOX. Margin status, nodal disease, American Joint Committee on Cancer (AJCC) T-stage, and normalization of cancer antigen 19-9 (CA19-9) after neoadjuvant therapy were prognostic for overall survival, whereas age, sex, perineural invasion, baseline tumor size, and baseline CA19-9 were not. The test for subgroup differences between ypN substages was not statistically significant in the multivariable model. Neoadjuvant FOLFIRINOX was associated with better survival than other regimens. CONCLUSIONS This meta-analysis identified margin status, nodal disease, AJCC T-stage, and normalization of CA19-9 after neoadjuvant therapy as prognostic factors for overall survival in patients with resected localized pancreatic ductal adenocarcinoma following neoadjuvant therapy.
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Affiliation(s)
- Ammar A Javed
- New York University Langone Health, New York University Grossman School of Medicine, New York City, NY 10016, United States
- Department of Surgery, Amsterdam UMC, University of Amsterdam, Amsterdam 1007 MB, the Netherlands
- Cancer Center Amsterdam, Amsterdam 1007 MB, the Netherlands
| | - Alyssar Habib
- New York University Langone Health, New York University Grossman School of Medicine, New York City, NY 10016, United States
| | - Omar Mahmud
- New York University Langone Health, New York University Grossman School of Medicine, New York City, NY 10016, United States
- Medical College, Aga Khan University, Karachi 74800, Pakistan
| | - Asad Saulat Fatimi
- New York University Langone Health, New York University Grossman School of Medicine, New York City, NY 10016, United States
- Medical College, Aga Khan University, Karachi 74800, Pakistan
| | - Mahip Grewal
- New York University Langone Health, New York University Grossman School of Medicine, New York City, NY 10016, United States
| | - Nabiha Mughal
- New York University Langone Health, New York University Grossman School of Medicine, New York City, NY 10016, United States
| | - Jin He
- Department of Surgery, Johns Hopkins School of Medicine, Baltimore, MD 21205, United States
| | - Christopher L Wolfgang
- New York University Langone Health, New York University Grossman School of Medicine, New York City, NY 10016, United States
| | - Lois Daamen
- Department of Radiation Oncology, University Medical Center Utrecht, Utrecht 3508 GA, the Netherlands
| | - Marc G Besselink
- Department of Surgery, Amsterdam UMC, University of Amsterdam, Amsterdam 1007 MB, the Netherlands
- Cancer Center Amsterdam, Amsterdam 1007 MB, the Netherlands
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Stoop TF, Sugawara T, Oba A, Feld IM, van Roessel S, van Veldhuisen E, Wu YHA, Nishino J, Ali M, Alseidi A, Sauvanet A, Mirabella A, Sa Cunha A, Kokkola A, Groot Koerkamp B, Pietrasz D, Kleive D, Butturini G, Malleo G, van Laarhoven HWM, Frigerio I, Dembinski J, He J, Gagnière J, Kleeff J, Ramia JM, Roberts KJ, Labori KJ, Marino MV, Falconi M, B. Mortensen M, Lesurtel M, Bonds M, Chatzizacharias N, Strobel O, Turrini O, Griffin O, Franklin O, Pfeiffer P, Schulick RD, Salvia R, de Wilde RF, Dokmak S, Rodriguez Franco S, Augustinus S, Burgdorf SK, Crippa S, Hackert T, Tarvainen T, Burns WR, Messersmith W, Wilmink JW, Burkhart RA, Del Chiaro M, Besselink MG. Adjuvant Chemotherapy After Resection of Localized Pancreatic Adenocarcinoma Following Preoperative FOLFIRINOX. JAMA Oncol 2025; 11:276-287. [PMID: 39847363 PMCID: PMC11926629 DOI: 10.1001/jamaoncol.2024.5917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Accepted: 10/05/2024] [Indexed: 01/24/2025]
Abstract
Importance The effect of adjuvant chemotherapy following resection of pancreatic adenocarcinoma after preoperative (m)FOLFIRINOX (combination leucovorin calcium [folinic acid], fluorouracil, irinotecan hydrochloride, and oxaliplatin in full or modified dosing) chemotherapy on overall survival (OS) is unclear because current studies do not account for the number of cycles of preoperative chemotherapy and adjuvant chemotherapy regimen. Objective To investigate the association of adjuvant chemotherapy following resection of pancreatic adenocarcinoma after preoperative (m)FOLFIRINOX with OS, taking into account the number of cycles of preoperative chemotherapy and adjuvant chemotherapy regimen. Design, Setting, and Participants This retrospective cohort study included patients with localized pancreatic adenocarcinoma treated with 2 to 11 cycles of preoperative (m)FOLFIRINOX followed by resection across 48 centers in 20 countries from 2010 to 2018. Patients who died within 3 months after surgery were excluded (landmark). Data were analyzed from February 1 to December 31, 2023. Exposures Preoperative (m)FOLFIRINOX chemotherapy followed by resection and eventually followed by adjuvant chemotherapy. Main Outcomes and Measures The primary outcome was OS, calculated from the 3-month landmark. Cox regression analysis, including interaction analyses, was performed to investigate the association of adjuvant chemotherapy with OS. Results Overall, 767 patients were included after resection of pancreatic adenocarcinoma (median [IQR] age, 62 [55-67] years; 404 [52.7%] male). Adjuvant chemotherapy was independently associated with prolonged OS (hazard ratio [HR], 0.66; 95% CI, 0.49-0.87), confirmed by adjusted OS curves. The interaction analysis to assess estimated treatment effect across subgroups was not statistically significant. The forest plot and interaction test suggest that the association of adjuvant chemotherapy was lower among patients receiving 8 or more cycles of preoperative (m)FOLFIRINOX, those who had radiological response, and those with ypN0 disease. Compared to no adjuvant chemotherapy, both adjuvant (m)FOLFIRINOX (HR, 0.57; 95% CI, 0.40-0.80) and other multiagent adjuvant regimens (HR, 0.61; 95% CI, 0.41-0.92) were associated with prolonged OS, whereas single-agent adjuvant chemotherapy was not (HR, 0.75; 95% CI, 0.55-1.03). Conclusions and Relevance In this cohort study, adjuvant (m)FOLFIRINOX and other multiagent chemotherapy regimens were associated with improved OS following resection of localized pancreatic adenocarcinoma after preoperative (m)FOLFIRINOX, whereas single-agent adjuvant chemotherapy was not. The impact of adjuvant chemotherapy on OS may be lower in subgroups such as patients with 8 or more preoperative cycles of (m)FOLFIRINOX, those having radiological response, and those with ypN0.
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Affiliation(s)
- Thomas F. Stoop
- Division of Surgical Oncology, Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora
- Amsterdam UMC, location University of Amsterdam, Department of Surgery, Amsterdam, the Netherlands
- Cancer Center Amsterdam, Amsterdam, the Netherlands
| | - Toshitaka Sugawara
- Division of Surgical Oncology, Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora
- Department of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Atsushi Oba
- Division of Surgical Oncology, Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora
- Department of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
- Department of Hepatobiliary and Pancreatic Surgery, Cancer Institute Hospital Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Isabel M. Feld
- Amsterdam UMC, location University of Amsterdam, Department of Surgery, Amsterdam, the Netherlands
- Cancer Center Amsterdam, Amsterdam, the Netherlands
| | - Stijn van Roessel
- Amsterdam UMC, location University of Amsterdam, Department of Surgery, Amsterdam, the Netherlands
- Cancer Center Amsterdam, Amsterdam, the Netherlands
| | - Eran van Veldhuisen
- Amsterdam UMC, location University of Amsterdam, Department of Surgery, Amsterdam, the Netherlands
- Cancer Center Amsterdam, Amsterdam, the Netherlands
| | - Y. H. Andrew Wu
- Division of Surgical Oncology, Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora
- Division of Hepatobiliary and Pancreatic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, Maryland
| | - Jo Nishino
- Division of Bioinformatics, Research Institute National Cancer Center Japan, Tokyo, Japan
| | - Mahsoem Ali
- Amsterdam UMC, location University of Amsterdam, Department of Surgery, Amsterdam, the Netherlands
- Cancer Center Amsterdam, Amsterdam, the Netherlands
| | - Adnan Alseidi
- Department of Surgery, Virginia Mason Medical Center, Seattle, Washington
| | - Alain Sauvanet
- Department of HPB Surgery and Liver Transplantation, Hôpital Beaujon, University Paris Cité, Clichy, France
| | - Antonello Mirabella
- General Surgery Department, Azienda Ospedaliera, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy
| | - Antonio Sa Cunha
- Department of Hepato-Biliary-Pancreatic Surgery, Liver Transplant Center, Université Paris-Sud, Université Paris-Saclay, Villejuif, France
| | - Arto Kokkola
- Department of Surgery, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
| | - Bas Groot Koerkamp
- Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Daniel Pietrasz
- Department of Hepato-Biliary-Pancreatic Surgery, Liver Transplant Center, Université Paris-Sud, Université Paris-Saclay, Villejuif, France
| | - Dyre Kleive
- Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | | | - Giuseppe Malleo
- Department of General and Pancreatic Surgery, The Pancreas Institute, University of Verona Hospital Trust, Verona, Italy
| | - Hanneke W. M. van Laarhoven
- Cancer Center Amsterdam, Amsterdam, the Netherlands
- Amsterdam UMC, location University of Amsterdam, Department of Medical Oncology, Amsterdam, the Netherlands
| | | | - Jeanne Dembinski
- Department of HPB Surgery and Liver Transplantation, Hôpital Beaujon, University Paris Cité, Clichy, France
| | - Jin He
- Division of Hepatobiliary and Pancreatic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, Maryland
| | - Johan Gagnière
- Department of Digestive and Hepatobiliary Surgery-Liver Transplantation, University Hospital of Clermont-Ferrand, Clermont-Ferrand, France
| | - Jörg Kleeff
- Department of Visceral, Vascular and Endocrine Surgery, Martin Luther University Halle-Wittenberg, Halle, Germany
| | - Jose M. Ramia
- Department of Surgery, Hospital General Universitario de Alicante, Alicante, Spain
| | - Keith J. Roberts
- Hepato-Pancreato-Biliary Unit, Department of Surgery, University Hospitals of Birmingham, Birmingham, United Kingdom
| | - Knut J. Labori
- Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Marco V. Marino
- General Surgery Department, Azienda Ospedaliera, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy
| | - Massimo Falconi
- Department of Pancreatic Surgery, IRCCS San Raffaele Hospital, Vita-Salute University, Milano, Italy
| | - Michael B. Mortensen
- Department of Surgery, Odense Pancreas Center, Odense University Hospital, Odense, Denmark
| | - Mickaël Lesurtel
- Department of Hepato-Biliary-Pancreatic Surgery, Liver Transplant Center, Université Paris-Sud, Université Paris-Saclay, Villejuif, France
| | - Morgan Bonds
- Department of Surgery, Virginia Mason Medical Center, Seattle, Washington
| | - Nikolaos Chatzizacharias
- Hepato-Pancreato-Biliary Unit, Department of Surgery, University Hospitals of Birmingham, Birmingham, United Kingdom
| | - Oliver Strobel
- Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany
- Division of Visceral Surgery, Department of General Surgery, Medical University of Vienna, Vienna, Austria
| | - Olivier Turrini
- Department of Surgical Oncology, Aix-Marseille University, Institut Paoli-Calmettes, CRCM, Marseille, France
| | - Oonagh Griffin
- National Surgical Center for Pancreatic Cancer, St. Vincent’s University Hospital, Dublin, Ireland
| | - Oskar Franklin
- Division of Surgical Oncology, Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora
- Department of Surgical and Perioperative Sciences, Umeå University, Umeå, Sweden
| | - Per Pfeiffer
- Department of Oncology, Odense University Hospital, Odense, Denmark
| | - Richard D. Schulick
- Division of Surgical Oncology, Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora
| | - Roberto Salvia
- Department of General and Pancreatic Surgery, The Pancreas Institute, University of Verona Hospital Trust, Verona, Italy
| | - Roeland F. de Wilde
- Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Safi Dokmak
- Department of HPB Surgery and Liver Transplantation, Hôpital Beaujon, University Paris Cité, Clichy, France
| | - Salvador Rodriguez Franco
- Division of Surgical Oncology, Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora
| | - Simone Augustinus
- Amsterdam UMC, location University of Amsterdam, Department of Surgery, Amsterdam, the Netherlands
- Cancer Center Amsterdam, Amsterdam, the Netherlands
| | - Stefan K. Burgdorf
- Department of Surgery and Transplantation, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Stefano Crippa
- Department of Pancreatic Surgery, IRCCS San Raffaele Hospital, Vita-Salute University, Milano, Italy
| | - Thilo Hackert
- Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany
- Department of General, Visceral and Thoracic Surgery, University Hospital Hamburg-Eppendorf, Hamburg, Germany
| | - Timo Tarvainen
- Department of Surgery, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
| | - William R. Burns
- Division of Hepatobiliary and Pancreatic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, Maryland
| | - Wells Messersmith
- Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora
| | - Johanna W. Wilmink
- Cancer Center Amsterdam, Amsterdam, the Netherlands
- Amsterdam UMC, location University of Amsterdam, Department of Medical Oncology, Amsterdam, the Netherlands
| | - Richard A. Burkhart
- Division of Hepatobiliary and Pancreatic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, Maryland
| | - Marco Del Chiaro
- Division of Surgical Oncology, Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora
| | - Marc G. Besselink
- Amsterdam UMC, location University of Amsterdam, Department of Surgery, Amsterdam, the Netherlands
- Cancer Center Amsterdam, Amsterdam, the Netherlands
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Leonhardt CS, Hank T, Pils D, Gustorff C, Sahora K, Schindl M, Verbeke CS, Strobel O, Klaiber U. Prognostic impact of resection margin status on survival after neoadjuvant treatment for pancreatic cancer: systematic review and meta-analysis. Int J Surg 2024; 110:453-463. [PMID: 38315795 PMCID: PMC10793837 DOI: 10.1097/js9.0000000000000792] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Accepted: 09/10/2023] [Indexed: 02/07/2024]
Abstract
BACKGROUND A greater than 1 mm tumour-free resection margin (R0 >1 mm) is a prognostic factor in upfront-resected pancreatic ductal adenocarcinoma. After neoadjuvant treatment (NAT); however, the prognostic impact of resection margin (R) status remains controversial. METHODS Randomised and non-randomised studies assessing the association of R status and survival in resected pancreatic ductal adenocarcinoma after NAT were sought by systematic searches of MEDLINE, Web of Science and CENTRAL. Hazard ratios (HR) and their corresponding 95% CI were collected to generate log HR using the inverse-variance method. Random-effects meta-analyses were performed and the results presented as weighted HR. Sensitivity and meta-regression analyses were conducted to account for different surgical procedures and varying length of follow-up, respectively. RESULTS Twenty-two studies with a total of 4929 patients were included. Based on univariable data, R0 greater than 1 mm was significantly associated with prolonged overall survival (OS) (HR 1.76, 95% CI 1.57-1.97; P<0.00001) and disease-free survival (DFS) (HR 1.66, 95% CI 1.39-1.97; P<0.00001). Using adjusted data, R0 greater than 1 mm was significantly associated with prolonged OS (HR 1.65, 95% CI 1.39-1.97; P<0.00001) and DFS (HR 1.76, 95% CI 1.30-2.39; P=0.0003). Results for R1 direct were comparable in the entire cohort; however, no prognostic impact was detected in sensitivity analysis including only partial pancreatoduodenectomies. CONCLUSION After NAT, a tumour-free margin greater than 1 mm is independently associated with improved OS as well as DFS in patients undergoing surgical resection for pancreatic cancer.
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Affiliation(s)
- Carl-Stephan Leonhardt
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
| | - Thomas Hank
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
| | - Dietmar Pils
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
| | - Charlotte Gustorff
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
| | - Klaus Sahora
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
| | - Martin Schindl
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
| | - Caroline S. Verbeke
- Department of Pathology, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Oliver Strobel
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
| | - Ulla Klaiber
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
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